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2.  Age Invariance in Semantic and Episodic Metamemory: Both Younger and Older Adults Provide Accurate Feeling of Knowing For Names of Faces 
Age differences in feeling-of-knowing (FOK) accuracy were examined for both episodic memory and semantic memory. Younger and older adults either viewed pictures of famous faces (semantic memory) or associated nonfamous faces and names (episodic memory) and were tested on their memory for the name of the presented face. Participants viewed the faces again and made a FOK prediction about future recognition of the name associated with the presented face. Finally, four-alternative forced-choice recognition memory for the name, cued by the face, was tested and confidence judgments (CJs) were collected for each recognition response. Age differences were not obtained in semantic memory or the resolution of semantic FOKs, defined by within-person correlations of FOKs with recognition memory performance. Although age differences were obtained in level of episodic memory, there were no age differences in the resolution of episodic FOKs. FOKs for correctly recognized items correlated reliably with CJs for both types of materials, and did not differ by age group. The results indicate age invariance in monitoring of retrieval processes for name-face associations.
PMCID: PMC3815973  PMID: 23537379
Metamemory; Aging; Feeling-of-Knowing; Episodic Memory; Semantic; Memory
4.  Effect of Omega-3 Fatty Acid Ethyl Esters on the Oxylipin Composition of Lipoproteins in Hypertriglyceridemic, Statin-Treated Subjects 
PLoS ONE  2014;9(11):e111471.
Oxylipins mediate inflammation, vascular tension, and more. Their presence in lipoproteins could explain why lipoproteins mediate nearly identical activities.
To determine how oxylipins are distributed in the lipoproteins of hypertriglyceridemic subjects, and whether omega-3 fatty acids alter them in a manner consistent with improved cardiovascular health, we recruited 15 dyslipidemic subjects whose levels of low density lipoprotein cholesterol (LDL-C) were at goal but who remained hypertriglyceridemic (200–499 mg/dL). They were treated them with the indicated dose of 4 g/d omega-3 acid ethyl esters (P-OM3) for 8 weeks. Measured oxylipins included mid-chain alcohols (HETEs, HEPEs and HDoHEs), ketones (KETEs), epoxides (as EpETrEs, EpETEs, and EpDPEs).
At baseline, arachidonate-oxylipins (HETEs, KETEs, and EpETrEs) were most abundant in plasma with the greatest fraction of total abundance (mean |95% CI|) being carried in high density lipoproteins (HDL); 42% |31, 57| followed by very low density lipoproteins (VLDL); 27% |20, 36|; and LDL 21% |16, 28|. EPA- and DHA-derived oxylipins constituted less than 11% of total. HDL carried alcohols and epoxides but VLDL was also rich in ketones. Treatment decreased AA-derived oxylipins across lipoprotein classes (−23% |−33, −12|, p = 0.0003), and expanded EPA−(322% |241, 422|, p<0.0001) and DHA-derived oxylipins (123% |80, 176|, p<0.0001).
Each lipoprotein class carries a unique oxylipin complement. P-OM3 treatment alters the oxylipin content of all classes, reducing pro-inflammatory and increasing anti-inflammatory species, consistent with the improved inflammatory and vascular status associated with the treatment.
Trial Registration NCT00959842
PMCID: PMC4230929  PMID: 25393536
5.  Association between n-3 polyunsaturated fatty acid content of red blood cells and inflammatory biomarkers in patients with peripheral artery disease 
Journal of vascular surgery  2013;58(5):1283-1290.
The n-3 polyunsaturated fatty acids (PUFA) are dietary components derived from fish oil with beneficial cardiovascular effects that may relate in part to anti-inflammatory properties. Peripheral artery disease (PAD) is characterized by a marked pro-inflammatory state. We hypothesized that the n-3 PUFA content of red blood cells (omega-3 index) would be correlated with biomarkers of inflammation and vascular function in a PAD cohort.
This was a cross-sectional study of subjects who presented to an outpatient vascular surgery clinic for evaluation of PAD. We used linear regression to evaluate the independent association between the omega-3 index, inflammatory biomarkers [C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), and tumor-necrosis-factor-α (TNF-α)] and endothelial function (brachial artery flow mediated dilation [FMD]).
64 subjects (61 claudicants and 3 with critical limb ischemia) were recruited for the study. The mean CRP level was 5.0 ± 5.0 mg/L and the mean omega-3 index was 5.0% ± 1.8%. In an unadjusted model, the omega-3 index was negatively associated with CRP (38% increase in CRP for one standard deviation decrease in the omega-3 index; P=.007) which remained significant after adjustment for age, body-mass index, smoking, the ABI and HDL (33%; P=.04). There was also evidence for independent associations between the omega-3 index and IL-6 (P=.001). There were no significant associations between the omega-3 index and vascular function tests.
In a cohort of patients with PAD, the omega-3 index was inversely associated with biomarkers of inflammation even after adjustment for covariates including the ABI. Because patients with PAD have a high inflammatory burden, further studies should be conducted to determine if manipulation of omega-3 index via dietary changes or fish oil supplementation could improve inflammation and symptoms in these patients.
PMCID: PMC4207080  PMID: 23830313
6.  Omega-3 fatty acids and domain-specific cognitive aging 
Neurology  2013;81(17):1484-1491.
To test the hypothesis that higher levels of red blood cell (RBC) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have a protective association with domain-specific cognitive function in women aged 65 years and older.
A total of 2,157 women with normal cognition enrolled in a clinical trial of postmenopausal hormone therapy were followed with annual cognitive testing for a median of 5.9 years. In this retrospective cohort study, we assessed the relationship between prerandomization RBC DHA + EPA levels and a) cognitive measures at baseline, and b) cognitive change over time. Endpoints were composite cognitive function and performance in 7 cognitive domains: fine motor speed, verbal memory, visual memory, spatial ability, verbal knowledge, verbal fluency, and working memory.
After adjustment for demographic, clinical, and behavioral characteristics, no significant (p < 0.01) cross-sectional cognitive differences were found between women in the high and low DHA + EPA tertiles at the time of the first annual cognitive battery. In addition, no significant (p < 0.01) differences were found between the high and low DHA + EPA tertiles in the rate of cognitive change over time.
We did not find an association between RBC DHA + EPA levels and age-associated cognitive decline in a cohort of older, dementia-free women.
PMCID: PMC3888166  PMID: 24068783
7.  n-3 Polyunsaturated fatty acids supplementation in peripheral artery disease: the OMEGA-PAD trial 
Despite current consensus guidelines recommending intensive cardiovascular risk factor management for peripheral artery disease (PAD), patients suffering from PAD continue to experience significant morbidity and mortality. This excess morbid burden is at least partially related to impaired vascular function and systemic inflammation. Interventions bridging this gap are critical. Dietary supplementation of n-3 polyunsaturated fatty acids (n-3 PUFA) has been shown to improve endothelial function and reduce inflammation in different cohorts, as well as to decrease cardiovascular events in secondary prevention trials in patients with coronary artery disease, Their effects in the PAD population are, however, less well understood. The OMEGA-PAD trial is a double-blinded, randomized, placebo-controlled trial that examines the impact of a high-dose, short-duration dietary oral supplementation of n-3 PUFA on vascular function and inflammation in patients with established PAD. The purpose of this article is to provide a detailed description of the design and methods of the OMEGA-PAD trial, and a summary of baseline characteristics of the cohort.
PMCID: PMC4074651  PMID: 24052491
fatty acids; peripheral artery disease; randomized controlled trials
8.  TGF-Beta Downregulation of Distinct Chloride Channels in Cystic Fibrosis-Affected Epithelia 
PLoS ONE  2014;9(9):e106842.
The cystic fibrosis transmembrane conductance regulator (CFTR) and Calcium-activated Chloride Conductance (CaCC) each play critical roles in maintaining normal hydration of epithelial surfaces including the airways and colon. TGF-beta is a genetic modifier of cystic fibrosis (CF), but how it influences the CF phenotype is not understood.
We tested the hypothesis that TGF-beta potently downregulates chloride-channel function and expression in two CF-affected epithelia (T84 colonocytes and primary human airway epithelia) compared with proteins known to be regulated by TGF-beta.
Measurements and Main Results
TGF-beta reduced CaCC and CFTR-dependent chloride currents in both epithelia accompanied by reduced levels of TMEM16A and CFTR protein and transcripts. TGF-beta treatment disrupted normal regulation of airway-surface liquid volume in polarized primary human airway epithelia, and reversed F508del CFTR correction produced by VX-809. TGF-beta effects on the expression and activity of TMEM16A, wtCFTR and corrected F508del CFTR were seen at 10-fold lower concentrations relative to TGF-beta effects on e-cadherin (epithelial marker) and vimentin (mesenchymal marker) expression. TGF-beta downregulation of TMEM16A and CFTR expression were partially reversed by Smad3 and p38 MAPK inhibition, respectively.
TGF-beta is sufficient to downregulate two critical chloride transporters in two CF-affected tissues that precedes expression changes of two distinct TGF-beta regulated proteins. Our results provide a plausible mechanism for CF-disease modification by TGF-beta through effects on CaCC.
PMCID: PMC4182049  PMID: 25268501
9.  Red blood cell fatty acid levels improve GRACE score prediction of 2-yr mortality in patients with myocardial infarction 
Blood omega-3 and omega-6 fatty acid levels have been associated with reduced risk for total mortality in patients with stable coronary heart disease (CHD), but their relationships with mortality in the setting of myocardial infarction (MI) are unknown.
To determine the association between red blood cell (RBC) fatty acid levels measured at admission and 2-year mortality in MI patients, independent of the GRACE risk score, a traditional mode of risk stratification,
Admission RBC fatty acid levels were measured in patients enrolled in a prospective, 24-center MI registry (TRIUMPH). Two-year mortality was modeled with Cox proportional hazards regression to assess the extent to which the inclusion of fatty acid levels would improve, over and above the GRACE score, risk stratification for 2-year mortality.
RBC fatty acid data were available from 1,144 patients who did not report taking fish oil supplements after discharge. Two RBC fatty acids [eicosapentaenoic acid (EPA n-3) and docosapentaenoic n-6 (DPA)] were univariate predictors of total mortality. The combined fatty acid c-statistic (0.60, p<0.001) improved the c-statistic of the GRACE score alone from 0.747 (p<0.001) to 0.768 (p<0.05 vs. GRACE alone). The net reclassification index improved by 31% (95% CI, 15% to 48%) and the relative incremental discrimination index improved by 19.8% (7.5% to 35.7%).
RBC EPA and DPA n-6 levels improved the prediction of 2-yr mortality over and above the GRACE score in MI patients.
PMCID: PMC3574624  PMID: 23044429
10.  Chemotherapy-Induced Monoamine Oxidase Expression in Prostate Carcinoma Functions as a Cytoprotective Resistance Enzyme and Associates with Clinical Outcomes 
PLoS ONE  2014;9(9):e104271.
To identify molecular alterations in prostate cancers associating with relapse following neoadjuvant chemotherapy and radical prostatectomy patients with high-risk localized prostate cancer were enrolled into a phase I-II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pre-treatment prostate tissue was acquired by needle biopsy and post-treatment tissue was acquired by prostatectomy. Prostate cancer gene expression measurements were determined in 31 patients who completed 4 cycles of neoadjuvant chemotherapy. We identified 141 genes with significant transcript level alterations following chemotherapy that associated with subsequent biochemical relapse. This group included the transcript encoding monoamine oxidase A (MAOA). In vitro, cytotoxic chemotherapy induced the expression of MAOA and elevated MAOA levels enhanced cell survival following docetaxel exposure. MAOA activity increased the levels of reactive oxygen species and increased the expression and nuclear translocation of HIF1α. The suppression of MAOA activity using the irreversible inhibitor clorgyline augmented the apoptotic responses induced by docetaxel. In summary, we determined that the expression of MAOA is induced by exposure to cytotoxic chemotherapy, increases HIF1α, and contributes to docetaxel resistance. As MAOA inhibitors have been approved for human use, regimens combining MAOA inhibitors with docetaxel may improve clinical outcomes.
PMCID: PMC4157741  PMID: 25198178
11.  Exclusive multipotency and preferential asymmetric divisions in post-embryonic neural stem cells of the fish retina 
Development (Cambridge, England)  2014;141(18):3472-3482.
The potency of post-embryonic stem cells can only be addressed in the living organism, by labeling single cells after embryonic development and following their descendants. Recently, transplantation experiments involving permanently labeled cells revealed multipotent neural stem cells (NSCs) of embryonic origin in the medaka retina. To analyze whether NSC potency is affected by developmental progression, as reported for the mammalian brain, we developed an inducible toolkit for clonal labeling and non-invasive fate tracking. We used this toolkit to address post-embryonic stem cells in different tissues and to functionally differentiate transient progenitor cells from permanent, bona fide stem cells in the retina. Using temporally controlled clonal induction, we showed that post-embryonic retinal NSCs are exclusively multipotent and give rise to the complete spectrum of cell types in the neural retina. Intriguingly, and in contrast to any other vertebrate stem cell system described so far, long-term analysis of clones indicates a preferential mode of asymmetric cell division. Moreover, following the behavior of clones before and after external stimuli, such as injuries, shows that NSCs in the retina maintained the preference for asymmetric cell division during regenerative responses. We present a comprehensive analysis of individual post-embryonic NSCs in their physiological environment and establish the teleost retina as an ideal model for studying adult stem cell biology at single cell resolution.
PMCID: PMC4197724  PMID: 25142461
Neural stem cells; Neural progenitor cells; Multipotency; Asymmetric division; Retina; Medaka
12.  Reduced Apolipoprotein Glycosylation in Patients with the Metabolic Syndrome 
PLoS ONE  2014;9(8):e104833.
The purpose of this study was to compare the apolipoprotein composition of the three major lipoprotein classes in patients with metabolic syndrome to healthy controls.
Very low density (VLDL), intermediate/low density (IDL/LDL, hereafter LDL), and high density lipoproteins (HDL) fractions were isolated from plasma of 56 metabolic syndrome subjects and from 14 age-sex matched healthy volunteers. The apolipoprotein content of fractions was analyzed by one-dimensional (1D) gel electrophoresis with confirmation by a combination of mass spectrometry and biochemical assays.
Metabolic syndrome patients differed from healthy controls in the following ways: (1) total plasma - apoA1 was lower, whereas apoB, apoC2, apoC3, and apoE were higher; (2) VLDL - apoB, apoC3, and apoE were increased; (3) LDL - apoC3 was increased, (4) HDL -associated constitutive serum amyloid A protein (SAA4) was reduced (p<0.05 vs. controls for all). In patients with metabolic syndrome, the most extensively glycosylated (di-sialylated) isoform of apoC3 was reduced in VLDL, LDL, and HDL fractions by 17%, 30%, and 25%, respectively (p<0.01 vs. controls for all). Similarly, the glycosylated isoform of apoE was reduced in VLDL, LDL, and HDL fractions by 15%, 26%, and 37% (p<0.01 vs. controls for all). Finally, glycosylated isoform of SAA4 in HDL fraction was 42% lower in patients with metabolic syndrome compared with controls (p<0.001).
Patients with metabolic syndrome displayed several changes in plasma apolipoprotein composition consistent with hypertriglyceridemia and low HDL cholesterol levels. Reduced glycosylation of apoC3, apoE and SAA4 are novel findings, the pathophysiological consequences of which remain to be determined.
PMCID: PMC4130598  PMID: 25118169
13.  Reconciling competence and transcriptional hierarchies with stochasticity in retinal lineages☆ 
Current Opinion in Neurobiology  2014;27(100):68-74.
•Problems with a strict retinal competence model are explained.•The apparent conflict between transcriptional hierarchies and stochasticity is resolved.•The underlying nature of retinal progenitor cell stochasticity is discussed.•Key issues that can be addressed in the face of stochasticity are enumerated.
Recent advances suggest that there is a stochastic contribution to the proliferation and fate choice of retinal progenitors. How does this stochasticity fit with the progression of temporal competence and the transcriptional hierarchies that also influence cell division and cell fate in the developing retina? Where may stochasticity arise in the system and how do we make progress in this field when we may never fully explain the behavior of individual progenitor cells?
PMCID: PMC4127786  PMID: 24637222
14.  Systematic review of clinical features of suspected colorectal cancer in primary care 
Canadian Family Physician  2014;60(8):e405-e415.
To systematically review the diagnostic accuracy of clinical features associated with colorectal cancer (CRC) presenting in primary care.
Data sources
MEDLINE and EMBASE were searched for studies in primary care that provided information on clinical features predictive of CRC. Positive predictive values were used to guide the determination of clinical features associated with increased risk of CRC.
Study selection
Systematic reviews or primary studies that provided possible clinical features predictive of CRC were included.
Clinical features of patients presenting in primary care that are associated with increased risk of CRC, listed in descending order of association, included palpable rectal or abdominal mass; rectal bleeding combined with weight loss; iron deficiency anemia; rectal bleeding mixed with stool; rectal bleeding in the absence of perianal symptoms; rectal bleeding combined with change in bowel habits; dark rectal bleeding; rectal bleeding and diarrhea; and change in bowel habits. Being male and increasing age were also, in general, associated with increased risk of CRC.
Recognition of clinical features associated with increased risk of CRC by FPs might help with earlier identification and referral among patients presenting in primary care. This review might help inform providers and CRC diagnostic assessment programs about indications for assessment and further investigation.
PMCID: PMC4131977  PMID: 25122831
15.  Guideline for referral of patients with suspected colorectal cancer by family physicians and other primary care providers 
Canadian Family Physician  2014;60(8):717-723.
The aim of this guideline is to assist FPs and other primary care providers with recognizing features that should raise their suspicions about the presence of colorectal cancer (CRC) in their patients.
Composition of the committee
Committee members were selected from among the regional primary care leads from the Cancer Care Ontario Provincial Primary Care and Cancer Network, the members of the Ontario Colorectal Cancer Screening Advisory Committee, and the members of the Cancer Care Ontario Gastrointestinal Cancer Disease Site Group.
This guideline was developed through systematic review of the evidence base, synthesis of the evidence, and formal external review involving Canadian stakeholders to validate the relevance of recommendations.
Evidence-based guidelines were developed to improve the management of patients presenting with clinical features of CRC within the Canadian context.
The judicious balancing of suspicion of CRC and level of risk of CRC should encourage timely referral by FPs and primary care providers. This guideline might also inform indications for referral to CRC diagnostic assessment programs.
PMCID: PMC4131960  PMID: 25122815
16.  Lignes directrices sur l’aiguillage des cas soupçonnés de cancer colorectal par un médecin de famille ou autre professionnel des soins primaires 
Canadian Family Physician  2014;60(8):e383-e390.
Ces lignes directrices ont pour but d’aider les médecins de famille et les autres professionnels des soins primaires à reconnaître les caractéristiques qui devraient susciter leurs soupçons quant à la présence d’un cancer colorectal (CCR) chez leurs patients.
Composition du comité
Les membres du comité ont été choisis parmi les dirigeants régionaux des soins primaires au sein du Réseau provincial des soins primaires et de la lutte contre le cancer, les membres du Comité consultatif sur le dépistage du cancer colorectal de l’Ontario et les membres du Groupe sur le siège de la maladie, Cancer gastrointestinal, d’Action Cancer Ontario.
Ces lignes directrices sont le fruit d’une revue systématique et d’une synthèse des données probantes, ainsi que d’un examen formel par des intervenants canadiens pour valider la pertinence des recommandations.
Des lignes directrices fondées sur des données probantes ont été élaborées pour améliorer la prise en charge des patients qui présentent des caractéristiques cliniques d’un CCR et ce, dans le contexte canadien.
Un équilibre judicieux entre une suspicion de CCR et le niveau de risque d’un tel cancer devrait favoriser une demande de consultation en temps opportun par les médecins de famille et les professionnels des soins primaires. Ces lignes directrices pourraient aussi orienter les décisions de demander une consultation à des programmes d’évaluation diagnostique du CCR.
PMCID: PMC4131973
17.  Three-Dimensional Microstructural Imaging of Sulfur Poisoning-Induced Degradation in a Ni-YSZ Anode of Solid Oxide Fuel Cells 
Scientific Reports  2014;4:5246.
Following exposure to ppm-level hydrogen sulfide at elevated temperatures, a section of a solid oxide fuel cell (SOFC) Ni-YSZ anode was examined using a combination of synchrotron-based x-ray nanotomography and x-ray fluorescence techniques. While fluorescence measurements provided elemental identification and coarse spatial mapping, x-ray nanotomography was used to map the detailed 3-D spatial distribution of Ni, YSZ, and a nickel-sulfur poisoning phase. The nickel-sulfur layer was found to form a scale covering most of the exposed nickel surface, blocking most fuel reformation and hydrogen oxidation reaction sites. Although the exposure conditions precluded the ability to develop a detailed kinetic description of the nickel-sulfur phase formation, the results provide strong evidence of the detrimental effects of 100 ppm hydrogen sulfide on typical Ni-YSZ anode materials.
PMCID: PMC4050380  PMID: 24912978
18.  Spectrum of Fates: a new approach to the study of the developing zebrafish retina 
Development (Cambridge, England)  2014;141(9):1971-1980.
The ability to image cells live and in situ as they proliferate and differentiate has proved to be an invaluable asset to biologists investigating developmental processes. Here, we describe a Spectrum of Fates approach that allows the identification of all the major neuronal subtypes in the zebrafish retina simultaneously. Spectrum of Fates is based on the combinatorial expression of differently coloured fluorescent proteins driven by the promoters of transcription factors that are expressed in overlapping subsets of retinal neurons. Here, we show how a Spectrum of Fates approach can be used to assess various aspects of neural development, such as developmental waves of differentiation, neuropil development, lineage tracing and hierarchies of fates in the developing zebrafish retina.
PMCID: PMC3994774  PMID: 24718991
Cell fate; Differentiation; Fluorescent proteins; Neuron; Retina; Zebrafish
19.  Structural Equation Modeling for Analyzing Erythrocyte Fatty Acids in Framingham 
Research has shown that several types of erythrocyte fatty acids (i.e., omega-3, omega-6, and trans) are associated with risk for cardiovascular diseases. However, there are complex metabolic and dietary relations among fatty acids, which induce correlations that are typically ignored when using them as risk predictors. A latent variable approach could summarize these complex relations into a few latent variable scores for use in statistical models. Twenty-two red blood cell (RBC) fatty acids were measured in Framingham (N = 3196). The correlation matrix of the fatty acids was modeled using structural equation modeling; the model was tested for goodness-of-fit and gender invariance. Thirteen fatty acids were summarized by three latent variables, and gender invariance was rejected so separate models were developed for men and women. A score was developed for the polyunsaturated fatty acid (PUFA) latent variable, which explained about 30% of the variance in the data. The PUFA score included loadings in opposing directions among three omega-3 and three omega-6 fatty acids, and incorporated the biosynthetic and dietary relations among them. Whether the PUFA factor score can improve the performance of risk prediction in cardiovascular diseases remains to be tested.
PMCID: PMC4052884  PMID: 24959197
20.  Does APOE Genotype Modify the Relations Between Serum Lipid and Erythrocyte Omega-3 Fatty Acid Levels? 
Earlier reports indicated that patients with the apolipoprotein APOE ε4 allele responded to fish oil supplementation with a rise in serum low-density lipoprotein cholesterol (LDL-C) compared to ε3 homozygotes. In this study, we used clinical laboratory data to test the hypothesis that the cross-sectional relation between RBC omega-3 fatty acid status (the Omega-3 Index) and LDL-C was modified by APOE genotype. Data from 136,701 patients were available to compare lipid biomarker levels across Omega-3 Index categories associated with heart disease risk in all APOE genotypes. We found no adverse interactions between APOE genotype and the Omega-3 Index for LDL-C, LDL particle number, apoB, HDL-C, or triglycerides. However, we did find evidence that ε2 homozygotes lack an association between omega-3 status and LDL-C, apoB, and LDL particle number. In summary, we found no evidence for a deleterious relationship between lipid biomarkers and the Omega-3 Index by APOE genotype.
Electronic supplementary material
The online version of this article (doi:10.1007/s12265-014-9554-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4098055  PMID: 24595593
APOE genotype; APOE4; Omega-3 fatty acids; Lipids; Low-density lipoproteins; Triglycerides; apoB
21.  A nutrient-sensitive restriction point is active during retinal progenitor cell differentiation 
Development (Cambridge, England)  2014;141(3):697-706.
In many growing tissues, slowly dividing stem cells give rise to rapidly proliferating progenitors that eventually exit the cell cycle and differentiate. Growth rates are limited by nutrient availability, but it is unclear which steps of the proliferation-differentiation programme are particularly sensitive to fuel supplies. We examined how nutrient deprivation (ND) affects stem and progenitor cells in the ciliary marginal zone (CMZ) of the amphibian retina, a well-characterised neurogenic niche. We show that ND specifically blocks the proliferation and differentiation of progenitor cells through an mTOR-mediated mechanism. By contrast, the identity and proliferation of retinal stem cells are insensitive to ND and mTOR inhibition. Re-feeding starved retinas in vitro rescues both proliferation and differentiation, and activation of mTOR is sufficient to stimulate differentiation even in ND retinas. These results suggest that an mTOR-mediated restriction point operates in vivo to couple nutrient abundance to the proliferation and differentiation programme in retinal progenitor cells.
PMCID: PMC3899821  PMID: 24449845
Differentiation; mTOR; Nutrient deprivation; Proliferation; Restriction point; Retina; Xenopus laevis
22.  Pathologic Response Rates of Gemcitabine/Cisplatin versus Methotrexate/Vinblastine/Adriamycin/Cisplatin Neoadjuvant Chemotherapy for Muscle Invasive Urothelial Bladder Cancer 
Advances in Urology  2013;2013:317190.
Objectives. To compare pathologic outcomes after treatment with gemcitabine and cisplatin (GC) versus methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) in the neoadjuvant setting. Methods. Data was retrospectively collected on 178 patients with T2-T4 bladder cancer who underwent radical cystectomy between 2003 and 2011. Outcomes of interest included those with complete response (pT0) and any response (≤pT1). Odds ratios were calculated using multivariate logistic regression. Results. Compared to those who did not receive neoadjuvant chemotherapy, there were more patients with complete response (28% versus 9%, OR 3.11 (95% CI: 1.45–6.64), P = 0.03) and any response (52% versus 25%, OR 3.23 (95% CI: 1.21–8.64), P = 0.01). Seventy-two patients received GC (n = 41) or MVAC (n = 31). CR was achieved in 29% and 22% of GC and MVAC patients, respectively (multivariate OR 0.39, 95% CI 0.10–1.58). Any response (≤pT1) was achieved in 56% of GC and 45% of MVAC patients (multivariate OR 0.45, 95% CI 0.12–1.71). Conclusions. We observed similar pathologic response rates for GC and MVAC neoadjuvant chemotherapy in this cohort of patients with muscle invasive urothelial cancer (MIBC). Our findings support the use of GC as an alternative regimen in the neoadjuvant setting.
PMCID: PMC3871504  PMID: 24382958
23.  Determinants of Erythrocyte Omega‐3 Fatty Acid Content in Response to Fish Oil Supplementation: A Dose–Response Randomized Controlled Trial 
The erythrocyte membrane content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which constitutes the omega‐3 index (O3I), predicts cardiovascular disease mortality. The amount of EPA+DHA needed to achieve a target O3I is poorly defined, as are the determinants of the O3I response to a change in EPA+DHA intake. The objective of this study was to develop a predictive model of the O3I response to EPA+DHA supplementation in healthy adults, specifically identifying factors that determine the response.
Methods and Results
A randomized, placebo‐controlled, double‐blind, parallel‐group study was conducted in 115 healthy men and women. One of 5 doses (0, 300, 600, 900, 1800 mg) of EPA+DHA was given daily as placebo or fish oil supplements for ≈5 months. The O3I was measured at baseline and at the end of the study. There were no significant differences in the clinical characteristics between the groups at baseline. The O3I increased in a dose‐dependent manner (P<0.0001), with the dose of EPA+DHA alone accounting for 68% (quadratic, P<0.0001) of the variability in the O3I response. Dose adjusted per unit body weight (g/kg) accounted for 70% (linear, P<0.0001). Additional factors that improved prediction of treatment response were baseline O3I, age, sex, and physical activity. Collectively, these explained 78% of the response variability (P<0.0001).
Our findings validate the O3I as a biomarker of EPA+DHA consumption and identify additional factors, particularly body weight, that can be used to tailor EPA+DHA recommendations to achieve a target O3I.
PMCID: PMC3886744  PMID: 24252845
blood cell; fatty acids; fish oil; metabolism; nutrition
24.  Edge Loading Has a Paradoxical Effect on Wear in Metal-on-Polyethylene Total Hip Arthroplasties 
Edge wear is an adverse factor that can negatively impact certain THAs. In some metal-on-metal THAs, it can lead to adverse tissue reactions including aseptic lymphocytic vasculitis-associated lesions and even to pseudotumor formation. In some ceramic-on-ceramic THAs, it can lead to squeaking and/or stripe wear. Edge wear in metal-on-metal and ceramic-on-ceramic THAs can also be associated with accelerated wear across the articulation of these joints.
I asked: Does edge wear occur in metal-on-polyethylene (MOP) articulations? And if so, does it increase joint wear?
I examined the evidence in the literature for edge wear occurring in MOP THA and then assessed the evidence in the literature for data supporting the concept that edge wear in MOP hips could accelerate wear across the articulation over time.
Extensive data in the literature confirm edge wear is common in MOP THA. Surprisingly, the evidence does not support that it accelerates wear across the articulation. In fact, substantial data support the concept that it does not.
These observations suggest, in terms of edge wear accelerating overall wear, MOP articulation may have a privileged position compared to hard-on-hard THA articulations.
PMCID: PMC3462843  PMID: 22644421
25.  Effects of prescription niacin and omega-3 fatty acids on lipids and vascular function in metabolic syndrome: a randomized controlled trial[S] 
Journal of Lipid Research  2012;53(11):2429-2435.
The metabolic syndrome includes both dyslipidemia and impaired vascular function. Because extended-release niacin (ERN) and prescription omega-3 acid ethyl-esters (P-OM3) independently improve these characteristics, we tested their effects in combination. Sixty metabolic syndrome subjects were randomized to 16 weeks of treatment on dual placebo, P-OM3 (4g/day), ERN (2 g/day), or combination in a double-blind trial. Lipoprotein subfractions and vascular endpoints were measured and tested using ANCOVA. ERN increased HDL cholesterol by 5.4 mg/dl from baseline (P = 0.04), decreased triglycerides (TG) by 39 mg/dl (−21%, P = 0.003), and decreased the augmentation index, which is a measure of vascular stiffness, by 3.5 units (P = 0.04). P-OM3 reduced TG by 26 mg/dl (−13%, P = 0.04). Combination treatment increased HDL cholesterol by 7.8 mg/dl (P = 002) and decreased TG by 72 mg/dl (−34%) but there was no improvement in vascular stiffness. Detailed analysis of lipoprotein subfractions revealed increased large, bouyant HDL2 (3.3 mg/dl; P = 0.002) and decreased VLDL1+2 (−32%; P < 0.0001), among subjects treated with combination therapy, that were not present with either therapy alone. ERN and P-OM3 alone improved characteristics of metabolic syndrome; however, whereas subjects on combination therapy did not have improved vascular stiffness, TG and HDL levels improved as did certain lipoprotein subfractions.
PMCID: PMC3466011  PMID: 22892157
fish oil; niacin; metabolic syndrome; very low density lipoprotein; high density lipoprotein; arterial stiffness; augmentation index; eicosapentaenoic acid; docosahexaenoic acid

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