Recent Submissions

  • Catecholaminergic manipulation alters dynamic network topology across cognitive states

    Shine, J.M.; van den Brink, R.L.; Hernaus, D. (MIT Press Journals, 2017)
    The human brain is able to flexibly adapt its information processing capacity to meet a variety of cognitive challenges. Recent evidence suggests that this flexibility is reflected in the dynamic reorganization of the functional connectome. The ascending catecholaminergic arousal systems of the brain are a plausible candidate mechanism for driving alterations in network architecture, enabling efficient deployment of cognitive resources when the environment demands them. We tested this hypothesis by analyzing both resting-state and task-based fMRI data following the administration of atomoxetine, a noradrenaline reuptake inhibitor, compared with placebo, in two separate human fMRI studies. Our results demonstrate that the manipulation of central catecholamine levels leads to a reorganization of the functional connectome in a manner that is sensitive to ongoing cognitive demands.
  • Status of cardiovascular PET radiation exposure and strategies for reduction: An Information Statement from the Cardiovascular PET Task Force

    Case, J.A.; deKemp, R.A.; Slomka, P.J. (Springer New York LLC, 2017)
    Cardiovascular positron emission tomography (PET) imaging provides high-quality visual and quantitative myocardial perfusion and function images. In addition, cardiovascular PET can assess myocardial viability, myocardial inflammatory disorders such as cardiac sarcoid, and infections of implanted devices including pacemakers, ventricular assist devices, and prosthetic heart valves. As with all nuclear cardiology procedures, the benefits need to be considered in relation to the risks of exposure to radiation. When performed properly, these assessments can be obtained while simultaneously minimizing radiation exposure. The purpose of this information statement is to present current concepts to minimize patient and staff radiation exposure while ensuring high image quality.
  • Factors Associated With HIV Testing Among Men in Haiti: Results From the 2012 Demographic and Health Survey

    Conserve, D.F.; Iwelunmor, J.; Whembolua, G.-L. (SAGE Publications Inc., 2017)
    HIV testing serves as the gateway to HIV prevention and treatment. However, research examining men's HIV testing behaviors in the Caribbean remains limited. The Andersen Behavioral Model of Health Services Utilization was used to examine factors associated with HIV testing among 7,354 men who participated in the 2012 Demographic and Health Survey conducted in Haiti. Few men (35%) reported having ever been tested for HIV. Logistic regression analyses revealed that HIV testing increased with education and wealth. Marital status was associated with HIV testing, with married men more likely to have been tested (adjusted odds ratio: 2.57, 95% CI [2.07, 3.19]) than unmarried men. Positive attitudes toward people living with HIV, indicated by willing to care for a relative who has HIV/AIDS, was also correlated with higher odds of having been tested (adjusted odds ratio: 1.28, 95% CI [1.08, 1.51]). Men who reported condom use during last sex were more likely to have been tested (odds ratio: 1.58, 95% CI [1.33, 1.88). The findings indicate that HIV testing rates remain low among men in Haiti and more efforts are needed to increase HIV testing among men who are not married, have low level of education, and engage in unprotected sex. Copyright The Author(s) 2016.
  • Placental but Not Peripheral Plasmodium falciparum Infection During Pregnancy Is Associated With Increased Risk of Malaria in Infancy

    Boudová, S.; Divala, T.; Mungwira, R. (Oxford University Press, 2017)
    Pregnancy-associated Plasmodium falciparum infection impacts the health of mothers and newborns, but little is known about the effects of these infections on infant susceptibility to malaria. We followed 473 mother-infant pairs during pregnancy and through 2 years of age. We observed that children born to mothers with placental malaria, but not those born to mothers with peripheral infection without evidence of placental sequestration, had increased risk of malaria during the first year of life compared with children born to mothers with no malaria during pregnancy. Malaria infections with placental sequestration have long-lasting impact on infant susceptibility to malaria infection. Copyright 2017 The Author.
  • Toxicity and quality of life report of a phase II study of stereotactic body radiotherapy (SBRT) for low and intermediate risk prostate cancer

    Boyer, M.J.; Papagikos, M.A.; Kiteley, R. (BioMed Central Ltd., 2017)
    Background: Clinical data indicates that delivery of larger daily doses of radiation may improve the therapeutic ratio for prostate cancer compared to conventional fractionation. A phase II study of stereotactic body radiotherapy with real-time motion management and daily plan re-optimization for low to intermediate risk prostate cancer was undertaken to evaluate this hypothesis. This report details the toxicity and quality of life following treatment. Methods: From 2009 to 2013, 60 patients with T1-T2c prostate cancer with a Gleason score of 6 and PSA ≤ 15 or Gleason score of 7 and PSA ≤ 10 were enrolled. Patients with nodal metastases, an American Urological Association symptom score > 18, or gland size > 100 g were not eligible. Patients were treated to 37 Gy in 5 fractions. Early and late genitourinary and gastrointestinal toxicity were graded based on NCI CTCAE v4.0 and quality of life was assessed by the American Urological Association symptom score, International Index of Erectile Function, and Expanded Prostate cancer Index Composite Short Form up to 36 months after treatment. Results: After a median follow-up of 27.6 months, no grade 3 or greater genitourinary toxicity was observed. Four patients (6.7%) reported a late grade 2 genitourinary toxicity. One patient (1.7%) reported a late grade 3 gastrointestinal toxicity. Five patients (8.3%) developed a late grade 2 gastrointestinal toxicity. The median American Urological Association symptom score increased from 4.5 prior to treatment to 11 while on treatment (p < 0.01), but was 5 at 36 months post-treatment (p = 0.65). Median International Index of Erectile Function scores decreased from 19 to 17 over the course of follow-up (p < 0.01). Only median scores within the Expanded Prostate Cancer Index Composite Short Form sexual domain were significantly decreased at 36 months post-treatment (67.9 vs 45.2, p = 0.02). There was no significant difference in median score within the urinary, bowel, or hormonal domains at 36 months of follow-up. Conclusions: Stereotactic body radiotherapy for low to intermediate risk prostate cancer is well tolerated with limited toxicity or decrease in quality of life. Longer follow-up is necessary to assess the efficacy of treatment. Trial registration: NCT00941915Registered 17 June 2009. Copyright 2017 The Author(s).
  • Creation and Initial Characterization of Isogenic Helicobacter pylori CagA EPIYA Variants Reveals Differential Activation of Host Cell Signaling Pathways

    Bridge, D.R.; Blum, F.C.; Jang, S. (Nature Publishing Group, 2017)
    The polymorphic CagA toxin is associated with Helicobacter pylori-induced disease. Previous data generated using non-isogenic strains and transfection models suggest that variation surrounding the C-Terminal Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs as well as the number of EPIYA motifs influence disease outcome. To investigate potential CagA-mediated effects on host cell signaling, we constructed and characterized a large panel of isogenic H. pylori strains that differ primarily in the CagA EPIYA region. The number of EPIYA-C motifs or the presence of an EPIYA-D motif impacted early changes in host cell elongation; however, the degree of elongation was comparable across all strains at later time points. In contrast, the strain carrying the EPIYA-D motif induced more IL-8 secretion than any other EPIYA type, and a single EPIYA-C motif induced comparable IL-8 secretion as isolates carrying multiple EPIYA-C alleles. Similar levels of ERK1/2 activation were induced by all strains carrying a functional CagA allele. Together, our data suggest that polymorphism in the CagA C-Terminus is responsible for differential alterations in some, but not all, host cell signaling pathways. Notably, our results differ from non-isogenic strain studies, thus highlighting the importance of using isogenic strains to study the role of CagA toxin polymorphism in gastric cancer development. Copyright 2017 The Author(s).
  • Description of Antihypertensive Medication Use in a Pediatric Practice: Single and Multiple Antihypertensive Medication Therapy

    Binka, E.; Mendley, S.; Gaskin, P. (Blackwell Publishing Inc., 2017)
    Prescription of multiple antihypertensive medications for the treatment of essential hypertension (HTN) has been well described in adults but not in children and adolescents. The authors describe the frequency with which children with essential HTN are prescribed a single vs two or more concomitantly administered antihypertensive medications. They also describe demographic features and comorbidities associated with the prescription of a single vs multiple antihypertensive medications. Multiple antihypertensive medication use in the management of pediatric HTN, as in the management of adult HTN, is not uncommon. In this single-center, retrospective study of 113 children with essential HTN, 28% of children were concomitantly prescribed two or more antihypertensive medications for poorly controlled blood pressure following prescription of a single medication. Demographic and comorbid conditions associated with the prescription of more than one antihypertensive medication include advanced hypertensive stage, race, and a family history of HTN.
  • PubRunner: A light-weight framework for updating text mining results [version 2]

    Busby, B.; Anekalla, K.R.; Courneya, J.P. (Faculty of 1000 Ltd, 2017)
    Biomedical text mining promises to assist biologists in quickly navigating the combined knowledge in their domain. This would allow improved understanding of the complex interactions within biological systems and faster hypothesis generation. New biomedical research articles are published daily and text mining tools are only as good as the corpus from which they work. Many text mining tools are underused because their results are static and do not reflect the constantly expanding knowledge in the field. In order for biomedical text mining to become an indispensable tool used by researchers, this problem must be addressed. To this end, we present PubRunner, a framework for regularly running text mining tools on the latest publications. PubRunner is lightweight, simple to use, and can be integrated with an existing text mining tool. The workflow involves downloading the latest abstracts from PubMed, executing a user-defined tool, pushing the resulting data to a public FTP or Zenodo dataset, and publicizing the location of these results on the public PubRunner website. We illustrate the use of this tool by re-running the commonly used word2vec tool on the latest PubMed abstracts to generate up-to-date word vector representations for the biomedical domain. This shows a proof of concept that we hope will encourage text mining developers to build tools that truly will aid biologists in exploring the latest publications. Copyright 2017 Anekalla KR et al.
  • Cancer Diagnostic and Predictive Biomarkers 2016

    Buonaguro, F.M.; Pauza, C.D.; Tornesello, M.L. (Hindawi Limited, 2017)
  • In Vivo Expansion of Melanoma-Specific T Cells Using Microneedle Arrays Coated with Immune-Polyelectrolyte Multilayers

    Zeng, Q.; Gammon, J.M.; Tostanoski, L.H. (American Chemical Society, 2017)
    Microneedles (MNs) are micron-scale polymeric or metallic structures that offer distinct advantages for vaccines by efficiently targeting skin-resident immune cells, eliminating injection-associated pain, and improving patient compliance. These advantages, along with recent studies showing therapeutic benefits achieved using traditional intradermal injections in human cancer patients, suggest MN delivery might enhance cancer vaccines and immunotherapies. We recently developed a new class of polyelectrolyte multilayers based on the self-assembly of model peptide antigens and molecular toll-like receptor agonists (TLRa) into ultrathin, conformal coatings. Here, we reasoned that these immune polyelectrolyte multilayers (iPEMs) might be a useful platform for assembling cancer vaccine components on MN arrays for intradermal delivery from these substrates. Using conserved human melanoma antigens and a potent TLRa vaccine adjuvant, CpG, we show that iPEMs can be assembled on MNs in an automated fashion. These films, prepared with up to 128 layers, are approximately 200 nm thick but provide cancer vaccine cargo loading &gt;225 ?g/cm2. In cell culture, iPEM cargo released from MNs is internalized by primary dendritic cells, promotes activation of these cells, and expands T cells during coculture. In mice, application of iPEM-coated MNs results in the codelivery of tumor antigen and CpG through the skin, expanding tumor-specific T cells during initial MN applications and resulting in larger memory recall responses during a subsequent booster MN application. This study support MNs coated with PEMs built from tumor vaccine components as a well-defined, modular system for generating tumor-specific immune responses, enabling new approaches that can be explored in combination with checkpoint blockade or other combination cancer therapies.
  • Conformational dynamics of a neurotransmitter: Sodium symporter in a lipid bilayer

    Adhikary, S.; Deredge, D.J.; Nagarajan, A. (National Academy of Sciences, 2017)
    Neurotransmitter:sodium symporters (NSSs) are integral membrane proteins responsible for the sodium-dependent reuptake of smallmolecule neurotransmitters from the synaptic cleft. The symporters for the biogenic amines serotonin (SERT), dopamine (DAT), and norepinephrine (NET) are targets of multiple psychoactive agents, and their dysfunction has been implicated in numerous neuropsychiatric ailments. LeuT, a thermostable eubacterial NSS homolog, has been exploited as a model protein for NSS members to canvass the conformational mechanism of transport with a combination of X-ray crystallography, cysteine accessibility, and solution spectroscopy. Despite yielding remarkable insights, these studies have primarily been conducted with protein in the detergent-solubilized state rather than embedded in a membrane mimic. In addition, solution spectroscopy has required site-specific labeling of nonnative cysteines, a labor-intensive process occasionally resulting in diminished transport and/or binding activity. Here, we overcome these limitations by reconstituting unlabeled LeuT in phospholipid bilayer nanodiscs, subjecting them to hydrogen-deuterium exchange coupled with mass spectrometry (HDX-MS), and facilitating interpretation of the data with molecular dynamics simulations. The data point to changes of accessibility and dynamics of structural elements previously implicated in the transport mechanism, in particular transmembrane helices (TMs) 1a and 7 as well as extracellular loops (ELs) 2 and 4. The results therefore illuminate the value of this strategy for interrogating the conformational mechanism of the more clinically significant mammalian membrane proteins including SERT and DAT, neither of which tolerates complete removal of endogenous cysteines, and whose activity is heavily influenced by neighboring lipids.
  • PubRunner: A light-weight framework for updating text mining results

    Anekalla, K.R.; Courneya, J.P.; Fiorini, N. (Faculty of 1000 Ltd, 2017)
    Biomedical text mining promises to assist biologists in quickly navigating the combined knowledge in their domain. This would allow improved understanding of the complex interactions within biological systems and faster hypothesis generation. New biomedical research articles are published daily and text mining tools are only as good as the corpus from which they work. Many text mining tools are underused because their results are static and do not reflect the constantly expanding knowledge in the field. In order for biomedical text mining to become an indispensable tool used by researchers, this problem must be addressed. To this end, we present PubRunner, a framework for regularly running text mining tools on the latest publications. PubRunner is lightweight, simple to use, and can be integrated with an existing text mining tool. The workflow involves downloading the latest abstracts from PubMed, executing a user-defined tool, pushing the resulting data to a public FTP, and publicizing the location of these results on the public PubRunner website. This shows a proof of concept that we hope will encourage text mining developers to build tools that truly will aid biologists in exploring the latest publications. Copyright 2017 Anekalla KR et al.
  • Patient-Reported Outcome and Observer-Reported Outcome Assessment in Rare Disease Clinical Trials: An ISPOR COA Emerging Good Practices Task Force Report

    Benjamin, K.; Vernon, M.K.; Patrick, D.L. (Elsevier Ltd, 2017)
    Background Rare diseases (RDs) affect a small number of people within a population. About 5000 to 8000 distinct RDs have been identified, with an estimated 6% to 8% of people worldwide suffering from an RD. Approximately 75% of RDs affect children. Frequently, these conditions are heterogeneous; many are progressive. Regulatory incentives have increased orphan drug designations and approvals. Objective To develop emerging good practices for RD outcomes research addressing the challenges inherent in identifying, selecting, developing, adapting, and implementing patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments for use in RD clinical trials. Good Practices for Outcomes Research This report outlines the challenges and potential solutions in determining clinical outcomes for RD trials. It follows the US Food and Drug Administration Roadmap to Patient-Focused Outcome Measurement in Clinical Trials. The Roadmap consists of three columns: 1) Understanding the Disease or Condition, 2) Conceptualizing Treatment Benefit, and 3) Selecting/Developing the Outcome Measure. Challenges in column 1 include factors such as incomplete natural history data and heterogeneity of disease presentation and patient experience. Solutions include using several information sources, for example, clinical experts and patient advocacy groups, to construct the condition's natural history and understand treatment patterns. Challenges in column 2 include understanding and measuring treatment benefit from the patient's perspective, especially given challenges in defining the context of use such as variations in age or disease severity/progression. Solutions include focusing on common symptoms across patient subgroups, identifying short-term outcomes, and using multiple types of COA instruments to measure the same constructs. Challenges in column 3 center around the small patient population and heterogeneity of the condition or study sample. Few disease-specific instruments for RDs exist. Strategies include adapting existing instruments developed for a similar condition or that contain symptoms of importance to the RD patient population, or using a generic instrument validated for the context of use. Conclusions This report provides state-of-the-art solutions to patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments challenges in clinical trials of patients with RDs. These recommended solutions are both pragmatic and creative and posed with clear recognition of the global regulatory context used in RD clinical development programs.
  • Barriers and facilitators to use of non-pharmacological treatments in chronic pain

    Becker, W.C.; Dorflinger, L.; Edmond, S.N. (BioMed Central Ltd., 2017)
    Background: Consensus guidelines recommend multi-modal chronic pain treatment with increased uptake of non-pharmacological pain treatment modalities (NPMs). We aimed to identify the barriers and facilitators to uptake of evidence-based NPMs from the perspectives of patients, nurses and primary care providers (PCPs). Methods: We convened eight separate groups and engaged each in a Nominal Group Technique (NGT) in which participants: (1) created an individual list of barriers (and, in a subsequent round, facilitators) to uptake of NPMs; (2) compiled a group list from the individual lists; and (3) anonymously voted on the top three most important barriers and facilitators. In a separate process, research staff reviewed each group's responses and categorized them based on staff consensus. Results: Overall, 26 patients (14 women) with chronic pain participated; their mean age was 55. Overall, 14 nurses and 12 PCPs participated. Seven healthcare professionals were men and 19 were women; the mean age was 45. We categorized barriers and facilitators as related to access, patient-provider interaction, treatment beliefs and support. Top-ranked patient-reported barriers included high cost, transportation problems and low motivation, while top-ranked facilitators included availability of a wider array of NPMs and a team-based approach that included follow-up. Top-ranked provider-reported barriers included inability to promote NPMs once opioid therapy was started and patient skepticism about efficacy of NPMs, while top-ranked facilitators included promotion of a facility-wide treatment philosophy and increased patient knowledge about risks and benefits of NPMs. Conclusions: In a multi-stakeholder qualitative study using NGT, we found a diverse array of potentially modifiable barriers and facilitators to NPM uptake that may serve as important targets for program development. Copyright 2017 The Author(s).
  • The grimace scale reliably assesses chronic pain in a rodent model of trigeminal neuropathic pain

    Akintola, T.; Raver, C.; Studlack, P. (Elsevier B.V., 2017)
    The limited success in translating basic science findings into effective pain management therapies reflects, in part, the difficulty in reliably assessing pain in experimental animals. This shortcoming is particularly acute in the field of chronic, ongoing pain. Quantitative analysis of facial expressions - the grimace score - was introduced as a promising tool, however, it is thought to reliably assess only pain of short or medium duration (minutes to hours). Here, we test the hypothesis that grimace scores are a reliable metric of ongoing neuropathic pain, by testing the prediction that chronic constriction injury of the infraorbital nerve (CCI-ION) will evoke significant increases in grimace scale scores. Mice and rats were subjected to CCI-ION, and tested for changes in mechanical hypersensitivity and in grimace scores, 10 or more days after surgery. Both rats and mice with CCI-ION had significantly higher grimace scores, and significantly lower thresholds for withdrawal from mechanical stimuli applied to the face, compared to sham-operated animals. Fentanyl reversed the changes in rat grimace scale scores, suggesting that these scores reflect pain perception. These findings validate the grimace scale as a reliable and sensitive metric for the assessment of ongoing pain in a rodent model of chronic, trigeminal neuropathic pain. Copyright 2017 The Authors
  • Erratum to: American Society of Nuclear Cardiology and Society of Nuclear Medicine and Molecular Imaging Joint Position Statement on the Clinical Indications for Myocardial Perfusion PET (J NUCL CARDIOL, (2016), 23, (1227-31), 10.1007/S12350-016-0626-9)

    Bateman, T.M.; Dilsizian, V.; Beanlands, R.S. (Springer New York LLC, 2017)
    Due to the Publisher's error, the above author names were omitted from the original article metadata. This erratum is being published to correct the scientific record, as well as the PubMed listing of the article. The author affiliations can be found below. No wrongdoing or responsibility for this error lies with the authors, and the content of the article remains unchanged.
  • Pediatric primary care providers' use of behavioral health consultation

    Arora, P.G.; Connors, E.H.; Coble, K. (American Psychiatric Association, 2017)
    This column describes a qualitative study in which 32 primary care providers (PCPs) reported barriers to and facilitators of using a behavioral health (BH) consultation program. Barriers included program incompatibility with organizational culture, limited exposure to the program, existing access to referral sources, and negative beliefs about BH consultation. Reported facilitators included having personal relationships with BH program staff, exposure to program information, and positive beliefs about BH consultation. PCPs recommended outreach activities and optimal program features to increase use of BH consultation.
  • Histone deacetylase 6 inhibition reduces cysts by decreasing cAMP and Ca2 in knock-out mouse models of polycystic kidney disease

    Yanda, M.K.; Liu, Q.; Cebotaru, V. (American Society for Biochemistry and Molecular Biology Inc., 2017)
    Autosomal dominant polycystic kidney disease (ADPKD) is associated with progressive enlargement of multiple renal cysts, often leading to renal failure that cannot be prevented by a current treatment. Two proteins encoded by two genes are associated with ADPKD: PC1 (pkd1), primarily a signaling molecule, and PC2 (pkd2), a Ca2 channel. Dysregulation of cAMP signaling is central to ADPKD, but the molecular mechanism is unresolved. Here, we studied the role of histone deacetylase 6 (HDAC6) in regulating cyst growth to test the possibility that inhibiting HDAC6 might help manage ADPKD. Chemical inhibition of HDAC6 reduced cyst growth in PC1-knock-out mice. In proximal tubule-derived, PC1-knock-out cells, adenylyl cyclase 6 and 3 (AC6 and -3) are both expressed. AC6 protein expression was higher in cells lacking PC1, compared with control cells containing PC1. Intracellular Ca2 was higher in PC1-knock-out cells than in control cells. HDAC inhibition caused a drop in intracellular Ca2 and increased ATP-simulated Ca2 release. HDAC6 inhibition reduced the release of Ca2 from the endoplasmic reticulum induced by thapsigargin, an inhibitor of endoplasmic reticulum Ca2-ATPase. HDAC6 inhibition and treatment of cells with the intracellular Ca2 chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid tetrakis(acetoxymethyl ester) reduced cAMP levels in PC1-knock-out cells. Finally, the calmodulin inhibitors W-7 and W-13 reduced cAMP levels, and W-7 reduced cyst growth, suggesting that AC3 is involved in cyst growth regulated by HDAC6. We conclude that HDAC6 inhibition reduces cell growth primarily by reducing intracellular cAMP and Ca2 levels. Our results provide potential therapeutic targets that may be useful as treatments for ADPKD.
  • Conformational Heterogeneity of the HIV Envelope Glycan Shield

    Yang, M.; Huang, J.; Simon, R. (Nature Publishing Group, 2017)
    To better understand the conformational properties of the glycan shield covering the surface of the HIV gp120/gp41 envelope (Env) trimer, and how the glycan shield impacts the accessibility of the underlying protein surface, we performed enhanced sampling molecular dynamics (MD) simulations of a model glycosylated HIV Env protein and related systems. Our simulation studies revealed a conformationally heterogeneous glycan shield with a network of glycan-glycan interactions more extensive than those observed to date. We found that partial preorganization of the glycans potentially favors binding by established broadly neutralizing antibodies; omission of several specific glycans could increase the accessibility of other glycans or regions of the protein surface to antibody or CD4 receptor binding; the number of glycans that can potentially interact with known antibodies is larger than that observed in experimental studies; and specific glycan conformations can maximize or minimize interactions with individual antibodies. More broadly, the enhanced sampling MD simulations described here provide a valuable tool to guide the engineering of specific Env glycoforms for HIV vaccine design. Copyright 2017 The Author(s).
  • Loss of epidermal AP1 transcription factor function reduces filaggrin level, alters chemokine expression and produces an ichthyosis-related phenotype

    Young, C.A.; Rorke, E.A.; Adhikary, G. (2017)
    AP1 transcription factors are important controllers of epidermal differentiation. Multiple family members are expressed in the epidermis in a differentiation-dependent manner, where they function to regulate gene expression. To study the role of AP1 factor signaling, TAM67 (dominant-negative c-jun) was inducibly expressed in the suprabasal epidermis. The TAM67-positive epidermis displays keratinocyte hyperproliferation, hyperkeratosis and parakeratosis, delayed differentiation, extensive subdermal vasodilation, nuclear loricrin localization, tail and digit pseudoainhum and reduced filaggrin level. These changes are associated with increased levels of IFN?, CCL3, CCL5, CXCL9, CXCL10, and CXCL11 (Th1-associated chemokines), and CCL1, CCL2, CCL5 and CCL11 (Th2-associated chemokines) in the epidermis and serum. S100A8 and S100A9 protein levels are also markedly elevated. These changes in epidermal chemokine level are associated with increased levels of the corresponding chemokine mRNA. The largest increases were observed for CXCL9, CXCL10, CXCL11, and S100A8 and S100A9. To assess the role of CXCL9, CXCL10, CXCL11, which bind to CXCR3, on phenotype development, we expressed TAM67 in CXCR3 knockout mice. Using a similar strategy, we examine the role of S100A8 and S100A9. Surprisingly, loss of CXCR3 or S100A8/A9 did not attenuate phenotype development. These studies suggest that interfering with epidermal AP1 factor signaling initiates a loss of barrier function leading to enhanced epidermal chemokine production, but that CXCR3 and S100A8/A9 do not mediate the phenotypic response.

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