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1.  Melatonin, the Hormone of Darkness: From Sleep Promotion to Ebola Treatment 
Brain disorders & therapy  2014;4(1):1000151.
Melatonin is a hormone secreted by the enigmatic pineal gland in response to darkness, hence the name hormone of darkness. It has generated a great deal of interest as a therapeutic modality for various diseases particularly sleep disorders. This pleiotropic molecule has anti-inflammatory, antioxidant and anticoagulopathic properties in addition to its endothelial protective effects. In this article we discuss melatonin secretion and mechanisms of action as well as therapeutic rationale. We also highlight the potential utility of melatonin in the deadly modern-day Ebola epidemic.
doi:10.4172/2168-975X.1000151
PMCID: PMC4334454
Ebola; Human; Jetlag; Melatonin; Pineal; Sleep
2.  The Authors Reply 
American Journal of Epidemiology  2014;179(4):530-532.
doi:10.1093/aje/kwt331
PMCID: PMC3908631  PMID: 24627920
3.  SHP-2 Mediates Target-Regulated Axonal Termination and NGF-Dependent Neurite Growth in Sympathetic Neurons 
Developmental biology  2002;252(2):170-187.
The tyrosine phosphatase SHP-2 has been implicated in a variety of signaling pathways, including those mediated by neurotrophins in neurons. To examine the role of SHP-2 in the development of sympathetic neurons, we inhibited the function of SHP-2 in transgenic mice by overexpressing a catalytically inactive SHP-2 mutant under the control of the human dopamine β-hydroxylase promoter. Expression of mutant SHP-2 did not influence the survival, axon initiation, or pathfinding abilities of the sympathetic neurons. However, mutant SHP-2 expression resulted in an overproduction of sympathetic fibers in sympathetic target organs. This was due to interference with SHP-2 function, as overexpression of wild type SHP-2 had no such effect. In vitro, NGF-dependent neurite growth was inhibited in neurons expressing mutant SHP-2 but not in those expressing wild type SHP-2. Mutant (but not wt) SHP-2 expression also inhibited NGF-stimulated ERK activation. The NGF-dependent survival pathway was less affected than the neurite growth pathway. Our results suggest that NGF-regulated axon growth signals, and to a lesser degree survival signals, are mediated through a SHP-2-dependent pathway in sympathetic neurons. The increased sympathetic innervation in target tissues of neurons expressing mutant SHP-2 may result from interference with normal “stop” signals dependent on signaling by gradients of NGF.
PMCID: PMC4303248  PMID: 12482708
tyrosine phosphatases; neurotrophins; ERKs; transgenic mouse
4.  Review of the role of dynamic 18F-NaF PET in diagnosing and distinguishing between septic and aseptic loosening in hip prosthesis 
Joint replacements may fail due to infection, dislocation, peri-prosthetic fracture and loosening. Between 0.4 and 4% of joint replacements are known to be complicated by infection and aseptic loosening 2–18%. Differentiating between infection and aseptic loosening has an important bearing on the ongoing strategy for antimicrobial therapy and surgical intervention, but distinguishing one from the other can be difficult and will often require a battery of clinical and biochemical tests including the use of varying radiological modalities to accurately identify whether problematic joints are infected or aseptically loose. Prompt diagnosis is important due to the development of a biofilm on the surface of the infected prosthesis, which makes treatment difficult. There is no consensus among experts on the ideal imaging technique nor the methodology for image interpretation, but there is an increasing trend to apply hybrid imaging in the investigation of painful joint prosthesis and recent attempts have been made using PET-CT to identify aseptic loosening and infection with 18F-fluorodeoxyglucose (FDG) and sodium fluoride 18F-Na. The aim of this paper is to evaluate the role of 18F-NaF sodium fluoride (18F-NaF) positron emission tomography (PET) in distinguishing between septic and aseptic failure in hip and knee replacements, in addition to evaluating the feasibility of using multi-sequential 18F-NaF PET-CT for the assessment of painful lower limb prostheses.
doi:10.1186/s13018-014-0147-7
PMCID: PMC4305262  PMID: 25592441
F-18 fluoride PET; Arthroplasty; Joint prosthesis; Septic loosening; Aseptic loosening
5.  Symptom onset in autosomal dominant Alzheimer disease 
Neurology  2014;83(3):253-260.
Objective:
To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD.
Methods:
We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study.
Results:
We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p < 10−16, r2 > 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex.
Conclusions:
Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research.
doi:10.1212/WNL.0000000000000596
PMCID: PMC4117367  PMID: 24928124
6.  Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor 
Cancer immunology research  2013;2(1):10.1158/2326-6066.CIR-13-0160.
RAF inhibitors selectively block ERK signaling in BRAF-mutant melanomas and have defined a genotype-guided approach to care for this disease. RAF inhibitors have the opposite effect in BRAF wild-type tumor cells, where they cause hyperactivation of ERK signaling. Here, we predict that RAF inhibitors can enhance T cell activation, based upon the observation that these agents paradoxically activate ERK signaling in BRAF wild-type cells. To test this hypothesis, we have evaluated the effects of the RAF inhibitor BMS908662 on T cell activation and signaling in vitro and in vivo. We observe that T cell activation is enhanced in a concentration-dependent manner and that this effect corresponds with increased ERK signaling, consistent with paradoxical activation of the pathway. Furthermore, we find that the combination of BMS908662 with CTLA-4 blockade in vivo potentiates T cell expansion, corresponding with hyperactivation of ERK signaling in T cells detectable ex vivo. Lastly, this combination demonstrates superior anti-tumor activity, compared to either agent alone, in two transplantable tumor models. This study provides clear evidence that RAF inhibitors can modulate T cell function by potentiating T cell activation in vitro and in vivo. Paradoxical activation of ERK signaling in T cells offers one mechanism to explain the enhanced antitumor activity seen when RAF inhibitors are combined with CTLA-4 blockade in preclinical models.
doi:10.1158/2326-6066.CIR-13-0160
PMCID: PMC3883307  PMID: 24416731
Melanoma; BRAF; RAF inhibitors; CTLA-4; immunotherapy; T cell
7.  Alcohol Intoxication and Condom Use Self-Efficacy Effects on Women’s Condom Use Intentions 
Addictive behaviors  2013;39(1):153-158.
Although research has consistently demonstrated that condom use self-efficacy significantly predicts condom use, there has been little investigation of whether acute alcohol intoxication moderates this relationship. Because alcohol intoxication is often associated with increased sexual risk taking, further examination of such moderating effects is warranted. Using a community sample of young heterosexual women (n = 436) with a history of heavy episodic drinking, this alcohol administration experiment examined the effects of intoxication and condom use self-efficacy on women’s condom negotiation and future condom use intentions. After a questionnaire session, alcohol condition (control, .10% target peak BAL) was experimentally manipulated between subjects. Participants then read and responded to a hypothetical risky sexual decision-making scenario. SEM analyses revealed that alcohol intoxication directly decreased women’s intentions to use condoms in the future. Women with greater condom use self-efficacy had stronger intentions to engage in condom negotiation; however, this effect was moderated by intoxication. Specifically, the association between condom use self-efficacy and condom negotiation intentions was stronger for intoxicated women than for sober women. These novel findings regarding the synergistic effects of alcohol intoxication and condom use self-efficacy support continued prevention efforts aimed at strengthening women’s condom use self-efficacy, which may reduce even those sexual risk decisions made during states of intoxication.
doi:10.1016/j.addbeh.2013.09.019
PMCID: PMC3940263  PMID: 24129265
alcohol; condom use self-efficacy; condom use; condom negotiation; sexual risk
8.  Jezebel at the welfare office: How racialized stereotypes of poor women's reproductive decisions and relationships shape policy implementation 
Journal of poverty  2014;18(2):109-129.
Current welfare scholarship lacks an analysis of how caseworkers discuss sexuality-related issues with clients. Seventy-two of 232 transcribed welfare interviews in three states included discussion of reproductive decisions and relationships. Overall, caseworkers’ language reflected negative myths regarding African American women's sexuality and motherhood. By virtue of their status as welfare recipients, regardless of their individual races, clients were placed into racialized myths through workers’ talk. This analysis demonstrates that though not present in every welfare interview and often veiled in bureaucratic language, negative ideas about poor women's sexuality persist in welfare policy and are deeply embedded in its day-to-day implementation.
doi:10.1080/10875549.2013.833159
PMCID: PMC4002050  PMID: 24791134
welfare reform; sexuality; race; gender; qualitative research
9.  NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells 
Immunity  2012;37(6):1009-1023.
Cytopenias are key prognostic indicators of life-threatening infection, contributing to immunosuppression and mortality. Here we define a role for Caspase-1-dependent death, known as pyroptosis, in infection-induced cytopenias by studying inflammasome activation in hematopoietic progenitor cells. The NLRP1a inflammasome is expressed in hematopoietic progenitor cells and its activation triggers their pyroptotic death. Active NLRP1a induced a lethal systemic inflammatory disease that was driven by Caspase-1 and IL-1β but was independent of apoptosis-associated speck-like protein containing a CARD (ASC) and ameliorated by IL-18. Surprisingly, in the absence of IL-1β-driven inflammation, active NLRP1a triggered pyroptosis of hematopoietic progenitor cells resulting in leukopenia in the steady state. During periods of hematopoietic stress induced by chemotherapy or lymphocytic choriomeningitis virus (LCMV) infection, active NLRP1a caused prolonged cytopenia, bone marrow hypoplasia and immunosuppression. Conversely, NLRP1-deficient mice showed enhanced recovery from chemotherapy and LCMV infection, demonstrating that NLRP1 acts as a cellular sentinel to alert Caspase-1 to hematopoietic and infectious stress.
doi:10.1016/j.immuni.2012.08.027
PMCID: PMC4275304  PMID: 23219391
inflammasome; NLRP1; IL-18; IL-1β; progenitor cells; pyroptosis; cytopenia; sepsis
10.  Identification of six novel P450 oxidoreductase missense variants in Ashkenazi and Moroccan Jewish populations 
Pharmacogenomics  2012;13(5):543-554.
Background
The enzyme NADPH–P450 oxidoreductase (POR) is the main electron donor to all microsomal CYPs. The possible contribution of common POR variants to inter- and intra-individual variability in drug metabolism is of great pharmacogenetic interest.
Aim
To search for POR polymorphic alleles and estimate their frequencies in a Jewish population.
Materials & methods
We analyzed the POR gene in 301 Ashkenazi and Moroccan Jews.
Results
A total of 30 POR SNPs were identified, nine in the noncoding regions and 21 in the protein-coding regions (ten synonymous, 11 missense). Six of these missense variants are previously undescribed (S102P, V164M, V191M, D344N, E398A and D648N).
Conclusion
The data collected in this study on missense POR SNPs, interpreted in light of the crystallographic structure of human POR, indicate that some POR missense variants may be potential biomarkers for future POR pharmacogenetic screening.
doi:10.2217/pgs.12.21
PMCID: PMC4270371  PMID: 22462747
allele frequencies; CYP oxidoreductase; haplotype; Jewish; populations; pharmacogenetics; POR
11.  Effect of Providing Conditional Economic Compensation on Uptake of Voluntary Medical Male Circumcision in Kenya 
JAMA  2014;312(7):703-711.
IMPORTANCE
Novel strategies are needed to increase the uptake of voluntary medical male circumcision (VMMC) in sub-Saharan Africa and enhance the effectiveness of male circumcision as an HIV prevention strategy.
OBJECTIVE
To determine whether small economic incentives could increase circumcision prevalence by addressing reported economic barriers to VMMC and behavioral factors such as present-biased decision making.
DESIGN, SETTING, AND PARTICIPANTS
Randomized clinical trial conducted between June 22, 2013, and February 4, 2014, among 1504 uncircumcised men aged 25 to 49 years in Nyanza region, Kenya. VMMC services were provided free of charge and participants were randomized to 1 of 3 intervention groups or a control group.
INTERVENTIONS
Participants in the 3 intervention groups received varying amounts of compensation conditional on undergoing circumcision at 1 of 9 study clinics within 2 months of enrollment. Compensation took the form of food vouchers worth 200 Kenya shillings (≈US $2.50), 700 Kenya shillings (≈US $8.75), or 1200 Kenya shillings (≈US $15.00), which reflected a portion of transportation costs and lost wages associated with getting circumcised. The control group received no compensation.
MAIN OUTCOMES AND MEASURES
VMMC uptake within 2 months.
RESULTS
Analysis of data for 1502 participants with complete data showed that VMMC uptake within 2 months was higher in the US $8.75 group (6.6%; 95% CI, 4.3%–9.5% [25 of 381]) and the US $15.00 group (9.0%; 95% CI, 6.3%–12.4% [34 of 377]) than in the US $2.50 group (1.9%; 95% CI, 0.8%–3.8% [7 of 374]) and the control group (1.6%; 95% CI, 0.6%–3.5% [6 of 370]). In logistic regression analysis, the US $8.75 group had significantly higher VMMC uptake than the control group (adjusted odds ratio [AOR] 4.3; 95% CI, 1.7–10.7), as did the US $15.00 group (AOR 6.2; 95% CI, 2.6–15.0). Effect sizes for the US $8.75 and US $15.00 groups did not differ significantly (P = .20).
CONCLUSIONS AND RELEVANCE
Among uncircumcised men in Kenya, compensation in the form of food vouchers worth approximately US $8.75 or US $15.00, compared with lesser or no compensation, resulted in a modest increase in the prevalence of circumcision after 2 months. The effects of more intense promotion or longer implementation require further investigation.
doi:10.1001/jama.2014.9087
PMCID: PMC4268484  PMID: 25042290
12.  IMPAIRMENT OF HUMAN CYP1A2-MEDIATED XENOBIOTIC METABOLISM BY ANTLEY-BIXLER SYNDROME VARIANTS OF CYTOCHROME P450 OXIDOREDUCTASE* 
Y459H and V492E mutations of cytochrome P450 reductase (CYPOR) cause Antley-Bixler Syndrome due to diminished binding of the FAD cofactor. To address whether these mutations impaired the interaction with drug metabolizing CYPs, a bacterial model of human liver expression of CYP1A2 and CYPOR was implemented. Four models were generated: PORnull, PORwt, PORYH, and PORVE, for which equivalent CYP1A2 and CYPOR levels were confirmed, except for PORnull, not containing any CYPOR. The mutant CYPORs were unable to catalyze cytochrome c and MTT reduction, and were unable to support EROD and MROD activities. Activity was restored by the addition of FAD, with V492E having a higher apparent FAD affinity than Y459H. The CYP1A2-activated procarcinogens, 2-aminoanthracene, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and 2-amino-3-methylimidazo(4,5-f)quinoline, were significantly less mutagenic in PORYH and PORVE models than in PORwt, indicating that CYP1A2, and likely other drug-metabolizing CYPs, are impaired by ABS-related POR mutations as observed in the steroidogenic CYPs.
doi:10.1016/j.abb.2008.04.014
PMCID: PMC4269338  PMID: 18455494
NADPH-cytochrome P450 oxidoreductase; Antley-Bixler Syndrome; POR; Polymorphism; Cytochrome P450; CYP1A2; P450 1A2; Protein-protein interaction; Drug-metabolizing enzymes; Adverse drug reactions
13.  “Real-World” Practical Evaluation Strategies: A Review of Telehealth Evaluation 
JMIR Research Protocols  2014;3(4):e75.
Background
Currently, the increasing interest in telehealth and significant technological breakthroughs of the past decade create favorable conditions for the widespread adoption of telehealth services. Therefore, expectations are high that telehealth can help alleviate prevailing challenges in health care delivery. However, in order to translate current research to policy and facilitate adoption by patients and health care providers, there is need for compelling evidence of the effectiveness of telehealth interventions. Such evidence is gathered from rigorously designed research studies, which may not always be practical in many real-world settings.
Objective
Our aim was to summarize current telehealth evaluation strategies and challenges and to outline practical approaches to conduct evaluation in real-world settings using one of our previously reported telehealth initiatives, the Diabetes Connect program, as a case study.
Methods
We reviewed commonly used current evaluation frameworks and strategies, as well as best practices based on successful evaluative efforts to date to address commonly encountered challenges in telehealth evaluation. These challenges in telehealth evaluation and commonly used frameworks are described relevant to the evaluation of Diabetes Connect, a 12-month Web-based blood glucose monitoring program.
Results
Designers of telehealth evaluation frameworks must give careful consideration to the elements of planning, implementation, and impact assessment of interventions. Evaluating performance at each of these phases is critical to the overall success of an intervention. Although impact assessment occurs at the end of a program, our review shows that it should begin at the point of problem definition. Critical to the success of an evaluative strategy is early planning that involves all stakeholders to identify the overall goals of the program and key measures of success at each phase of the program life cycle. This strategy should enable selection of an appropriate evaluation strategy and measures to aid in the ongoing development and implementation of telehealth and provide better evidence of program impact.
Conclusions
We recommend a pragmatic, multi-method, multi-phase approach to telehealth evaluation that is flexible and can be adapted to the characteristics and challenges unique to each telehealth program.
doi:10.2196/resprot.3459
PMCID: PMC4275475  PMID: 25524892
telehealth; eHealth; evaluation; evaluation framework; diabetes mellitus; technology
14.  Differential Calmodulin-Modulatory and Electron Transfer Properties of Neuronal Nitric Oxide Synthase Mu Compared to the Alpha Variant 
FEBS letters  2013;587(24):3973-3978.
Neuronal nitric oxide synthase μ (nNOSμ) contains 34 additional residues in an autoregulatory element compared to nNOSα. Cytochrome c and flavin reductions in the absence of calmodulin (CaM) were faster in nNOSμ than nNOSα, while rates in the presence of CaM were smaller. The magnitude of stimulation by CaM is thus notably lower in nNOSμ. No difference in NO production was observed, while electron transfer between the FMN and heme moieties and formation of an inhibitory ferrous-nitrosyl complex were slower in nNOSμ. Thus, the insert affects electron transfer rates, modulation of electron flow by CaM, and heme-nitrosyl complex formation.
doi:10.1016/j.febslet.2013.10.032
PMCID: PMC3897158  PMID: 24211446
neuronal nitric oxide synthase; calmodulin; electron transfer; reductase; flavoproteins; heme
15.  Pharmaceutical Availability across Levels of Care: Evidence from Facility Surveys in Ghana, Kenya, and Uganda 
PLoS ONE  2014;9(12):e114762.
Objective
In this study we use facility-level data from nationally representative surveys conducted in Ghana, Kenya, and Uganda to understand pharmaceutical availability within the three countries.
Methods
In 2012, we conducted a survey to capture information on pharmaceuticals and other facility indicators from over 200 facilities in each country. We analyze data on the availability of pharmaceuticals and quantify its association with various facility-level indicators. We analyze both availability of essential medicines, as defined by the various essential medicine lists (EMLs) of each respective country, and availability of all surveyed pharmaceuticals deemed important for treatment of various high-burden diseases, including those on the EMLs.
Results
We find that there is heterogeneity with respect to availability across the three countries with Ghana generally having better availability than Uganda and Kenya. To analyze the relationship between facility-level factors and pharmaceutical stock-out we use a binomial regression model. We find that the factors associated with stock-out vary by country, but across all countries both presence of a laboratory at the facility and presence of a vehicle at the facility are significantly associated with reduced stock-out.
Conclusion
The results of this study highlight the poor availability of essential medicines across these three countries and suggest more needs to be done to strengthen the supply system so that stock remains uninterrupted.
doi:10.1371/journal.pone.0114762
PMCID: PMC4263677  PMID: 25500832
16.  Neonatal body condition, immune responsiveness, and hematocrit predict longevity in a wild bird population 
Ecology  2014;95(11):3027-3034.
Measures of body condition, immune function, and hematological health are widely used in ecological studies of vertebrate populations, predicated on the assumption that these traits are linked to fitness. However, compelling evidence that these traits actually predict long-term survival and reproductive success among individuals in the wild is lacking. Here, we show that body condition (i.e., size-adjusted body mass) and cutaneous immune responsiveness to phytohaemagglutinin (PHA) injection among neonates positively predict recruitment and subsequent longevity in a wild, migratory population of house wrens (Troglodytes aedon). However, neonates with intermediate hematocrit had the highest recruitment and longevity. Neonates with the highest PHA responsiveness and intermediate hematocrit prior to independence eventually produced the most offspring during their lifetime breeding on the study site. Importantly, the effects of PHA responsiveness and hematocrit were revealed while controlling for variation in body condition, sex, and environmental variation. Thus, our data demonstrate that body condition, cutaneous immune responsiveness, and hematocrit as a neonate are associated with individual fitness. Although hematocrit's effect is more complex than traditionally thought, our results suggest a previously underappreciated role for this trait in influencing survival in the wild.
doi:10.1890/14-0418.1
PMCID: PMC4260523  PMID: 25505800
fitness; phytohaemagglutinin; recruitment; survival; Troglodytes aedon
17.  Genetic and environmental variation in condition, cutaneous immunity, and haematocrit in house wrens 
BMC Evolutionary Biology  2014;14(1):242.
Background
Life-history studies of wild bird populations often focus on the relationship between an individual’s condition and its capacity to mount an immune response, as measured by a commonly-employed assay of cutaneous immunity, the PHA skin test. In addition, haematocrit, the packed cell volume in relation to total blood volume, is often measured as an indicator of physiological performance. A multi-year study of a wild population of house wrens has recently revealed that those exhibiting the highest condition and strongest PHA responses as nestlings are most likely to be recruited to the breeding population and to breed through two years of age; in contrast, intermediate haematocrit values result in the highest recruitment to the population. Selection theory would predict, therefore, that most of the underlying genetic variation in these traits should be exhausted resulting in low heritability, although such traits may also exhibit low heritability because of increased residual variance. Here, we examine the genetic and environmental variation in condition, cutaneous immunity, and haematocrit using an animal model based on a pedigree of approximately 2,800 house wrens.
Results
Environmental effects played a paramount role in shaping the expression of the fitness-related traits measured in this wild population, but two of them, condition and haematocrit, retained significant heritable variation. Condition was also positively correlated with both the PHA response and haematocrit, but in the absence of any significant genetic correlations, it appears that this covariance arises through parallel effects of the environment acting on this suite of traits.
Conclusions
The maintenance of genetic variation in different measures of condition appears to be a pervasive feature of wild bird populations, in contradiction of conventional selection theory. A major challenge in future studies will be to explain how such variation persists in the face of the directional selection acting on condition in house wrens and other species.
doi:10.1186/s12862-014-0242-8
PMCID: PMC4272546  PMID: 25471117
Animal model; Condition; Haematocrit; Heritability; Genetic variation; Immunity; Life-history theory; PHA; Troglodytes aedon
18.  Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease 
JAMA neurology  2014;71(9):1111-1122.
Importance
Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in three specific genes, in contrast to late-onset Alzheimer Disease (LOAD), which has a more polygenetic risk profile.
Design, Setting, and Participants
We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of ADAD (N=79) and LOAD (N=444) human participants using resting state functional connectivity MRI (rs-fcMRI) at multiple international academic sites.
Main Outcomes and Measures
For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity as measured by clinical dementia rating (CDR). In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within five RSNs.
Results
Functional connectivity decreases with increasing CDR were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in each type of AD accurately predicted CDR stage in the other, further demonstrating similarity of functional connectivity loss in each disease type. Among ADAD participants, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared to asymptomatic mutation non-carriers.
Conclusions and Relevance
rs-fcMRI changes with progressing AD severity are similar between ADAD and LOAD. Rs-fcMRI may be a useful endpoint for LOAD and ADAD therapy trials. ADAD disease process may be an effective model for LOAD disease process.
doi:10.1001/jamaneurol.2014.1654
PMCID: PMC4240274  PMID: 25069482
Resting-state functional connectivity; autosomal dominant Alzheimer's disease; late-onset Alzheimer's disease; default mode network; apolipoprotein E (APOE)
19.  Activation of the NLRP3 Inflammasome Complex is Not Required for Stress-Induced Death of Pancreatic Islets 
PLoS ONE  2014;9(11):e113128.
Loss of pancreatic beta cells is a feature of type-2 diabetes. High glucose concentrations induce endoplasmic reticulum (ER) and oxidative stress-mediated apoptosis of islet cells in vitro. ER stress, oxidative stress and high glucose concentrations may also activate the NLRP3 inflammasome leading to interleukin (IL)-1β production and caspase-1 dependent pyroptosis. However, whether IL-1β or intrinsic NLRP3 inflammasome activation contributes to beta cell death is controversial. This possibility was examined in mouse islets. Exposure of islets lacking functional NLRP3 or caspase-1 to H2O2, rotenone or thapsigargin induced similar cell death as in wild-type islets. This suggests that oxidative or ER stress do not cause inflammasome-mediated cell death. Similarly, deficiency of NLRP3 inflammasome components did not provide any protection from glucose, ribose or gluco-lipotoxicity. Finally, genetic activation of NLRP3 specifically in beta cells did not increase IL-1β production or cell death, even in response to glucolipotoxicity. Overall, our results show that glucose-, ER stress- or oxidative stress-induced cell death in islet cells is not dependent on intrinsic activation of the NLRP3 inflammasome.
doi:10.1371/journal.pone.0113128
PMCID: PMC4236141  PMID: 25405767
20.  Dietary vitamin D intake and risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition – the EPIC-InterAct study 
Background
Prospective cohort studies have indicated that serum vitamin D levels are inversely related to risk of type 2 diabetes. However, such studies cannot determine the source of vitamin D. Therefore, we examined the association of dietary vitamin D intake with incident type 2 diabetes within the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study in a heterogeneous European population including 8 countries with large geographical variation.
Methods
Using a case-cohort design, 11,245 incident cases of type 2 diabetes and a representative subcohort (N=15,798) were included in the analyses. Hazard ratios (HR) and 95% confidence intervals (CIs) for type 2 diabetes were calculated using a Prentice-weighted Cox regression adjusted for potential confounders. 24-h diet recall data from a subsample (N=2347) were used to calibrate habitual intake data derived from dietary questionnaires.
Results
Median follow-up time was 10.8 years. Dietary vitamin D intake was not significantly associated with the risk of type 2 diabetes. HR and 95 % CIs for the highest compared to the lowest quintile of uncalibrated vitamin D intake was 1.09 (0.97-1.22), (ptrend=0.17). No associations were observed in a sex-specific analysis. The overall pooled effect [HR (95% CI)] using the continuous calibrated variable was 1.00 (0.97-1.03) per increase of 1 μg/day dietary vitamin D.
Conclusion
This observational study does not support an association between higher dietary vitamin D intake and type-2 diabetes incidence. This result has to be interpreted in light of the limited contribution of dietary vitamin D on the overall vitamin D status of a person.
doi:10.1038/ejcn.2013.235
PMCID: PMC4234029  PMID: 24253760
vitamin D; type-2 diabetes; dietary intake; observational study; EPIC
21.  Regulation of Valvular Interstitial Cell Mineralization by Components of the Extracellular Matrix 
The composition of the extracellular matrix (ECM) is believed to play a role in heart valve disease, and is highly relevant to the design of heart valve tissue engineering scaffolds, yet the interaction of valvular interstitial cells (VICs) with the ECM environment has not been well characterized. Thus, the transformation of VICs to an osteoblast-like phenotype was quantified in VICs cultured on different types of ECM coatings. The results show that the number and size of calcific nodules formed in VIC cultures, as well as the expression of the mineralization markers alkaline phosphatase (ALP) and CBFa1, were highly dependent upon the composition of the culture surface. In fact, VICs cultured on certain ECM components, namely collagen and fibronectin, were resistant to calcification, even upon treatment with several mineralization-inducing growth factors. Meanwhile, cultures of VICs on fibrin, laminin, and heparin coatings not only had a high number of calcified nodules, but also elevated levels of ALP and CBFa1. Nodule composition analysis revealed the presence of multiple types of mineralization, including hydroxyapatite. Although apoptotic and necrotic cells were more concentrated in nodules than in other parts of the VIC cultures, the nodules contained a strong majority population of viable cells. By demonstrating this ECM-dependence of VIC calcification, we aim to identify appropriate biomaterial environments for heart valve tissue engineering as well as elucidate mechanisms of valvular disease.
doi:10.1002/jbm.a.32187
PMCID: PMC4230299  PMID: 18671262
valvular interstitial cells; calcification; biomaterials; extracellular matrix
22.  Nylon-3 Polymers that Enable Selective Culture of Endothelial Cells 
Journal of the American Chemical Society  2013;135(44):16296-16299.
Substrates that selectively encourage the growth of specific cell types are valuable for the engineering of complex tissues. Some cell-selective peptides have been identified from extracellular matrix proteins; these peptides have proven useful for biomaterials-based approaches to tissue repair or regeneration. However, there are very few examples of synthetic materials that display selectivity in supporting cell growth. We describe nylon-3 polymers that support in vitro culture of endothelial cells, but do not support the culture of smooth muscle cells or fibroblasts. These materials may be promising for vascular biomaterials applications.
doi:10.1021/ja408634a
PMCID: PMC3996459  PMID: 24156536
23.  Role of Neuroimaging in HIV Associated Neurocognitive Disorders (HAND) 
Seminars in neurology  2014;34(1):89-102.
HIV enters the brain soon after seroconversion and can cause HIV associated neurocognitive disorders (HAND). While the more severe and progressive forms of HAND are less prevalent due to combination antiretroviral therapy (cART), ~ 40% of HIV-infected (HIV+) patients continue to have cognitive impairment. Some HIV+ individuals who have effective plasma HIV-1 RNA suppression with cART still develop HAND. It is often difficult to diagnose HAND in the outpatient setting as detailed neuropsychological performance testing is required.
Additional biomarkers that are relatively easy to obtain and clinically relevant are needed for assessing HIV associated neuropathologic changes. Recently developed non-invasive magnetic resonance imaging (MRI) techniques have great potential to serve as biomarkers. We review the application of some of these neuroimaging techniques [magnetic resonance spectroscopy (MRS), volumetric MRI, diffusion tensor imaging (DTI), functional MRI (fMRI)] in HIV+ individuals. Each of the neuroimaging methods offers unique insight into mechanisms underlying neuroHIV, could monitor disease progression, and may assist in evaluating the efficacy of particular cART regimens. It is hoped that considerable progress will continue to occur such that some of these neuroimaging methods will be incorporated across multiple sites and included in future HAND guidelines.
doi:10.1055/s-0034-1372346
PMCID: PMC4217280  PMID: 24715492
HIV; neuroimaging; magnetic resonance spectroscopy; volumetrics; diffusion tensor imaging; functional MRI
24.  The potential of alcohol “heat-of-the-moment” scenarios in HIV prevention: A qualitative study exploring intervention implications 
Archives of sexual behavior  2013;42(8):1487-1499.
Scenarios simulating real-world risk situations have proven effective for substance use intervention methods and could potentially prove useful as an HIV-prevention method. This study explored qualitatively the development and use of such “in-the-moment” methods. We interviewed 97 moderate-drinking women (50% Caucasian) after participation in an experiment requiring that they project themselves into a risky-sex scenario. Most participants (58%) reported experiencing the scenario as a reflective tool characterized by two primary themes: (a) increased awareness of risk; and (b) contemplation of behavior change. Findings suggest that “in-the-moment” methods depicting real-world risk situations and providing opportunities to reflect about behavioral choices and subsequent outcomes could prove a useful adjunct to HIV/AIDS-prevention interventions. Such methods could potentially augment existing prevention protocols.
doi:10.1007/s10508-013-0125-x
PMCID: PMC4089951  PMID: 23740468
HIV prevention; women; scenarios; sexual risk taking; alcohol
25.  Systematic review of microendoscopic discectomy for lumbar disc herniation 
European Spine Journal  2013;22(11):2458-2465.
Study design
Systematic review.
Objective
To search and analyse randomised controlled trials (RCTs) published since the Cochrane review by Gibson and Waddell (2007) comparing microendoscopic discectomy (MED) with open discectomy (OD) or microdiscectomy (MD) and to assess whether MED improves patient-reported outcomes.
Summary of background
Discectomy for symptomatic herniated lumbar discs is an effective operative treatment. A number of operative techniques exist including OD, MD, and MED. A 2007 Cochrane review identified OD as an effective treatment for symptom improvement, and found sufficient evidence for MD. However, evidence for MED was lacking.
Methods
A systematic review of Medline and Embase was carried out. Aiming to identify RCTs carried out after 2007, which compared OD with MD and MED which reported the Oswestry disability index (ODI) as an outcome.
Results
Four RCTs were identified. None of the studies found a significant difference in the ODI scores between study groups at any time point. Three studies compared MED to OD and one compared OD, MD, and MED. The largest study reported an increased number of severe complications in the MED group.
Conclusions
There is some evidence to suggest that MED performed by surgeons skilled in the technique in tertiary referral centres is as effective as OD.
doi:10.1007/s00586-013-2848-8
PMCID: PMC3886516  PMID: 23793558
Microendoscopic discectomy; Lumbar disc herniation; Sciatica; Discectomy

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