february - Institute for Immunity, Transplantation and Infection

ITI PUBLICATIONS – FEBRUARY 2014

1)J Hand Surg Am. 2014 Feb;39(2):324-9. doi: 10.1016/j.jhsa.2013.11.011.

Incidence of Failure of Continuous Peripheral Nerve Catheters for Postoperative Analgesia in Upper Extremity Surgery.

Ahsan ZS1, Carvalho B1, Yao J2.

PURPOSE:To explore the incidence of failure of continuous peripheral nerve blockade (CPNB) after upper extremity operations.

METHODS:Patient data regarding postoperative CPNB were retrospectively obtained from our institution's regional anesthesia database. Documented information on the first postoperative day included pain assessment ratings (numerical verbal pain scale, patient-reported breakthrough pain upon perceived return of sensation, appearance of the catheter site, complications, time of return of sensation, day of return of sensation, residual blockade, patient satisfaction with the block, and whether patient would receive the block again).

RESULTS:A total of 207 patients received CPNB for postoperative analgesia. The failure rate on the first postoperative day for infraclavicular (133 patients) and supraclavicular (58 patients)

CPNB was 19% and 26%, respectively. Interscalene CPNB (16 patients) yielded 3 incidences of failure. No significant difference was found between supraclavicular and infraclavicular block techniques. In addition, no significant differences were found between the incidences of CPNB failures with potentially more painful surgeries involving bone compared with potentially less painful soft tissue procedures.

CONCLUSIONS:The CPNB technique used for hand surgery postoperative analgesia was associated with nontrivial failure rates. The potential of CPNB failure and resulting breakthrough pain upon recovery from the primary nerve block is important to help establish patient expectations.

TYPE OF STUDY/LEVEL OF EVIDENCE:Therapeutic IV.

Copyright © 2014 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

KEYWORDS:Analgesia, failure, indwelling pain catheter, postoperative pain

PMID: 24480691 [PubMed - in process]

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2)Nature. 2014 Jan 30;505(7485):706-9. doi: 10.1038/nature12946.

Landscape and variation of RNA secondary structure across the human transcriptome.

Wan Y1, Qu K2, Zhang QC3, Flynn RA3, Manor O4, Ouyang Z5, Zhang J3, Spitale RC3,

Snyder MP6, Segal E4, Chang HY3.

In parallel to the genetic code for protein synthesis, a second layer of information is embedded in all RNA transcripts in the form of RNA structure. RNA structure influences practically every step in the gene expression program. However, the nature of most RNA structures or effects of sequence variation on structure are not known. Here we report the initial landscape and variation of RNA secondary structures (RSSs) in a human family trio (mother, father and their child). This provides a comprehensive RSS map of human coding and non-coding RNAs. We identify unique

RSS signatures that demarcate open reading frames and splicing junctions, and define authentic microRNA-binding sites. Comparison of native deproteinized RNA isolated from cells versus refolded purified RNA suggests that the majority of the RSS information is encoded within RNA

sequence. Over 1,900 transcribed single nucleotide variants (approximately 15% of all transcribed single nucleotide variants) alter local RNA structure. We discover simple sequence and spacing rules that determine the ability of point mutations to impact RSSs. Selective depletion of 'riboSNitches' versus structurally synonymous variants at precise locations suggests selection for specific RNA shapes at thousands of sites, including 3' untranslated regions, binding sites of microRNAs and RNA-binding proteins genome-wide. These results highlight the potentially broad contribution of RNA structure and its variation to gene regulation.

Comment in Molecular biology: A second layer of information in RNA. [Nature. 2014]


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3)Phys Rev Lett. 2013 Dec 6;111(23):232002. Epub 2013 Dec 4.

Measurement of Top Quark Polarization in Top-Antitop Events from Proton-Proton

Collisions at sqrt[s]=7 TeV Using the ATLAS Detector.

This Letter presents measurements of the polarization of the top quark in top-antitop quark pair events, using 4.7 fb^{-1} of proton-proton collision data recorded with the ATLAS detector at the Large Hadron Collider at sqrt[s]=7 TeV. Final states containing one or two isolated leptons

(electrons or muons) and jets are considered. Two measurements of α_{ℓ}P, the product of the leptonic spin-analyzing power and the top quark polarization, are performed assuming that the polarization is introduced by either a CP conserving or a maximally CP violating production process. The measurements obtained, α_{ℓ}P_{CPC}=-0.035±0.014(stat)±0.037(syst) and

α_{ℓ}P_{CPV}=0.020±0.016(stat)_{-0.017}^{+0.013}(syst), are in good agreement with the standard model prediction of negligible top quark polarization.


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4)Methods Mol Biol. 2014;1109:1-22. doi: 10.1007/978-1-4614-9437-9_1.

Reporter gene technologies for imaging cell fates in hematopoiesis.

Kusy S, Contag CH.

Advances in noninvasive imaging technologies that allow for in vivo dynamic monitoring of cells and cellular function in living research subjects have revealed new insights into cell biology in the context of intact organs and their native environment. In the field of hematopoiesis and stem cell research, studies of cell trafficking involved in injury repair and hematopoietic engraftment have made great progress using these new tools. Stem cells present unique challenges for imaging since after transplantation, they proliferate dramatically and differentiate.

Therefore, the imaging modality used needs to have a large dynamic range, and the genetic regulatory elements used need to be stably expressed during differentiation. Multiple imaging technologies using different modalities are available, and each varies in sensitivity, ease of data acquisition, signal to noise ratios (SNR), substrate availability, and other parameters that affect utility for monitoring cell fates and function. For a given application, there may be several different approaches that can be used. For mouse models, clinically validated technologies such as magnetic resonance imaging (MRI) and positron emission tomography (PET) have been joined by optical imaging techniques such as in vivo bioluminescence imaging (BLI) and fluorescence imaging (FLI), and all have been used to monitor bone marrow and stem cells after transplantation into mice. Photoacoustic imaging that utilizes the sound created by the thermal expansion of absorbed light to generate an image best represents hybrid technologies. Each

modality requires that the cells of interest be marked with a genetic reporter that acts as a label making them uniquely visible using that technology. For each modality, there are several labels to choose from. Multiple methods for applying these different labels are available. This chapter provides an overview of the imaging technologies and commonly used labels for each, as well as detailed protocols for gene delivery into hematopoietic cells for the purposes of applying these specific labels to cell trafficking. The goal of this chapter is to provide adequate background information to allow the design and implementation of an experimental system for in vivo imaging in mice.PMID: 24473775 [PubMed - in process]

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5)J Pediatr. 2014 Jan 25. pii: S0022-3476(13)01560-6. doi: 10.1016/j.jpeds.2013.12.014. [Epub ahead of print]

Developmental Outcomes of Very Preterm Infants with Tracheostomies.

Demauro SB1, D'Agostino JA2, Bann C3, Bernbaum J4, Gerdes M4, Bell EF5, Carlo WA6,

D'Angio CT3, Das A7, Higgins R8, Hintz SR9, Laptook AR10, Natarajan G11, Nelin L12,

Poindexter BB13, Sanchez PJ14, Shankaran S11, Stoll BJ15, Truog W16, Van Meurs KP9, Vohr

B10, Walsh MC17, Kirpalani H4; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.

OBJECTIVES:To evaluate the neurodevelopmental outcomes of very preterm (<30 weeks) infants who underwent tracheostomy.

STUDY DESIGN:Retrospective cohort study from 16 centers of the Eunice Kennedy Shriver

National Institute of Child Health and Human Development Neonatal Research Network over 10 years (2001-2011). Infants who survived to at least 36 weeks (N = 8683), including 304 infants with tracheostomies, were studied. Primary outcome was death or neurodevelopmental impairment (NDI; a composite of ≥1 of developmental delay, neurologic impairment, profound hearing loss, severe visual impairment) at a corrected age of 18-22 months. Outcomes were compared using multiple logistic regression. We assessed the impact of timing by comparing outcomes of infants who underwent tracheostomy before and after 120 days of life.

RESULTS:Tracheostomies were associated with all neonatal morbidities examined and with most adverse neurodevelopmental outcomes. Death or NDI occurred in 83% of infants with tracheostomies and 40% of those without (OR adjusted for center 7.0, 95% CI 5.2-9.5). After adjustment for potential confounders, odds of death or NDI remained higher (OR 3.3, 95% CI

2.4-4.6), but odds of death alone were lower (OR 0.4, 95% CI 0.3-0.7) among infants with tracheostomies. Death or NDI was lower in infants who received their tracheostomies before, rather than after, 120 days of life (aOR 0.5, 95% CI 0.3-0.9).

CONCLUSIONS:Tracheostomy in preterm infants is associated with adverse developmental outcomes and cannot mitigate the significant risk associated with many complications of prematurity. These data may inform counseling about tracheostomy in this vulnerable population. Copyright © 2014 Mosby, Inc. All rights reserved.

KEYWORDS:BPD, Bayley, Bayley Scales of Infant Development, Bronchopulmonary dysplasia, Eunice Kennedy Shriver National Institute of Child Health and Human Development,

IVH, Intraventricular hemorrhage, NDI, NEC, NICHD, NRN, Necrotizing enterocolitis,

Neonatal Research Network, Neurodevelopmental impairment, ROP, Retinopathy of prematurity

PMID: 24472229 [PubMed - as supplied by publisher]

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6)Respir Med. 2014 Jan 15. pii: S0954-6111(14)00025-0. doi: 10.1016/j.rmed.2014.01.005.

[Epub ahead of print]

Complement components as potential therapeutic targets for asthma treatment.

Khan MA1, Nicolls MR2, Surguladze B3, Saadoun I4.

Asthma is the most common respiratory disorder, and is characterized by distal airway inflammation and hyperresponsiveness. This disease challenges human health because of its increasing prevalence, severity, morbidity, and the lack of a proper and complete cure. Asthma is characterized by TH2-skewed inflammation with elevated pulmonary levels of IL-4, IL-5, and

IL-13 levels. Although there are early forays into targeting TH2 immunity, less-specific corticosteroid therapy remains the immunomodulator of choice. Innate immune injury mediated by complement components also act as potent mediators of the allergic inflammatory responses and offer a new and exciting possibility for asthma immunotherapy. The complement cascade consists of a number of plasma- and membrane-bound proteins, and the cleavage products of these proteins (C3 and C5) regulate the magnitude of adaptive immune responses. Complement protein are responsible for many pathophysiological features of asthma, including inflammatory cell infiltration, mucus secretion, increases in vascular permeability, and smooth muscle cell contraction. This review highlights the complement-mediated injury during asthma inflammation, and how blockade of active complement mediators may have therapeutic application. Copyright © 2014 Elsevier Ltd. All rights reserved.

KEYWORDS:AHR, ASM, Anaphylatoxins, Asthma, BAL, Complement mediated injury, MAC,

Treg, airway hyperresponsiveness, airway smooth muscle, bronchoalveolar lavage, membrane attack complex, regulatory T cells


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7)Aliment Pharmacol Ther. 2014 Jan 27. doi: 10.1111/apt.12629. [Epub ahead of print]

Tenofovir is superior to entecavir for achieving complete viral suppression in HBeAgpositive chronic hepatitis B patients with high HBV DNA.

Gao L, Trinh HN, Li J, Nguyen MH.

BACKGROUND:Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are the two first-line anti-viral therapies for chronic hepatitis B (CHB); however, there are limited studies directly comparing their effectiveness.

AIM:To compare the effectiveness of ETV and TDF in nucleos(t)ide-naïve CHB patients with high hepatitis B virus (HBV) DNA levels, defined as serum HBV DNA greater than 6 log10

IU/mL.

METHODS:We performed a retrospective multicentre cohort study of adult CHB patients who were seen between 2009 and 2012 at four Northern California community gastroenterology and hepatology clinics.

RESULTS:We identified 59 consecutive patients treated with TDF and 216 patients treated with

ETV. Pre-treatment characteristics were similar between the two groups. Among HBeAgnegative patients, there was no significant difference in viral suppression rates between ETV and

TDF (P = 0.72). In contrast, among HBeAg-positive patients, those treated with TDF achieved viral suppression significantly more rapidly than those treated with ETV (P < 0.0001); the

Kaplan-Meier estimated probability of complete suppression was 18% vs. 11% at 6 months, 51% vs. 28% at 12 months and 72% vs. 39% at 18 months respectively. Multivariate Cox proportional

hazards analysis indicated that treatment with TDF compared to ETV was a significant predictor of viral suppression, but only for HBeAg-positive patients (HR = 2.59; 95% CI 1.58-4.22; P <

0.001).

CONCLUSION:Tenofovir is significantly more effective than entecavir for achieving complete viral suppression in HBeAg-positive, nucleos(t)ide-naïve chronic hepatitis B patients with HBV

DNA greater than 6 log10 IU/mL. © 2014 John Wiley & Sons Ltd.


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8)Int J Semant Web Inf Syst. 2013;9(1):45-78.

PragmatiX: An Interactive Tool for Visualizing the Creation Process Behind

Collaboratively Engineered Ontologies.

Walk S1, Pöschko J1, Strohmaier M1, Andrews K2, Tudorache T3, Noy NF3, Nyulas C3,

Musen MA3.

With the emergence of tools for collaborative ontology engineering, more and more data about the creation process behind collaborative construction of ontologies is becoming available.

Today, collaborative ontology engineering tools such as Collaborative Protégé offer rich and structured logs of changes, thereby opening up new challenges and opportunities to study and analyze the creation of collaboratively constructed ontologies. While there exists a plethora of visualization tools for ontologies, they have primarily been built to visualize aspects of the final product (the ontology) and not the collaborative processes behind construction (e.g. the changes made by contributors over time). To the best of our knowledge, there exists no ontology visualization tool today that focuses primarily on visualizing the history behind collaboratively constructed ontologies. Since the ontology engineering processes can influence the quality of the final ontology, we believe that visualizing process data represents an important stepping-stone towards better understanding of managing the collaborative construction of ontologies in the future. In this application paper, we present a tool - PragmatiX - which taps into structured change logs provided by tools such as Collaborative Protégé to visualize various pragmatic aspects of collaborative ontology engineering. The tool is aimed at managers and leaders of collaborative ontology engineering projects to help them in monitoring progress, in exploring issues and problems, and in tracking quality-related issues such as overrides and coordination among contributors. The paper makes the following contributions: (i) we present PragmatiX, a tool for visualizing the creation process behind collaboratively constructed ontologies (ii) we illustrate the functionality and generality of the tool by applying it to structured logs of changes of two large collaborative ontology-engineering projects and (iii) we conduct a heuristic evaluation of the tool with domain experts to uncover early design challenges and opportunities for improvement. Finally, we hope that this work sparks a new line of research on visualization tools for collaborative ontology engineering projects.

KEYWORDS:Collaborative Ontology Engineering, ontology engineering visualization, ontology evaluation, ontology monitoring, ontology tool, pragmatic analysis

PMID: 24465189 [PubMed] PMCID: PMC3901413

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9)Curr Opin Imunol. 2013 Dec 8;26C:115-122. doi: 10.1016/j.coi.2013.11.005. [Epub ahead of print]

HLA-DM and HLA-DO, key regulators of MHC-II processing and presentation.

Mellins ED1, Stern LJ2.

Peptide loading of class II MHC molecules in endosomal compartments is regulated by HLA-

DM. HLA-DO modulates HLA-DM function, with consequences for the spectrum of MHCbound epitopes presented at the cell surface for interaction with T cells. Here, we summarize and discuss recent progress in investigating the molecular mechanisms of action of HLA-DM and

HLA-DO and in understanding their roles in immune responses. Key findings are the longawaited structures of HLA-DM in complex with its class II substrate and with HLA-DO, and observation of a novel phenotype - autoimmunity combined with immunodeficiency - in mice lacking HLA-DO. We also highlight several areas where gaps persist in our knowledge about this pair of proteins and their molecular biology and immunobiology.

Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.


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10)J Allergy clin Immunol. 2014 Jan 22. pii: S0091-6749(13)01851-4. doi:

10.1016/j.jaci.2013.11.030. [Epub ahead of print]

Mechanisms of vitamin D3 metabolite repression of IgE-dependent mast cell activation.

Yip KH1, Kolesnikoff N1, Yu C2, Hauschild N1, Taing H2, Biggs L1, Goltzman D3, Gregory

PA1, Anderson PH4, Samuel MS5, Galli SJ6, Lopez AF5, Grimbaldeston MA7.

BACKGROUND:Mast cells have gained notoriety based on their detrimental contributions to

IgE-mediated allergic disorders. Although mast cells express the vitamin D receptor (VDR), it is not clear to what extent 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3) or its predominant inactive precursor metabolite in the circulation, 25-hydroxyvitamin D3 (25OHD3), can influence IgEmediated mast cell activation and passive cutaneous anaphylaxis (PCA) in vivo.

OBJECTIVE:We sought to assess whether the vitamin D3 metabolites 25OHD3 and

1α,25(OH)2D3 can repress IgE-dependent mast cell activation through mast cell-25hydroxyvitamin D-1α-hydroxylase (CYP27B1) and mast cell-VDR activity.

METHODS:We measured the extent of vitamin D3 suppression of IgE-mediated mast cell degranulation and mediator production in vitro, as well as the vitamin D3-induced curtailment of

PCA responses in WBB6F1-KitW/W-v or C57BL/6J-KitW-sh/W-sh mice engrafted with mast cells that did or did not express VDR or CYP27B1.

RESULTS:Here we show that mouse and human mast cells can convert 25OHD3 to

1α,25(OH)2D3 through CYP27B1 activity and that both of these vitamin D3 metabolites suppressed IgE-induced mast cell-derived proinflammatory and vasodilatory mediator production in a VDR-dependent manner in vitro. Furthermore, epicutaneously applied vitamin

D3 metabolites significantly reduced the magnitude of skin swelling associated with IgEmediated PCA reactions in vivo; a response that required functional mast cell-VDRs and mast cell-CYP27B1.

CONCLUSION:Taken together, our findings provide a mechanistic explanation for the antiinflammatory effects of vitamin D3 on mast cell function by demonstrating that mast cells can actively metabolize 25OHD3 to dampen IgE-mediated mast cell activation in vitro and in vivo.

Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by

Mosby, Inc. All rights reserved.

KEYWORDS:1α,25(OH)(2)D(3), 1α,25-Dihydroxyvitamin D(3), 2,4-Dinitrophenol, 25-

Hydroxyvitamin D(3), 25-hydroxyvitamin D-1α-hydroxylase, 25OHD(3), BMCMC, Bone marrow–derived cultured mast cell, CBMC, CYP27B1, Cord blood–derived mast cell, CysLT,

Cysteinyl leukotriene, DMEM, DNP, Dulbecco modified Eagle medium, EPGW, Erk, EtOH,

Ethanol, Ethanol, propylene glycol, and water, Extracellular signal-regulated kinase, FITC,

Fluorescein isothiocyanate, IMDM, IgE, Iscove modified Eagle medium, JNK, Mast cells, NF-

κB, Nuclear factor κB, PBMC, PCA, Passive cutaneous anaphylaxis, Peripheral blood–derived mast cell, TSLP, Thymic stromal lymphopoietin, VDR, Vitamin D receptor, WT, Wild-type, anaphylaxis, c-Jun N-terminal kinase, inflammation, vitamin D receptor, vitamin D(3)


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11)J Vasc Interv Radiol. 2014 Jan 20. pii: S1051-0443(13)01664-3. doi:

10.1016/j.jvir.2013.11.018. [Epub ahead of print]

Limitations of Body Surface Area-Based Activity Calculation for Radioembolization of

Hepatic Metastases in Colorectal Cancer.

Lam MG1, Louie JD2, Abdelmaksoud MH2, Fisher GA3, Cho-Phan CD3, Sze DY4.

PURPOSE:To calculate absorbed radiation doses in patients treated with resin microspheres prescribed by the body surface area (BSA) method and to analyze dose-response and toxicity relationships.

MATERIALS AND METHODS:A retrospective review was performed of 45 patients with colorectal carcinoma metastases who received single-session whole-liver resin microsphere radioembolization. Prescribed treatment activity was calculated using the BSA method. Liver volumes and whole-liver absorbed doses (DWL) were calculated. DWL was correlated with toxicity and radiographic and biochemical response.

RESULTS:The standard BSA-based administered activity (range, 0.85-2.58 GBq) did not correlate with DWL (mean, 50.4 Gy; range, 29.8-74.7 Gy; r = -0.037; P = .809) because liver weight was highly variable (mean, 1.89 kg; range, 0.94-3.42 kg) and strongly correlated with

DWL (r = -0.724; P < .001) but was not accounted for in the BSA method. Patients with larger livers were relatively underdosed, and patients with smaller livers were relatively overdosed.

Patients who received DWL > 50 Gy experienced more toxicity and adverse events (> grade 2 liver toxicity, 46% vs 17%; P < .05) but also responded better to the treatment than patients who received DWL< 50 Gy (disease control, 88% vs 24%; P < .01).

CONCLUSIONS:Using the standard BSA formula, the administered activity did not correlate with DWL. Based on this short-term follow-up after salvage therapy in patients with late stage metastatic colorectal carcinoma, dose-response and dose-toxicity relationships support using a protocol based on liver volume rather than BSA to prescribe the administered activity.

© 2013 Published by SIR on behalf of SIR.

KEYWORDS:(90)Y, (99m)Tc-MAA, BSA, CEA, D(WL), RECIST, REILD, Response

Evaluation Criteria in Solid Tumors, SPECT, body surface area, carcinoembryonic antigen, mCRC, metastatic colorectal carcinoma, radioembolization-induced liver disease, single photon emission computed tomography, technetium-99m macroaggregated albumin, whole-liver absorbed dose, yttrium-90


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12)Neurology. 2014 Jan 22. [Epub ahead of print]

APOE {varepsilon}4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory.

Kerchner GA, Berdnik D, Shen JC, Bernstein JD, Fenesy MC, Deutsch GK, Wyss-Coray T, Rutt

BK.

OBJECTIVES:Using high-resolution structural MRI, we endeavored to study the relationships among APOE ε4, hippocampal subfield and stratal anatomy, and episodic memory.

METHODS:Using a cross-sectional design, we studied 11 patients with Alzheimer disease dementia, 14 patients with amnestic mild cognitive impairment, and 14 age-matched healthy controls with no group differences in APOE ε4 carrier status. Each subject underwent ultra-highfield 7.0-tesla MRI targeted to the hippocampus and neuropsychological assessment.

RESULTS:We found a selective, dose-dependent association of APOE ε4 with greater thinning of the CA1 apical neuropil, or stratum radiatum/stratum lacunosum-moleculare (CA1-SRLM), a hippocampal subregion known to exhibit early vulnerability to neurofibrillary pathology in

Alzheimer disease. The relationship between the ε4 allele and CA1-SRLM thinning persisted after controlling for dementia severity, and the size of other hippocampal subfields and the entorhinal cortex did not differ by APOE ε4 carrier status. Carriers also exhibited worse episodic memory function but similar performance in other cognitive domains compared with noncarriers.

In a statistical mediation analysis, we found support for the hypothesis that CA1-SRLM thinning may link the APOE ε4 allele to its phenotypic effects on memory.

CONCLUSIONS:The APOE ε4 allele segregated dose-dependently and selectively with CA1-

SRLM thinning and worse episodic memory performance in a pool of older subjects across a cognitive spectrum. These findings highlight a possible role for this gene in influencing a critical hippocampal subregion and an associated symptomatic manifestation.


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13)Nat Mater. 2014 Jan 23;13(2):106-9. doi: 10.1038/nmat3868.

Tracking gene and cell fate for therapeutic gain.

Kooreman NG1, Ransohoff JD1, Wu JC2.


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14)Arthritis Rheumatol. 2014 Jan;66(1):101-6. doi: 10.1002/art.38213.

Brief report: carboxypeptidase B serves as a protective mediator in osteoarthritis.

Lepus CM, Song JJ, Wang Q, Wagner CA, Lindstrom TM, Chu CR, Sokolove J, Leung LL,

Robinson WH.

OBJECTIVE:We previously demonstrated that carboxypeptidase B (CPB) protects against joint erosion in rheumatoid arthritis by inactivating complement component C5a. We also found that levels of CPB are abnormally high in the synovial fluid of individuals with another joint disease, osteoarthritis (OA). We undertook this study to investigate whether CPB plays a role in the pathogenesis of OA.

METHODS:We compared the development of OA in CPB-deficient (Cpb2(-/-) ) mice and wildtype mice by subjecting them to medial meniscectomy and histologically assessing cartilage damage, osteophyte formation, and synovitis in the stifle joints 4 months later. We measured levels of proCPB, proinflammatory cytokines, and complement components in synovial fluid samples from patients with symptomatic and radiographic knee OA. Finally, we used enzymelinked immunosorbent assay, flow cytometry, and hemolytic assays to assess the effect of CPB on formation of membrane attack complex (MAC)-a complement effector critical to OA pathogenesis.

RESULTS:Cpb2(-/-) mice developed dramatically greater cartilage damage than did wild-type mice (P < 0.01) and had a greater number of osteophytes (P < 0.05) and a greater degree of synovitis (P < 0.05). In synovial fluid samples from OA patients, high levels of proCPB were associated with high levels of proinflammatory cytokines and complement components, and levels of proCPB correlated positively with those of MAC. In in vitro complement activation assays, activated CPB suppressed the formation of MAC as well as MAC-induced hemolysis.

CONCLUSION:Our data suggest that CPB protects against inflammatory destruction of the joints in OA, at least in part by inhibiting complement activation.

Copyright © 2014 by the American College of Rheumatology.


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15)Blood. 2014 Jan 21. [Epub ahead of print]

B cell receptors expressed by lymphomas of hepatitis C virus (HCV)-infected patients rarely react with the viral proteins.

Ng PP, Kuo CC, Wang S, Einav S, Arcaini L, Paulli M, Portlock CS, Marcotrigiano J, Tarr A,

Ball J, Levy R, Levy S.

Chronic HCV infection has been implicated in the induction and maintenance of B-cell lymphomas. The strongest evidence for this comes from clinical observations of tumor regressions upon anti-viral treatments. Here we used multiple methods to test the hypothesis that the expansion of HCV-specific B cells gives rise to lymphomas. We obtained lymphoma tissues from HCV-infected lymphoma patients, including some that later regressed upon anti-viral treatments. We expressed the lymphoma B-cell receptors (BCRs) as soluble IgGs and membrane

IgMs, and analyzed their reactivity with HCV proteins and with HCV virions. We confirmed previous reports that HCV-associated lymphomas use a restricted immunoglobulin variable region (V) gene repertoire. However, we found no evidence for their binding to the HCV antigens. We conclude that most lymphomas of HCV-infected patients do not arise from B cells aimed at eliminating the virus.PMID: 24449209 [PubMed - as supplied by publisher]

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16)J Exp Med. 2014 Feb 10;211(2):263-80. doi: 10.1084/jem.20111741. Epub 2014 Jan 20.

Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension.

Sawada H, Saito T, Nickel NP, Alastalo TP, Glotzbach JP, Chan R, Haghighat L, Fuchs G,

Januszyk M, Cao A, Lai YJ, Perez Vde J, Kim YM, Wang L, Chen PI, Spiekerkoetter E, Mitani

Y, Gurtner GC, Sarnow P, Rabinovitch M.

Idiopathic pulmonary arterial hypertension (PAH [IPAH]) is an insidious and potentially fatal disease linked to a mutation or reduced expression of bone morphogenetic protein receptor 2

(BMPR2). Because intravascular inflammatory cells are recruited in IPAH pathogenesis, we hypothesized that reduced BMPR2 enhances production of the potent chemokine granulocyte macrophage colony-stimulating factor (GM-CSF) in response to an inflammatory perturbation.

When human pulmonary artery (PA) endothelial cells deficient in BMPR2 were stimulated with tumor necrosis factor (TNF), a twofold increase in GM-CSF was observed and related to enhanced messenger RNA (mRNA) translation. The mechanism was associated with disruption of stress granule formation. Specifically, loss of BMPR2 induced prolonged phospho-p38 mitogen-activated protein kinase (MAPK) in response to TNF, and this increased GADD34-PP1

phosphatase activity, dephosphorylating eukaryotic translation initiation factor (eIF2α), and derepressing GM-CSF mRNA translation. Lungs from IPAH patients versus unused donor controls revealed heightened PA expression of GM-CSF co-distributing with increased TNF and expanded populations of hematopoietic and endothelial GM-CSF receptor α (GM-CSFRα)positive cells. Moreover, a 3-wk infusion of GM-CSF in mice increased hypoxia-induced PAH, in association with increased perivascular macrophages and muscularized distal arteries, whereas blockade of GM-CSF repressed these features. Thus, reduced BMPR2 can subvert a stress granule response, heighten GM-CSF mRNA translation, increase inflammatory cell recruitment, and exacerbate PAH.PMID: 24446489 [PubMed - in process]

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17)Pediatr Infect Dis J. 2014 Jan 17. [Epub ahead of print]

Polymerase Chain Reaction in Cerebrospinal Fluid for the Diagnosis of Congenital

Toxoplasmosis.

Olariu TR, Remington JS, Montoya JG.

BACKGROUND:Congenital toxoplasmosis (CT) can result in visual impairment, hearing loss, serious neurologic sequelae and death in the infant. We studied the potential of the polymerase chain reaction (PCR) in cerebrospinal fluid (CSF) for diagnosis of congenital toxoplasmosis.

METHODS:For this purpose we studied both congenitally infected (diagnosed clinically and serologically) and non-infected infants born to untreated mothers.

RESULTS:The infants ranged in age from 0 to 180 days. CSF PCR was positive in 27 of the 58

(46.5%) congenitally infected infants and was negative in each of the 103 infants without CT.

The frequency of positive CSF PCR varied according to whether infants had major clinical signs of the disease; PCR was positive in 70.9%, 53.3% and 50.9% of those with hydrocephalus, cerebral calcifications and/or eye disease, respectively. Three of six infants who were negative for both IgM and IgA antibodies had a positive PCR in their CSF as the confirmatory test for diagnosis of congenital toxoplasmosis. IgM and IgA antibodies and CSF PCR, when combined, yielded a higher sensitivity for diagnosis of congenital toxoplasmosis when compared with the performance of each test alone.

CONCLUSIONS:Our findings reveal that in infants with clinical and serologic findings suggestive of congenital toxoplasmosis and born to untreated mothers, CSF PCR has the potential to increase the frequency of cases in which the diagnosis is confirmed.


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18)Biochem Pharmacol. 2014 Jan 17. pii: S0006-2952(14)00032-X. doi:

10.1016/j.bcp.2014.01.008. [Epub ahead of print]

Microglial Dysfunction in Brain Aging and Alzheimer's Disease.

Mosher KI1, Wyss-Coray T2.

Microglia, the immune cells of the central nervous system, have long been a subject of study in the Alzheimer's disease (AD) field due to their dramatic responses to the pathophysiology of the disease. With several large-scale genetic studies in the past year implicating microglial molecules in AD, the potential significance of these cells has become more prominent than ever before. As a disease that is tightly linked to aging, it is perhaps not entirely surprising that microglia of the AD brain share some phenotypes with aging microglia. Yet the relative impacts of both conditions on microglia are less frequently considered in concert. Furthermore,

microglial "activation" and "neuroinflammation" are commonly analyzed in studies of neurodegeneration but are somewhat ill-defined concepts that in fact encompass multiple cellular processes. In this review, we have enumerated six distinct functions of microglia and discuss the specific effects of both aging and AD. By calling attention to the commonalities of these two states, we hope to inspire new approaches for dissecting microglial mechanisms.

Copyright © 2014. Published by Elsevier Inc.

KEYWORDS:Aging, Alzheimer's disease, Microglia, Neurodegeneration, Neuroinflammation


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19)J Am Soc Echocardiogr. 2014 Jan 17. pii: S0894-7317(13)00969-3. doi:

10.1016/j.echo.2013.12.011. [Epub ahead of print]

Relationship between Echocardiographic and Magnetic Resonance Derived Measures of

Right Ventricular Size and Function in Patients with Pulmonary Hypertension.

Shiran H1, Zamanian RT2, McConnell MV3, Liang DH4, Dash R4, Heidary S4, Sudini NL5,

Wu JC4, Haddad F4, Yang PC4.

BACKGROUND:Transthoracic echocardiographic (TTE) imaging is the mainstay of clinical practice for evaluating right ventricular (RV) size and function, but its accuracy in patients with pulmonary hypertension has not been well validated.

METHODS:Magnetic resonance imaging (MRI) and TTE images were retrospectively reviewed in 40 consecutive patients with pulmonary hypertension. RV and left ventricular volumes and ejection fractions were calculated using MRI. TTE areas and indices of RV ejection fraction

(RVEF) were compared.

RESULTS:The average age was 42 ± 12 years, with a majority of women (85%). There was a wide range of mean pulmonary arterial pressures (27-81 mm Hg) and RV end-diastolic volumes

(111-576 mL), RVEFs (8%-67 %), and left ventricular ejection fractions (26%-72%) by MRI.

There was a strong association between TTE and MRI-derived parameters: RV end-diastolic area

(by TTE imaging) and RV end-diastolic volume (by MRI), R2 = 0.78 (P < .001); RV fractional area change by TTE imaging and RVEF by MRI, R2 = 0.76 (P < .001); and tricuspid annular plane systolic excursion by TTE imaging and RVEF by MRI, R2 = 0.64 (P < .001). By receiver operating characteristic curve analysis, an RV fractional area change < 25% provided excellent discrimination of moderate systolic dysfunction (RVEF < 35%), with an area under the curve of

0.97 (P < .001). An RV end-diastolic area index of 18 cm2/m2 provided excellent discrimination for moderate RV enlargement (area under the curve, 0.89; P < .001).

CONCLUSIONS:Echocardiographic estimates of RV volume (by RV end-diastolic area) and function (by RV fractional area change and tricuspid annular plane systolic excursion) offer good approximations of RV size and function in patients with pulmonary hypertension and allow the accurate discrimination of normal from abnormal.

Copyright © 2014 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.

KEYWORDS:2D, 3D, Echocardiography, ICC, Intraclass correlation coefficient, LV, LVEF,

Left ventricular, Left ventricular ejection fraction, MRI, Magnetic resonance imaging, PH,

Pulmonary hypertension, ROC, RV, RVEDA, RVEDV, RVEF, RVFAC, RVOT, Receiver operating characteristic, Right ventricle, Right ventricular, Right ventricular ejection fraction,

Right ventricular end-diastolic area, Right ventricular end-diastolic volume, Right ventricular

fractional area change, Right ventricular outflow tract, TAPSE, TTE, Three-dimensional,

Transthoracic echocardiographic, Tricuspid annular plane systolic excursion, Two-dimensional


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20)Nat Methods. 2014 Jan 19. doi: 10.1038/nmeth.2808. [Epub ahead of print]

Objective comparison of particle tracking methods.

Chenouard N1, Smal I2, de Chaumont F3, Maška M4, Sbalzarini IF5, Gong Y5, Cardinale J5,

Carthel C6, Coraluppi S6, Winter M7, Cohen AR7, Godinez WJ8, Rohr K8, Kalaidzidis Y9,

Liang L10, Duncan J10, Shen H11, Xu Y12, Magnusson KE13, Jaldén J13, Blau HM14, Paul-

Gilloteaux P15, Roudot P16, Kervrann C16, Waharte F15, Tinevez JY17, Shorte SL17,

Willemse J18, Celler K18, van Wezel GP18, Dan HW19, Tsai YS19, de Solórzano CO20, Olivo-

Marin JC3, Meijering E2.

Particle tracking is of key importance for quantitative analysis of intracellular dynamic processes from time-lapse microscopy image data. Because manually detecting and following large numbers of individual particles is not feasible, automated computational methods have been developed for these tasks by many groups. Aiming to perform an objective comparison of methods, we gathered the community and organized an open competition in which participating teams applied their own methods independently to a commonly defined data set including diverse scenarios. Performance was assessed using commonly defined measures. Although no single method performed best across all scenarios, the results revealed clear differences between the various approaches, leading to notable practical conclusions for users and developers.


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21)Nat Biotechnol. 2014 Feb;32(2):158-68. doi: 10.1038/nbt.2782. Epub 2014 Jan 19.

The promise and challenge of high-throughput sequencing of the antibody repertoire.

Georgiou G1, Ippolito GC2, Beausang J3, Busse CE4, Wardemann H4, Quake SR5.

Efforts to determine the antibody repertoire encoded by B cells in the blood or lymphoid organs using high-throughput DNA sequencing technologies have been advancing at an extremely rapid pace and are transforming our understanding of humoral immune responses. Information gained from high-throughput DNA sequencing of immunoglobulin genes (Ig-seq) can be applied to detect B-cell malignancies with high sensitivity, to discover antibodies specific for antigens of interest, to guide vaccine development and to understand autoimmunity. Rapid progress in the development of experimental protocols and informatics analysis tools is helping to reduce sequencing artifacts, to achieve more precise quantification of clonal diversity and to extract the most pertinent biological information. That said, broader application of Ig-seq, especially in clinical settings, will require the development of a standardized experimental design framework that will enable the sharing and meta-analysis of sequencing data generated by different laboratories.PMID: 24441474 [PubMed - in process]

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22)Nat Biotechnol. 2014 Feb;32(2):149-57. doi: 10.1038/nbt.2783. Epub 2014 Jan 19.

Beyond model antigens: high-dimensional methods for the analysis of antigen-specific T cells.

Newell EW1, Davis MM2.

Adaptive immune responses often begin with the formation of a molecular complex between a Tcell receptor (TCR) and a peptide antigen bound to a major histocompatibility complex (MHC) molecule. These complexes are highly variable, however, due to the polymorphism of MHC genes, the random, inexact recombination of TCR gene segments, and the vast array of possible self and pathogen peptide antigens. As a result, it has been very difficult to comprehensively study the TCR repertoire or identify and track more than a few antigen-specific T cells in mice or humans. For mouse studies, this had led to a reliance on model antigens and TCR transgenes.

The study of limited human clinical samples, in contrast, requires techniques that can simultaneously survey TCR phenotype and function, and TCR reactivity to many T-cell epitopes.

Thanks to recent advances in single-cell and cytometry methodologies, as well as highthroughput sequencing of the TCR repertoire, we now have or will soon have the tools needed to comprehensively analyze T-cell responses in health and disease.


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23)Exp Gerontol. 2014 Jan 15. pii: S0531-5565(14)00008-4. doi: 10.1016/j.exger.2014.01.005.


Mechanisms shaping the naïve T cell repertoire in the elderly - Thymic involution or peripheral homeostatic proliferation?

Qi Q1, Zhang DW1, Weyand CM1, Goronzy JJ2.

The ability of the human immune system to repel infections is drastically diminished with age.

Elderly individuals are more susceptible to new threats and are less able to control endogenous infections. The thymus, which is the sole source of new T cells, has been proposed as a target for regenerative efforts to improve immune competence, as thymic activity is dramatically reduced after puberty. In this review, we review the role of the thymus in the maintenance of T cell homeostasis throughout life and contrast the differences in mice and humans. We propose that in humans, lack of thymic T cell generation does not explain a decline in T cell receptor diversity nor would thymic rejuvenation restore diversity. Initial studies using next generation sequencing are beginning to establish lower boundaries of T cell receptor diversity. With increasing sequencing depth and the development of new statistical models, we are now in the position to test this model and to assess the impact of age on T cell diversity and clonality.

Published by Elsevier Inc.

KEYWORDS:Aging, Immunosenescence, T cell receptor repertoire, T cells, Thymus


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24)Autoimmun Rev. 2014 Jan 15. pii: S1568-9972(14)00063-9. doi:

10.1016/j.autrev.2014.01.051. [Epub ahead of print]

Putting the value into biosimilar decision making: The judgment value criteria.

Mendes de Abreu M1, Strand V2, Levy RA3, Araujo DV4.

Uncertainties remain the key issue surrounding biosimilars, although decisions regarding their use must be made. The challenges for policymakers, doctors, patients and others seeking to navigate in the uncharted waters of biosimilars must be clarified. At the most basic level, scientific understanding of the issue remains limited and when making decisions, policymakers must consider all those affected by health policy decisions, particularly the ultimate recipients of these medicines: the patients. The biosimilar-value chain relies on measurement of

comparabilities. The goal is to demonstrate how, from a molecular perspective, closely similar they are or are not and how potential small differences may be relevant to clinical outcomes. To critically understand these points, this conceptual paper will present a knowledge-value chain and discuss each dimension assigning value in the decision making process re-utilization of biosimilars. Copyright © 2014 Elsevier B.V. All rights reserved.

KEYWORDS:Biosimilars, Decision process, Immunogenicity, Value chain, Value in health


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25)Annu Rev Immunol. 2014 Jan 15. [Epub ahead of print]

Immunology of Relapse and Remission in Multiple Sclerosis.

Steinman L.

Eighty percent of individuals with multiple sclerosis (MS) initially develop a clinical pattern with periodic relapses followed by remissions, called relapsing-remitting MS (RRMS). This period of fluctuating disease may last for a decade or more. Clinical relapses reflect acute inflammation in the central nervous system (CNS), composed of the brain and spinal cord. Often, different anatomic areas in the CNS are involved each time a relapse occurs, resulting in varied clinical manifestations in each instance. Relapses are nearly always followed by some degree of remission, though recovery to baseline status before the flare is often incomplete. There are nine approved drugs for treatment of RRMS. The most potent drug for inhibiting relapses, the humanized anti-α4 integrin antibody known as Natalizumab, blocks homing of mononuclear cells to the CNS. The mechanisms of action of the approved drugs for RRMS provide a strong foundation for understanding the pathobiology of the relapse. Despite substantial progress in controlling relapses with the current armamentarium of medications, there is much to learn and ever more effective and safe therapies to develop. Expected final online publication date for the

Annual Review of Immunology Volume 32 is March 21, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.


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26)Ann Am Thorac Soc. 2014 Jan;11 Suppl 1:S79. doi: 10.1513/AnnalsATS.201307-240MG.

Aspergillus invasion increases with progressive airway ischemia.

Hsu JL, Jiang X, Khan MA, Sobel RA, Clemons KV, Stevens DA, Nicolls MR.

Background: Despite the prevalence of Aspergillus-related disease, little is known of the hostpathogen interaction. We used a novel orthotopic tracheal transplant model of Aspergillus infection to assess the effects of tissue ischemia and hypoxia on airway infectivity. We hypothesized that Aspergillus invasion would increase with the progressive ischemia of the graft because of the mold's angiotropic nature and its capacity to thrive in hypoxic conditions.

Methods: Fungal burden and depth of invasion were graded histopathologically. We used laser

Doppler flowmetry and FITC-lectin to determine blood perfusion and a fiberoptic microsensor to measure airway tissue oxygen tension. We evaluated differences between syngeneic and allogeneic animals. To evaluate the role of hypoxia-inducible factor (HIF) on Aspergillus invasion, we compared transplants in mice with Von Hippel-Lindau haplodeficiency in Tie2 lineage cells (Tie2+ cell VHL) to wild-type (WT) control mice. Measurements and Main Results:

We demonstrated a high efficacy (80%) for producing a localized tracheal infection at the donorrecipient anastomosis; Aspergillus was more invasive in allogeneic compared with syngeneic

groups. The overall kinetics of both noninfected and infected allografts were similar, demonstrating a progressive loss of perfusion and oxygenation, which reached a nadir by transplant day 10 to 12. The extent of Aspergillus invasion directly correlated with the degree of graft hypoxia and ischemia. Tie2+ cell VHL haplodeficient mice had improved perfusion compared with WT control mice through stabilization of the HIF-1α protein. In Tie2+ cell VHL haplodeficient mice, Aspergillus fumigatus displayed a minimally invasive phenotype, whereas in control mice Aspergillus was highly invasive. Conclusions: For the first time, we identify ischemia as a putative risk factor for Aspergillus invasion. Therapeutic approaches focused on preserving vascular health, including up-regulating HIF expression, may play an important role in limiting Aspergillus infections.PMID: 24437427 [PubMed - in process]

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27)Semin Intervent Radiol. 2013 Mar;30(1):12-20.

Intra-Arterial Therapies for Metastatic Colorectal Cancer.

Wang DS, Louie JD, Sze DY.

Intra-arterial therapies for unresectable hepatic metastases from colorectal cancer include radioembolization (RE) with yttrium-90 microspheres, transarterial chemoembolization (TACE), hepatic arterial infusion, and percutaneous hepatic perfusion using an organ isolation system. In this article, we discuss our approach toward treatment selection, followed by details of how RE and TACE are performed at our institution.

KEYWORDS:colorectal cancer, drug-eluting beads, irinotecan, liver metastases, radioembolization


PMCID: PMC3700785 [Available on 2014/3/1]

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28)J Pediatr. 2014 Jan 13. pii: S0022-3476(13)01508-4. doi: 10.1016/j.jpeds.2013.10.091. [Epub ahead of print]

Urine Protein Biomarkers for the Diagnosis and Prognosis of Necrotizing Enterocolitis in

Infants.

Sylvester KG1, Ling XB2, Liu GY3, Kastenberg ZJ4, Ji J2, Hu Z2, Wu S2, Peng S2, Abdullah

F5, Brandt ML6, Ehrenkranz RA7, Harris MC8, Lee TC6, Simpson BJ7, Bowers C9, Moss RL9.

OBJECTIVES:To test the hypothesis that an exploratory proteomics analysis of urine proteins with subsequent development of validated urine biomarker panels would produce molecular classifiers for both the diagnosis and prognosis of infants with necrotizing enterocolitis (NEC).

STUDY DESIGN:Urine samples were collected from 119 premature infants (85 NEC, 17 sepsis,

17 control) at the time of initial clinical concern for disease. The urine from 59 infants was used for candidate biomarker discovery by liquid chromatography/mass spectrometry. The remaining

60 samples were subject to enzyme-linked immunosorbent assay for quantitative biomarker validation.

RESULTS:A panel of 7 biomarkers (alpha-2-macroglobulin-like protein 1, cluster of differentiation protein 14, cystatin 3, fibrinogen alpha chain, pigment epithelium-derived factor, retinol binding protein 4, and vasolin) was identified by liquid chromatography/mass spectrometry and subsequently validated by enzyme-linked immunosorbent assay. These proteins were consistently found to be either up- or down-regulated depending on the presence, absence, or severity of disease. Biomarker panel validation resulted in a receiver-operator

characteristic area under the curve of 98.2% for NEC vs sepsis and an area under the curve of

98.4% for medical NEC vs surgical NEC.

CONCLUSIONS:We identified 7 urine proteins capable of providing highly accurate diagnostic and prognostic information for infants with suspected NEC. This work represents a novel approach to improving the efficiency with which we diagnose early NEC and identify those at risk for developing severe, or surgical, disease.Copyright © 2014 Mosby, Inc. All rights reserved.

KEYWORDS:A2ML1, Alpha-2-macroglobulin-like protein 1, CD14, CST3, Cluster of differentiation protein 14, Cystatin 3, ELISA, Enzyme-linked immunosorbent assay, FGA,

Fibrinogen alpha chain, IL, LCMS, Liquid chromatography/mass spectrometry, NEC,

Necrotizing enterocolitis, PEDF, Pigment epithelium-derived factor, RET4, ROC, Receiveroperator characteristic, Retinol binding protein 4, VASN, Vasolin, interleukin


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29)J Rheumatol. 2014 Jan 15. [Epub ahead of print]

One-year Efficacy and Safety Results of Secukinumab in Patients With Rheumatoid

Arthritis: Phase II, Dose-finding, Double-blind, Randomized, Placebo-controlled Study.

Genovese MC, Durez P, Richards HB, Supronik J, Dokoupilova E, Aelion JA, Lee SH, Codding

CE, Kellner H, Ikawa T, Hugot S, Ligozio G, Mpofu S.

OBJECTIVE:To evaluate the longer-term safety and efficacy of secukinumab, a fully human monoclonal antiinterleukin-17A antibody, in patients with rheumatoid arthritis.

METHODS:In this 52-week, double-blind, placebo-controlled (up to Week 20) study

(NCT00928512), patients responding inadequately to disease-modifying antirheumatic drugs

(DMARD) or biologics were randomized to receive monthly subcutaneous injections of secukinumab (25, 75, 150, or 300 mg), or placebo. The efficacy and safety results up to Week 20 have been reported previously. Here, efficacy results from Week 20 to 52 and safety results from

Week 20 to 60 are presented.

RESULTS:Of 237 patients randomized, 174 (73.4%) completed the study. Patients with improved American College of Rheumatology (ACR) and 28-joint Disease Activity Score

(DAS28) C-reactive protein (CRP) responses at Week 16 sustained their responses through

Week 52. In patients taking 150 mg of secukinumab, responses were improved through Week 52

(ACR50: Week 16 = 45%, Week 52 = 55%; DAS28-CRP ≤ 2.6: Week 16 = 25%, Week 52 =

40%). The rate of adverse events (AE) from weeks 20 to 60 was 64.8%, with most AE being mild to moderate in severity. The overall rate of infections was 31.9%, most being mild. The most predominant infection was nasopharyngitis, and was not associated with dose or concurrent neutropenia. Serious AE were reported in 21 patients (8.9%). There were 3 reports of malignancies (ovarian, lung, basal cell), and no deaths between weeks 20 and 60.

CONCLUSION:Patients with active RA who failed to respond to DMARD and other biologics showed an improvement after longterm treatment with 150 mg of secukinumab. The frequency of AE remained stable over time and secukinumab had a consistent safety profile over 60 weeks.


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30)Allergy Asthma Clin Immunol. 2014 Jan 15;10(1):1. doi: 10.1186/1710-1492-10-1.

Safety and feasibility of oral immunotherapy to multiple allergens for food allergy.

Bégin P, Winterroth LC, Dominguez T, Wilson SP, Bacal L, Mehrotra A, Kausch B, Trela A,

Hoyte E, O'Riordan G, Seki S, Blakemore A, Woch M, Hamilton RG, Nadeau KC.

BACKGROUND:Thirty percent of children with food allergy are allergic to more than one food.

Previous studies on oral immunotherapy (OIT) for food allergy have focused on the administration of a single allergen at the time. This study aimed at evaluating the safety of a modified OIT protocol using multiple foods at one time.

METHODS:Participants underwent double-blind placebo-controlled food challenges (DBPCFC) up to a cumulative dose of 182 mg of food protein to peanut followed by other nuts, sesame, dairy or egg. Those meeting inclusion criteria for peanut only were started on single-allergen

OIT while those with additional allergies had up to 5 foods included in their OIT mix. Reactions during dose escalations and home dosing were recorded in a symptom diary.

RESULTS:Forty participants met inclusion criteria on peanut DBPCFC. Of these, 15 were mono-allergic to peanut and 25 had additional food allergies. Rates of reaction per dose did not differ significantly between the two groups (median of 3.3% and 3.7% in multi and single OIT group, respectively; p = .31). In both groups, most reactions were mild but two severe reactions requiring epinephrine occurred in each group. Dose escalations progressed similarly in both groups although, per protocol design, those on multiple food took longer to reach equivalent doses per food (median +4 mo.; p < .0001).

CONCLUSIONS:Preliminary data show oral immunotherapy using multiple food allergens simultaneously to be feasible and relatively safe when performed in a hospital setting with trained personnel. Additional, larger, randomized studies are required to continue to test safety and efficacy of multi-OIT.

TRIAL REGISTRATION:Clinicaltrial.gov NCT01490177.

PMID: 24428859 [PubMed] PMCID: PMC3913318

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31)Autoimmun Rev. 2014 Jan 11. pii: S1568-9972(14)00062-7. doi:

10.1016/j.autrev.2014.01.050. [Epub ahead of print]

The IL-23/IL-17 axis in psoriatic arthritis.

Suzuki E1, Mellins ED2, Gershwin ME1, Nestle FO3, Adamopoulos IE4.

Psoriatic arthritis (PsA) is an immune-mediated chronic inflammatory disease, affecting both the skin and joints. Disease progression is associated with aberrant cytokine expression, and TNF blockade is the most successful therapy to date. However, not all patients are responsive to anti-

TNF treatment, highlighting the need to better understand the cellular and molecular mechanisms that govern the disease. PsA associations with single nucleotide polymorphisms in IL23R as well as TRAF3IP2 (Act1), a molecule downstream of the IL-17 receptor (IL-17R), have linked the IL-

23/IL-17 axis to disease pathology. Although both cytokines are implicated in PsA, a full picture of their cellular targets and pathogenic mechanisms has not yet emerged. In this review, we focus on the IL-23/IL-17 axis-elicited responses mediated by osteoclasts, keratinocytes and neutrophils. Expanding our understanding of the cellular and molecular mechanisms that dictate pathogenicity in PsA will contribute to developing novel treatment strategies to combat disease.

Copyright © 2014 Elsevier B.V. All rights reserved.

KEYWORDS:IL-17, IL-23, Interleukin-17A, NF-κB, PsA, Psoriatic arthritis, nuclear factor kappa-light-chain-enhancer of activated B cells, psoriatic arthritis


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32)Br J Cancer. 2014 Jan 14. doi: 10.1038/bjc.2013.830. [Epub ahead of print]

Inhibition of CXCR7 extends survival following irradiation of brain tumours in mice and rats.

Walters MJ1, Ebsworth K1, Berahovich RD1, Penfold ME1, Liu SC2, Al Omran R2, Kioi M2,

Chernikova SB2, Tseng D2, Mulkearns-Hubert EE3, Sinyuk M3, Ransohoff RM4, Lathia JD5,

Karamchandani J6, Koort HE7, Zhang P1, Powers JP1, Jaen JC1, Schall TJ1, Merchant M8,

Recht L8, Brown JM2.

Background:In experimental models of glioblastoma multiforme (GBM), irradiation (IR) induces local expression of the chemokine CXCL12/SDF-1, which promotes tumour recurrence. The role of CXCR7, the high-affinity receptor for CXCL12, in the tumour's response to IR has not been addressed.Methods:We tested CXCR7 inhibitors for their effects on tumour growth and/or animal survival post IR in three rodent GBM models. We used immunohistochemistry to determine where CXCR7 protein is expressed in the tumours and in human GBM samples. We used neurosphere formation assays with human GBM xenografts to determine whether CXCR7 is required for cancer stem cell (CSC) activity in vitro.Results:CXCR7 was detected on tumour cells and/or tumour-associated vasculature in the rodent models and in human GBM. In human

GBM, CXCR7 expression increased with glioma grade and was spatially associated with

CXCL12 and CXCL11/I-TAC. In the rodent GBM models, pharmacological inhibition of

CXCR7 post IR caused tumour regression, blocked tumour recurrence, and/or substantially prolonged survival. CXCR7 expression levels on human GBM xenograft cells correlated with neurosphere-forming activity, and a CXCR7 inhibitor blocked sphere formation by sorted

CSCs.Conclusions:These results indicate that CXCR7 inhibitors could block GBM tumour recurrence after IR, perhaps by interfering with CSCs.British Journal of Cancer advance online publication, 14 January 2014; doi:10.1038/bjc.2013.830 www.bjcancer.com.


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33)PLoS One. 2014 Jan 8;9(1):e83867. doi: 10.1371/journal.pone.0083867. eCollection 2014.

Health and Exercise-Related Medical Issues among 1,212 Ultramarathon Runners:

Baseline Findings from the Ultrarunners Longitudinal TRAcking (ULTRA) Study.

Hoffman MD1, Krishnan E2.

Regular exercise is associated with substantial health benefits; however, little is known about the health impact of extreme levels of exercise. This study examined the prevalence of chronic diseases, health-care utilization, and risk factors for exercise-related injuries among ultramarathon runners. Retrospective, self-reported enrollment data from an ongoing longitudinal observational study of 1,212 active ultramarathon runners were analyzed. The most prevalent chronic medical conditions were allergies/hay fever (25.1%) and exercise-induced asthma

(13.0%), but there was a low prevalence of serious medical issues including cancers (4.5%), coronary artery disease (0.7%), seizure disorders (0.7%), diabetes (0.7%), and human immunodeficiency virus (HIV) infection (0.2%). In the year preceding enrollment, most (64.6%) reported an exercise-related injury that resulted in lost training days (median of 14 days), but little nonattendance of work or school due to illness, injury, or exercise-related medical conditions (medians of 0 days for each). The knee was the most common area of exercise-related

injury. Prior year incidence of stress fractures was 5.5% with most (44.5%) involving the foot.

Ultramarathon runners who sustained exercise-related injuries were younger (p<0.001) and less experienced (p<0.01) than those without injury. Stress fractures were more common (p<0.01) among women than men. We conclude that, compared with the general population, ultramarathon runners appear healthier and report fewer missed work or school days due to illness or injury. Ultramarathon runners have a higher prevalence of asthma and allergies than the general population, and the prevalence of serious medical issues was nontrivial and should be recognized by those providing medical care to these individuals. Ultramarathon runners, compared with shorter distance runners, have a similar annual incidence of exercise-related injuries but higher proportion of stress fractures involving the foot, and it is the younger and less experienced ultramarathoners who appear most at risk for injury.

PMID: 24416176 [PubMed - in process] PMCID: PMC3885517

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34)Liver Transpl. 2014 Jan 10. doi: 10.1002/lt.23820. [Epub ahead of print]

Ethnic disparities and liver transplantation rates in hepatocellular carcinoma patients in the recent era: Results from the SEER registry.

Wong RJ, Devaki P, Nguyen L, Cheung R, Nguyen MH.

Hepatocellular carcinoma (HCC) is a leading cause of morbidity and mortality. Following implementation of the model for end stage liver disease (MELD) system, rates of liver transplantation (LT) for HCC patients increased. However, it is not clear if this trend continued into the recent time period. Utilizing the Surveillance, Epidemiology, and End Results 1998-

2010 registry, we retrospectively analyzed trends in LT among HCC patients using three time periods: 1998-2003, 2004-2008, and 2009-2010). A total of 60,772 HCC patients were identified. With more recent time periods, the proportion of localized stage HCC increased

(45.0% in 1998-2003 vs. 50.4% in 2004-2008 vs. 51.7% in 2009-2010, p<0.001). While the proportion of HCC patients within Milan criteria also increased with time (22.8% vs. 31.8% vs.

37.1%, p<0.001), the proportion of these patients receiving LT increased from 1998-2003 to

2004-2008, but decreased in 2009-2010. However, the actual frequency of LT was similar in

2004-2008 (208.2/year) and 2009-2010 (201.5/year). Multivariate logistic regression, inclusive of sex, age, ethnicity, Milan criteria, tumor stage, tumor size and number, and time periods, demonstrated a lower likelihood of LT in 2009-2010 compared to 1998-2003 (OR 0.63, 95% CI

0.57-0.71). Blacks (OR 0.48, 95% CI 0.41-0.56), Asians (OR 0.65, 95% CI 0.57-0.73), and

Hispanics (OR 0.76, 95% CI 0.68-0.85) were all less likely to receive LT compared to non-

Hispanic whites. Despite increasing proportion of earlier staged HCC diagnosed, LT rates are declining in the recent era. In addition, ethnic minorities were significantly less likely to receive

LT. The growing imbalance between the number of transplant-eligible HCC patients and the shortage of donor livers emphasizes the need to improve donor availability and curative alternatives to LT. Liver Transpl , 2014. © 2014 AASLD.©2014. American Association for the

Study of Liver Diseases.

KEYWORDS:MELD, Milan criteria, donor shortage, racial disparities, transplant waitlist


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35)J Acquir Immune Defic Syndr. 2014 Jan 9. [Epub ahead of print]

Systemic Cytokine Levels Show Limited Correlation with Risk of HIV-1 Acquisition.

Lehman DA, Ronen K, Blish CA, Baeten JM, Jalalian-Lechak Z, Jaoko W, Mandaliya K,

Richardson BA, McClelland RS, Overbaugh J.

It has been hypothesized that immune activation and inflammation may increase HIV-1 susceptibility and that cytokines may be useful biomarkers for risk. Within a prospective cohort, we conducted a nested case-control analysis of plasma cytokine levels among women who acquired HIV-1 <3 months after sampling, compared to three different control groups. We observed associations between lower IL-6 and IL-10 and higher IL-7 levels with HIV-1 acquisition, however these associations were inconsistent when comparing to different control groups. Inconsistent results within our study and among prior studies suggest that reproducible findings are needed before cytokines are useful biomarkers for HIV-1 susceptibility.


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36)Int J Radiat Oncol Biol Phys. 2014 Feb 1;88(2):254-62. doi: 10.1016/j.ijrobp.2013.07.022.

The Tumor Radiobiology of SRS and SBRT: Are More Than the 5 Rs Involved?

Brown JM1, Carlson DJ2, Brenner DJ3.

Stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiation therapy (SABR), are rapidly becoming accepted practice for the radiation therapy of certain tumors. Typically, SRS and SBRT involve the delivery of 1 or a few large-dose fractions of 8 to 30 Gy per fraction: a major paradigm shift from radiation therapy practice over the past 90 years, when, with relatively large amounts of normal tissues receiving high doses, the goal was to maximize tumor response for an acceptable level of normal tissue injury. The development of SRS and SBRT have come about because of technologic advances in image guidance and treatment delivery techniques that enable the delivery of large doses to tumors with reduced margins and high gradients outside the target, thereby minimizing doses to surrounding normal tissues. Because the results obtained with SRS and SBRT have been impressive, they have raised the question whether classic radiobiological modeling, and the linear-quadratic (LQ) model, are appropriate for large doses per fraction. In addition to objections to the LQ model, the possibility of additional biological effects resulting from endothelial cell damage, enhanced tumor immunity, or both have been raised to account for the success of SRS and SBRT. In this review, we conclude that the available preclinical and clinical data do not support a need to change the LQ model or to invoke phenomena over and above the classic 5 Rs of radiobiology and radiation therapy, with the likely exception that for some tumors high doses of irradiation may produce enhanced antitumor immunity. Thus, we suggest that for most tumors, the standard radiobiology concepts of the 5 Rs are sufficient to explain the clinical data, and the excellent results obtained from clinical studies are the result of the much larger biologically effective doses that are delivered with SRS and SBRT.Copyright © 2014 Elsevier

Inc. All rights reserved.PMID: 24411596 [PubMed - in process] PMCID: PMC3893711

[Available on 2015/2/1]

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37)Genet Med. 2014 Jan 9. doi: 10.1038/gim.2013.194. [Epub ahead of print]

Noninvasive prenatal diagnosis in a fetus at risk for methylmalonic acidemia.

Gu W1, Koh W1, Blumenfeld YJ2, El-Sayed YY2, Hudgins L3, Hintz SR4, Quake SR5.

Purpose:Prenatal diagnosis of fetal Mendelian disorders can benefit from noninvasive approaches using fetal cell-free DNA in maternal plasma. Detecting metabolic disorders before birth can result in immediate treatment postpartum in order to optimize outcome.Methods:We developed a mathematical model and an experimental methodology to analyze the case of a fetus with a 25% risk of inheriting two known mutations in MUT that cause methylmalonic acidemia.

To accomplish this, we measured allelic counts at the mutation sites and the fetal fraction from high minor-allele-frequency single-nucleotide polymorphism positions.Results:By counting linked alleles, the test was able to distinguish 11 positive markers from the negative controls and thereby determine whether or not the mutations carried by the parents were inherited by the fetus. For a homozygous fetus, the Z-score of the mutation site was 5.97, whereas the median Zscore of all the linked alleles was 4.56 when all negative (heterozygous) controls had a Z-score

<2.5.Conclusion:The application of this methodology for diagnosing methylmalonic acidemia shows that this is a cost-effective and noninvasive approach to diagnosing known mutations related to Mendelian disorders in the fetus.Genet Med advance online publication 9 January

2014Genetics in Medicine (2014); doi:10.1038/gim.2013.194.PMID: 24406457 [PubMed - as supplied by publisher]

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38)Arthritis Rheum. 2014 Jan 8. doi: 10.1002/art.38342. [Epub ahead of print]

1extending the floor and the ceiling for assessment of physical function.

Fries JF, Lingala B, Siemons L, Glas CA, Cella D, Hussain YN, Bruce B, Krishnan E.

Objective. The objective of the current study was to improve the assessment of physical function by improving the precision of assessment at the floor (extremely poor function) and at the ceiling

(extremely good health) of the health continuum. Methods. Under the NIH PROMIS program, we developed new physical function floor and ceiling items to supplement the existing item bank. Using item response theory (IRT) and the standard PROMIS methodology, we developed

30 floor items and 26 ceiling items and administered them during a 12-month prospective observational study of 737 individuals at the extremes of health status. Change over time was compared across anchor instruments and across items by means of effect sizes. Using the observed changes in scores, we back-calculated sample size requirements for the new and comparison measures. Results. We studied 444 subjects with chronic illness and/or extreme age, and 293 generally fit subjects including athletes in training. IRT analyses confirmed that the new floor and ceiling items outperformed reference items (p<0.001). The estimated post-hoc sample size requirements were reduced by a factor of two to four at the floor and a factor of two at the ceiling. Conclusion. Extending the range of physical function measurement can substantially improve measurement quality, can reduce sample size requirements and improve research efficiency. The paradigm shift from Disability to Physical Function includes the entire spectrum of physical function, signals improvement in the conceptual base of outcome assessment, and may be transformative as medical goals more closely approach societal goals for health. © 2013

American College of Rheumatology.Copyright © 2013 American College of Rheumatology.


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39)Theranostics. 2013 Dec 9;3(11):914-5. doi: 10.7150/thno.6333. eCollection 2013.

Cardiovascular molecular imaging as a tool to study biology.

Rodriguez-Porcel M1, Wu JC2.

PMID: 24396501 [PubMed - in process] PMCID: PMC3879107

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40)Ophthalmology. 2014 Jan 4. pii: S0161-6420(13)01111-1. doi: 10.1016/j.ophtha.2013.11.029.


Intraocular Pressure in Eyes Receiving Monthly Ranibizumab in 2 Pivotal Age-Related

Macular Degeneration Clinical Trials.

Bakri SJ1, Moshfeghi DM2, Francom S3, Rundle AC3, Reshef DS3, Lee PP4, Schaeffer C3,

Rubio RG3, Lai P3.

PURPOSE:To characterize preinjection intraocular pressure (IOP) in eyes receiving monthly ranibizumab versus sham or verteporfin photodynamic therapy (PDT) for age-related macular degeneration (AMD).

DESIGN:Post hoc analysis of IOP data from 2 phase 3 clinical trials, the Minimally

Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular

AMD (MARINA) and the Anti-VEGF Antibody for the Treatment of Predominantly Classic

Choroidal Neovascularization in AMD (ANCHOR) trial.

PARTICIPANTS:All safety-evaluable patients who received 1 or more injections of sham or

PDT or of ranibizumab and had 1 or more postbaseline IOP measurements recorded for the study eye.

METHODS:Preinjection IOP measurements for study eyes (n = 1125) and fellow eyes in

MARINA and ANCHOR at baseline and at each monthly visit through month 24 were analyzed.

MAIN OUTCOME MEASURES:End points evaluated were maximum preinjection IOP during the 24-month treatment period; any occurrence of absolute preinjection IOP of 21 mmHg or more, 25 mmHg or more, or 30 mmHg or more; any occurrence of IOP increase of 6 mmHg or more, 8 mmHg or more, or 10 mmHg or more from baseline; any combination of IOP increase of

6 mmHg or more or 8 mmHg or more from baseline with concurrent absolute preinjection IOP of

21 mmHg or more or 25 mmHg or more; glaucoma-related adverse events; new glaucoma medications used for 45 days or more; and glaucoma filtration or laser surgeries.

RESULTS:Across treatment groups, 60.1% to 70.9% of study eyes had a maximum preinjection

IOP of less than 21 mmHg. Comparing ranibizumab 0.5 mg versus sham or PTD treatment, respectively: 39.9% versus 29.1% and 10.9% versus 5.1% had maximum preinjection IOPs of 21 mmHg or more or 25 mmHg or more, respectively; 44.1% versus 29.9% and 24.2% versus

13.6% had IOP increases from baseline of 6 mmHg or more or 8 mmHg or more, respectively;

26.1% versus 13.6% and 16.8% versus 9.0% had 1 or more IOP increase from baseline of 6 mmHg or more or 8 mmHg or more, respectively, with a concurrent IOP of 21 mmHg or more;

9.6% versus 3.7% and 7.5% versus 2.4% had 1 or more IOP increase from baseline of 6 mmHg or more or 8 mmHg or more, respectively, with a concurrent IOP of 25 mmHg or more. No differences were observed in fellow eyes.

CONCLUSIONS:Most ranibizumab-treated eyes did not experience sustained preinjection IOP of 21 mmHg or more (>2 consecutive visits) over 24 months. When evaluating the combined

IOP end point, more ranibizumab-treated eyes had 1 or more IOP increase from baseline of 6 mmHg or more or 8 mmHg or more, with concurrent highest IOPs of 21 mmHg or more and 25 mmHg or more versus sham or PDT. Intraocular pressure should be monitored in eyes receiving ranibizumab.

Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.


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41)Nature. 2013 Dec 25. doi: 10.1038/nature12875. [Epub ahead of print]

Selection and evaluation of clinically relevant AAV variants in a xenograft liver model.

Lisowski L1, Dane AP2, Chu K3, Zhang Y3, Cunningham SC4, Wilson EM5, Nygaard S6,

Grompe M6, Alexander IE7, Kay MA3.

Recombinant adeno-associated viral (rAAV) vectors have shown early promise in clinical trials.

The therapeutic transgene cassette can be packaged in different AAV capsid pseudotypes, each having a unique transduction profile. At present, rAAV capsid serotype selection for a specific clinical trial is based on effectiveness in animal models. However, preclinical animal studies are not always predictive of human outcome. Here, in an attempt to further our understanding of these discrepancies, we used a chimaeric human-murine liver model to compare directly the relative efficiency of rAAV transduction in human versus mouse hepatocytes in vivo. As predicted from preclinical and clinical studies, rAAV2 vectors functionally transduced mouse and human hepatocytes at equivalent but relatively low levels. However, rAAV8 vectors, which are very effective in many animal models, transduced human hepatocytes rather poorlyapproximately 20 times less efficiently than mouse hepatocytes. In light of the limitations of the rAAV vectors currently used in clinical studies, we used the same murine chimaeric liver model to perform serial selection using a human-specific replication-competent viral library composed of DNA-shuffled AAV capsids. One chimaeric capsid composed of five different parental AAV capsids was found to transduce human primary hepatocytes at high efficiency in vitro and in vivo, and provided species-selected transduction in primary liver, cultured cells and a hepatocellular carcinoma xenograft model. This vector is an ideal clinical candidate and a reagent for gene modification of human xenotransplants in mouse models of human diseases.

More importantly, our results suggest that humanized murine models may represent a more precise approach for both selecting and evaluating clinically relevant rAAV serotypes for gene therapeutic applications.PMID: 24390344 [PubMed - as supplied by publisher]

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42)Mol Ther. 2014 Jan 6. doi: 10.1038/mt.2013.290. [Epub ahead of print]

Somatic Correction of Junctional Epidermolysis Bullosa by a Highly Recombinogenic AAV

Variant.

Melo SP1, Lisowski L2, Bashkirova E1, Zhen HH1, Chu K3, Keene DR4, Marinkovich MP5,

Kay MA3, Oro AE1.

Definitive correction of disease causing mutations in somatic cells by homologous recombination (HR) is an attractive therapeutic approach for the treatment of genetic diseases.

However, HR-based somatic gene therapy is limited by the low efficiency of gene targeting in mammalian cells and replicative senescence of primary cells ex vivo, forcing investigators to explore alternative strategies such as retro- and lentiviral gene transfer, or genome editing in induced pluripotent stem cells. Here, we report correction of mutations at the LAMA3 locus in primary keratinocytes derived from a patient affected by recessive inherited Herlitz junctional epidermolysis bullosa (H-JEB) disorder using recombinant adenoassociated virus (rAAV)mediated HR. We identified a highly recombinogenic AAV serotype, AAV-DJ, that mediates

efficient gene targeting in keratinocytes at clinically relevant frequencies with a low rate of random integration. Targeted H-JEB patient cells were selected based on restoration of adhesion phenotype, which eliminated the need for foreign sequences in repaired cells, enhancing the clinical use and safety profile of our approach. Corrected pools of primary cells assembled functional laminin-332 heterotrimer and fully reversed the blistering phenotype both in vitro and in skin grafts. The efficient targeting of the LAMA3 locus by AAV-DJ using phenotypic selection, together with the observed low frequency of off-target events, makes AAV-DJ based somatic cell targeting a promising strategy for ex vivo therapy for this severe and often lethal epithelial disorder.Molecular Therapy (2014); doi:10.1038/mt.2013.290.


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43)Nat Neurosci. 2014 Feb;17(2):296-303. doi: 10.1038/nn.3600. Epub 2014 Jan 5.

Flies and humans share a motion estimation strategy that exploits natural scene statistics.

Clark DA1, Fitzgerald JE2, Ales JM3, Gohl DM4, Silies MA4, Norcia AM5, Clandinin TR4.

Sighted animals extract motion information from visual scenes by processing spatiotemporal patterns of light falling on the retina. The dominant models for motion estimation exploit intensity correlations only between pairs of points in space and time. Moving natural scenes, however, contain more complex correlations. We found that fly and human visual systems encode the combined direction and contrast polarity of moving edges using triple correlations that enhance motion estimation in natural environments. Both species extracted triple correlations with neural substrates tuned for light or dark edges, and sensitivity to specific triple correlations was retained even as light and dark edge motion signals were combined. Thus, both species separately process light and dark image contrasts to capture motion signatures that can improve estimation accuracy. This convergence argues that statistical structures in natural scenes have greatly affected visual processing, driving a common computational strategy over 500 million years of evolution.PMID: 24390225 [PubMed - in process]

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44)Annu Rev Immunol. 2014 Jan 2. [Epub ahead of print]

γδ T Cells: First Line of Defense and Beyond.

Chien YH, Meyer C, Bonneville M.

γδ T cells, αβ T cells, and B cells are present together in all but the most primitive vertebrates, suggesting that each population contributes to host immune competence uniquely and that all three are necessary for maintaining immune competence. Functional and molecular analyses indicate that in infections, γδ T cells respond earlier than αβ T cells do and that they emerge late after pathogen numbers start to decline. Thus, these cells may be involved in both establishing and regulating the inflammatory response. Moreover, γδ T cells and αβ T cells are clearly distinct in their antigen recognition and activation requirements as well as in the development of their antigen-specific repertoire and effector function. These aspects allow γδ T cells to occupy unique temporal and functional niches in host immune defense. We review these and other advances in γδ T cell biology in the context of their being the major initial IL-17 producers in acute infection. Expected final online publication date for the Annual Review of Immunology

Volume 32 is March 21, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.


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45)Cir Res. 2014 Jan 3;114(1):21-7. doi: 10.1161/CIRCRESAHA.113.302895.

Cardiac stem cell biology: glimpse of the past, present, and future.

Matsa E, Sallam K, Wu JC.

Cardiac regeneration strategies and de novo generation of cardiomyocytes have long been significant areas of research interest in cardiovascular medicine. In this review, we outline a variety of common cell sources and methods used to regenerate cardiomyocytes and highlight the important role that key Circulation Research articles have played in this flourishing field.

KEYWORDS:adult stem cells, embryonic stem cells, induced pluripotent stem cells


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46)J Neuroimmune Pharmacol. 2014 Jan 3. [Epub ahead of print]

Sorting Through the Roles of Beclin 1 in Microglia and Neurodegeneration.

O'Brien CE, Wyss-Coray T.

Beclin 1 has a well-established role in regulating autophagy, a cellular degradation pathway.

Although the yeast ortholog of beclin 1 (Atg6/Vps30) was discovered to also regulate vacuolar protein sorting nearly 30 years ago, the varied functions of beclin 1 in mammalian cells are only beginning to be sorted out. We recently described a role for beclin 1 in regulating recycling of phagocytic receptors in microglia, a function analogous to that of its yeast ortholog. Microglia lacking beclin 1 have a reduced phagocytic capacity, which impairs clearance of amyloid β (Aβ) in a mouse model of Alzheimer's Disease (AD). Here we summarize these findings and discuss the implications for beclin 1-regulated receptor recycling in neurodegenerative disease.


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47)Diabetes. 2013 Dec;62(12):4208-19. doi: 10.2337/db13-0614.

Diminished adenosine A1 receptor expression in pancreatic α-cells may contribute to the pathology of type 1 diabetes.

Yip L, Taylor C, Whiting CC, Fathman CG.

Prediabetic NOD mice exhibit hyperglucagonemia, possibly due to an intrinsic α-cell defect.

Here, we show that the expression of a potential glucagon inhibitor, the adenosine A1 receptor

(Adora1), is gradually diminished in α-cells of NOD mice, autoantibody-positive (AA(+)) and overtly type 1 diabetic (T1D) patients during the progression of disease. We demonstrated that islet inflammation was associated with loss of Adora1 expression through the alternative splicing of Adora1. Expression of the spliced variant (Adora1-Var) was upregulated in the pancreas of

12-week-old NOD versus age-matched NOD.B10 (non-diabetes-susceptible) control mice and was detected in the pancreas of AA(+) patients but not in control subjects or overtly diabetic patients, suggesting that inflammation drives the splicing of Adora1. We subsequently demonstrated that Adora1-Var expression was upregulated in the islets of NOD.B10 mice after exposure to inflammatory cytokines and in the pancreas of NOD.SCID mice after adoptive transfer of activated autologous splenocytes. Adora1-Var encodes a dominant-negative Nterminal truncated isoform of Adora1. The splicing of Adora1 and loss of Adora1 expression on

α-cells may explain the hyperglucagonemia observed in prediabetic NOD mice and may contribute to the pathogenesis of human T1D and NOD disease.PMID: 24264405 [PubMed - indexed for MEDLINE] PMCID: PMC3837064 [Available on 2014/12/1]

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48)Clin Pharmacol Ther. 2013 Dec;94(6):627-9. doi: 10.1038/clpt.2013.181.

Network medicine in disease analysis and therapeutics.

Chen B, Butte AJ.

Two parallel trends are occurring in drug discovery. The first is that we are moving away from a symptom-based disease classification system to a system based on molecules and molecular states. The second is that we are shifting from targeting a single molecule toward targeting multiple molecules, pathways, or networks. Network medicine is an approach to understanding disease and discovering therapeutics looking at many molecules and how they interrelate, and it may play a critical role in the adoption of both trends.

PMID: 24241637 [PubMed - indexed for MEDLINE]

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49)Immunity. 2013 Nov 14;39(5):963-75. doi: 10.1016/j.immuni.2013.10.005. Epub 2013 Oct

24.

A beneficial role for immunoglobulin E in host defense against honeybee venom.

Marichal T, Starkl P, Reber LL, Kalesnikoff J, Oettgen HC, Tsai M, Metz M, Galli SJ.

Allergies are widely considered to be misdirected type 2 immune responses, in which immunoglobulin E (IgE) antibodies are produced against any of a broad range of seemingly harmless antigens. However, components of insect venoms also can sensitize individuals to develop severe IgE-associated allergic reactions, including fatal anaphylaxis, upon subsequent venom exposure. We found that mice injected with amounts of honeybee venom similar to that which could be delivered in one or two stings developed a specific type 2 immune response that increased their resistance to subsequent challenge with potentially lethal amounts of the venom.

Our data indicate that IgE antibodies and the high affinity IgE receptor, FcεRI, were essential for such acquired resistance to honeybee venom. The evidence that IgE-dependent immune responses against venom can enhance survival in mice supports the hypothesis that IgE, which also contributes to allergic disorders, has an important function in protection of the host against noxious substances. Copyright © 2013 Elsevier Inc. All rights reserved.

Comment in Antibodies: taking the sting out. [Nat Rev Immunol. 2013] A sting in the tale of

TH2 immunity. [Immunity. 2013]


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50)Immunity. 2013 Nov 14;39(5):846-57. doi: 10.1016/j.immuni.2013.08.036. Epub 2013 Oct

10.

A single peptide-major histocompatibility complex ligand triggers digital cytokine secretion in CD4(+) T cells.

Huang J, Brameshuber M, Zeng X, Xie J, Li QJ, Chien YH, Valitutti S, Davis MM.

We have developed a single-molecule imaging technique that uses quantum-dot-labeled peptidemajor histocompatibility complex (pMHC) ligands to study CD4(+) T cell functional sensitivity.

We found that naive T cells, T cell blasts, and memory T cells could all be triggered by a single

pMHC to secrete tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2) cytokines with a rate of ∼ 1,000, ∼ 10,000, and ∼ 10,000 molecules/min, respectively, and that additional pMHCs did not augment secretion, indicating a digital response pattern. We also found that a single pMHC localized to the immunological synapse induced the slow formation of a long-lasting T cell receptor (TCR) cluster, consistent with a serial engagement mechanism. These data show that scaling up CD4(+) T cell cytokine responses involves increasingly efficient T cell recruitment rather than greater cytokine production per cell.Copyright © 2013 Elsevier Inc. All rights reserved.PMID: 24120362 [PubMed - indexed for MEDLINE] PMCID: PMC3846396


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51)Arthritis Rheum. 2013 Dec;65(12):3271-8. doi: 10.1002/art.38171.

Chronic kidney disease and the risk of incident gout among middle-aged men: a seven-year prospective observational study.

Krishnan E.

OBJECTIVE:The kidney is the major organ that facilitates excretion of urate in humans.

Surprisingly, few studies have assessed whether a reduced glomerular filtration rate (GFR) and/or kidney damage is associated with a higher incidence of gout, and this study was undertaken to address this question.

METHODS:Data from a 7-year followup of patients enrolled in the Multiple Risk Factor

Intervention Trial, a primary prevention trial for cardiovascular disease among 12,866 men ages

35-57 years, were used for the present investigation. Presence of gout was determined by the study physicians from the original trial. Chronic kidney disease was defined using criteria similar to those proposed by the National Kidney Foundation. The Cox proportional hazards regression model was used to assess the association between gout and chronic kidney disease, after accounting for the effects of potential confounders.

RESULTS:Overall, there were 722 cases of physician- diagnosed incident gout over 76,602 person-years of followup. The standardized incidence ratio of gout among those with chronic kidney disease was 1,217 (95% confidence interval [95% CI] 1,191-1,244). The adjusted hazard ratio (HR) among those with chronic kidney disease was 1.61 (95% CI 1.60-1.61). Each standard deviation decline in the estimated GFR was associated with an HR of 1.43 (95% CI 1.35-1.51).

Including the serum urate level, as well as the urate-chronic kidney disease interaction term, as variables in the second analysis did not attenuate the HR. Proteinuria and hematuria, two markers of kidney damage, were associated with an elevated risk of gout independent of the estimated

GFR.

CONCLUSION:Chronic kidney disease manifesting as reduced glomerular function or as presence of blood or protein in the urine increases the risk of incident gout.

Copyright © 2013 by the American College of Rheumatology.


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52)J Diabetes Res. 2013;2013:342479. doi: 10.1155/2013/342479. Epub 2013 Jul 22.

IL-10 induction from implants delivering pancreatic islets and hyaluronan.

Bollyky PL, Vernon RB, Falk BA, Preisinger A, Gooden MD, Nepom GT, Gebe JA.

Local induction of pro-tolerogenic cytokines, such as IL-10, is an appealing strategy to help facilitate transplantation of islets and other tissues. Here, we describe a pair of implantable

devices that capitalize on our recent finding that hyaluronan (HA) promotes IL-10 production by activated T cells. The first device is an injectable hydrogel made of crosslinked HA and heparan sulfate loaded with anti-CD3/anti-CD28 antibodies and IL-2. T cells embedded within this hydrogel prior to polymerization go on to produce IL-10 in vivo. The second device is a bioengineered implant consisting of a polyvinyl alcohol sponge scaffold, supportive collagen hydrogel, and alginate spheres mediating sustained release of HA in fluid form. Pancreatic islets that expressed ovalbumin (OVA) antigen were implanted within this device for 14 days into immunodeficient mice that received OVA-specific DO.11.10 T cells and a subsequent immunization with OVA peptide. Splenocytes harvested from these mice produced IL-10 upon re-challenge with OVA or anti-CD3 antibodies. Both of these devices represent model systems that will be used, in future studies, to further evaluate IL-10 induction by HA, with the objective of improving the survival and function of transplanted islets in the setting of autoimmune (type

1) diabetes. PMID: 23971054 [PubMed - indexed for MEDLINE] PMCID: PMC3736405

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53)Exp Hematol. 2013 Nov;41(11):934-43. doi: 10.1016/j.exphem.2013.07.002. Epub 2013 Aug

14.

Comparison of transduction efficiency among various lentiviruses containing GFP reporter in bone marrow hematopoietic stem cell transplantation.

Wang N, Rajasekaran N, Hou T, Lisowski L, Mellins ED.

HIV-derived lentiviral vectors have been used widely to transduce non-dividing cells, such as hematopoietic stem cells (HSCs), in the setting of gene therapy. In this study, we screened lentiviral vectors for their ability to drive expression of the murine MHC class II chaperone, invariant chain (Ii) and a GFP reporter. The vectors included T2A vector with T2A-separated Ii and GFP under the same MSCV promoter, dual-promoter vectors with separate promoters for Ii and GFP (called MSCV or EF1a according to the promoter driving Ii expression), and a vector with EF1a driving a fusion of Ii/GFP (called Fusion vector). T2A and MSCV induced the highest levels of Ii and GFP expression, respectively, after direct transfection of 293T cells. All vectors except the Fusion vector drove expression of functional Ii, based on the enhancement of MHC class II level, which is a known consequence of Ii expression. Comparing the vectors after they were packaged into lentiviruses and used to transduce 293T, we found that MSCV and EF1a vectors mediated higher Ii and GFP expression. In ckit(+) bone marrow (BM) cells, MSCV still induced the highest Ii and GFP expression, whereas EF1a induced only robust Ii expression.

Regardless of the vector, both Ii and GFP levels were significantly reduced in BM cells compared to 293T cells. When in vivo expression was assessed in cells derived from MSCVtransduced BM-HSCs, up to 80% of myeloid cells were GFP(+), but no Ii expression was observed. In contrast, transplantation of EF1a-transduced BM-HSCs led to much higher in vivo

Ii expression. Thus, among those compared, dual-promoter vector-based lentivirus with the EF1a promoter driving the gene of interest is optimal for murine BM-HSC transduction.

Copyright © 2013 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.

All rights reserved. PMID: 23954710 [PubMed - indexed for MEDLINE] PMCID:

PMC3833897 [Available on 2014/11/1]

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54)Biochemistry. 2013 Sep 3;52(35):5985-96. doi: 10.1021/bi400854d. Epub 2013 Aug 21.

Applications of small molecule probes in dissecting mechanisms of bacterial virulence and host responses.

Puri AW, Bogyo M.

Elucidating the molecular and biochemical details of bacterial infections can be challenging because of the many complex interactions that exist between a pathogen and its host.

Consequently, many tools have been developed to aid the study of bacterial pathogenesis. Small molecules are a valuable complement to traditional genetic techniques because they can be used to rapidly perturb genetically intractable systems and to monitor post-translationally regulated processes. Activity-based probes are a subset of small molecules that covalently label an enzyme of interest based on its catalytic mechanism. These tools allow monitoring of enzyme activation within the context of a native biological system and can be used to dissect the biochemical details of enzyme function. This review describes the development and application of activitybased probes for examining aspects of bacterial infection on both sides of the host-pathogen interface.PMID: 23937332 [PubMed - indexed for MEDLINE] PMCID: PMC3838904


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55)Nucleic Acids Res. 2013 Nov 1;41(20):9424-37. doi: 10.1093/nar/gkt717. Epub 2013 Aug 9.

Robust gene silencing mediated by antisense small RNAs in the pathogenic protist

Entamoeba histolytica.

Morf L, Pearson RJ, Wang AS, Singh U.

RNA interference uses small RNAs (sRNA), which target genes for sequence-specific silencing.

The parasite Entamoeba histolytica contains an abundant repertoire of 27 nt antisense (AS) sRNA with 5'-polyphosphate termini, but their roles in regulating gene expression have not been well established. We demonstrate that a gene-coding region to which large numbers of AS sRNAs map can serve as a 'trigger' and silence the gene fused to it. Silencing is mediated by generation of AS sRNAs with 5'-polyphosphate termini that have sequence specificity to the fused gene. The mechanism of silencing is independent of the placement of the trigger relative to the silenced gene but is dependent on the sRNA concentration to the trigger. Silencing requires transcription of the trigger-gene fusion and is maintained despite loss of the trigger plasmid. We used this approach to silence multiple amebic genes, including an E. histolytica Myb gene, which is upregulated during oxidative stress response. Silencing of the EhMyb gene decreased parasite viability under oxidative stress conditions. Thus, we have developed a new tool for genetic manipulation in E. histolytica with many advantages over currently available technologies.

Additionally, these data shed mechanistic insights into a eukaryotic RNA interference pathway with many novel aspects.PMID: 23935116 [PubMed - indexed for MEDLINE]

PMCID: PMC3814356

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56)Methods Mol Biol. 2013;1036:81-8. doi: 10.1007/978-1-62703-511-8_7.

Generation of human iPSCs from human peripheral blood mononuclear cells using nonintegrative Sendai virus in chemically defined conditions.

Churko JM, Burridge PW, Wu JC.

Human-induced pluripotent stem cells (hiPSCs) have received enormous attention because of their ability to differentiate into multiple cell types that demonstrate the patient's original

phenotype. The use of hiPSCs is particularly valuable to the study of cardiac biology, as human cardiomyocytes are difficult to isolate and culture and have a limited proliferative potential. By deriving iPSCs from patients with heart disease and subsequently differentiating these hiPSCs to cardiomyocytes, it is feasible to study cardiac biology in vitro and model cardiac diseases. While there are many different methods for deriving hiPSCs, clinical use of these hiPSCs will require derivation by methods that do not involve modification of the original genome (non-integrative) or incorporate xeno-derived products (such as bovine serum albumin) which may contain xenoagents. Ideally, this derivation would be carried out under chemically defined conditions to prevent lot-to-lot variability and enhance reproducibility. Additionally, derivation from cell types such as fibroblasts requires extended culture (4-6 weeks), greatly increasing the time required to progress from biopsy to hiPSC. Herein, we outline a method of culturing peripheral blood mononuclear cells (PBMCs) and reprogramming PBMCs into hiPSCs using a non-integrative

Sendai virus.PMID: 23807788 [PubMed - indexed for MEDLINE]

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57)PLoS Pathog. 2013;9(6):e1003408. doi: 10.1371/journal.ppat.1003408. Epub 2013 Jun 6.

The systemic immune state of super-shedder mice is characterized by a unique neutrophildependent blunting of TH1 responses.

Gopinath S, Hotson A, Johns J, Nolan G, Monack D.

Host-to-host transmission of a pathogen ensures its successful propagation and maintenance within a host population. A striking feature of disease transmission is the heterogeneity in host infectiousness. It has been proposed that within a host population, 20% of the infected hosts, termed super-shedders, are responsible for 80% of disease transmission. However, very little is known about the immune state of these super-shedders. In this study, we used the model organism Salmonella enterica serovar Typhimurium, an important cause of disease in humans and animal hosts, to study the immune state of super-shedders. Compared to moderate shedders, super-shedder mice had an active inflammatory response in both the gastrointestinal tract and the spleen but a dampened T(H)1 response specific to the secondary lymphoid organs. Spleens from super-shedder mice had higher numbers of neutrophils, and a dampened T cell response, characterized by higher levels of regulatory T cells (T(regs)), fewer T-bet(+) (T(H)1) T cells as well as blunted cytokine responsiveness. Administration of the cytokine granulocyte colony stimulating factor (G-CSF) and subsequent neutrophilia was sufficient to induce the supershedder immune phenotype in moderate-shedder mice. Similar to super-shedders, these G-CSFtreated moderate-shedders had a dampened T(H)1 response with fewer T-bet(+) T cells and a loss of cytokine responsiveness. Additionally, G-CSF treatment inhibited IL-2-mediated TH1 expansion. Finally, depletion of neutrophils led to an increase in the number of T-bet(+) T(H)1 cells and restored their ability to respond to IL-2. Taken together, we demonstrate a novel role for neutrophils in blunting IL-2-mediated proliferation of the TH1 immune response in the spleens of mice that are colonized by high levels of S. Typhimurium in the gastrointestinal tract.

PMID: 23754944 [PubMed - indexed for MEDLINE] PMCID: PMC3675027

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58)PLoS One. 2013 May 29;8(5):e64555. doi: 10.1371/journal.pone.0064555. Print 2013.

Characterization of influenza vaccine immunogenicity using influenza antigen microarrays.

Price JV, Jarrell JA, Furman D, Kattah NH, Newell E, Dekker CL, Davis MM, Utz PJ.

BACKGROUND:Existing methods to measure influenza vaccine immunogenicity prohibit detailed analysis of epitope determinants recognized by immunoglobulins. The development of highly multiplex proteomics platforms capable of capturing a high level of antibody binding information will enable researchers and clinicians to generate rapid and meaningful readouts of influenza-specific antibody reactivity.

METHODS:We developed influenza hemagglutinin (HA) whole-protein and peptide microarrays and validated that the arrays allow detection of specific antibody reactivity across a broad dynamic range using commercially available antibodies targeted to linear and conformational

HA epitopes. We derived serum from blood draws taken from 76 young and elderly subjects immediately before and 28±7 days post-vaccination with the 2008/2009 trivalent influenza vaccine and determined the antibody reactivity of these sera to influenza array antigens.

RESULTS:Using linear regression and correcting for multiple hypothesis testing by the

Benjamini and Hochberg method of permutations over 1000 resamplings, we identified antibody reactivity to influenza whole-protein and peptide array features that correlated significantly with age, H1N1, and B-strain post-vaccine titer as assessed through a standard microneutralization assay (p<0.05, q <0.2). Notably, we identified several peptide epitopes that were inversely correlated with regard to age and seasonal H1N1 and B-strain neutralization titer (p<0.05, q

<0.2), implicating reactivity to these epitopes in age-related defects in response to H1N1 influenza. We also employed multivariate linear regression with cross-validation to build models based on age and pre-vaccine peptide reactivity that predicted vaccine-induced neutralization of seasonal H1N1 and H3N2 influenza strains with a high level of accuracy (84.7% and 74.0%, respectively).

CONCLUSION:Our methods provide powerful tools for rapid and accurate measurement of broad antibody-based immune responses to influenza, and may be useful in measuring response to other vaccines and infectious agents.PMID: 23734205 [PubMed - indexed for MEDLINE]

PMCID: PMC3667171

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59)Am J Hum Genet. 2013 Jun 6;92(6):904-16. doi: 10.1016/j.ajhg.2013.04.025. Epub 2013

May 30.

Genome-wide characterization of shared and distinct genetic components that influence blood lipid levels in ethnically diverse human populations.

Coram MA, Duan Q, Hoffmann TJ, Thornton T, Knowles JW, Johnson NA, Ochs-Balcom HM,

Donlon TA, Martin LW, Eaton CB, Robinson JG, Risch NJ, Zhu X, Kooperberg C, Li Y, Reiner

AP, Tang H.

Blood lipid concentrations are heritable risk factors associated with atherosclerosis and cardiovascular diseases. Lipid traits exhibit considerable variation among populations of distinct ancestral origin as well as between individuals within a population. We performed association analyses to identify genetic loci influencing lipid concentrations in African American and

Hispanic American women in the Women's Health Initiative SNP Health Association Resource.

We validated one African-specific high-density lipoprotein cholesterol locus at CD36 as well as

14 known lipid loci that have been previously implicated in studies of European populations.

Moreover, we demonstrate striking similarities in genetic architecture (loci influencing the trait, direction and magnitude of genetic effects, and proportions of phenotypic variation explained) of lipid traits across populations. In particular, we found that a disproportionate fraction of lipid variation in African Americans and Hispanic Americans can be attributed to genomic loci

exhibiting statistical evidence of association in Europeans, even though the precise genes and variants remain unknown. At the same time, we found substantial allelic heterogeneity within shared loci, characterized both by population-specific rare variants and variants shared among multiple populations that occur at disparate frequencies. The allelic heterogeneity emphasizes the importance of including diverse populations in future genetic association studies of complex traits such as lipids; furthermore, the overlap in lipid loci across populations of diverse ancestral origin argues that additional knowledge can be gleaned from multiple populations.

Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. PMID: 23726366 [PubMed - indexed for MEDLINE] PMCID:

PMC3675231

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60)J Vasc Interv Radiol. 2013 Jun;24(6):872-3. doi: 10.1016/j.jvir.2013.03.007.

Measuring (and manipulating) cellular immune activation.

Sze DY.

Comment on Prognostic utility of serum neopterin in obstructive jaundice secondary to malignant lesions treated by percutaneous transhepatic biliary drainage. [J Vasc Interv Radiol.

2013]


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61)PLoS Phatog. 2013;9(4):e1003296. doi: 10.1371/journal.ppat.1003296. Epub 2013 Apr 25.

Have it your way: how polymorphic, injected kinases and pseudokinases enable

Toxoplasma to subvert host defenses.

Boothroyd JC.


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62)BMC Nephrol. 2013 Apr 26;14:97. doi: 10.1186/1471-2369-14-97.

Risk factors of short-term mortality after acute nonvariceal upper gastrointestinal bleeding in patients on dialysis: a population-based study.

Yang JY, Lee TC, Montez-Rath ME, Chertow GM, Winkelmayer WC.

BACKGROUND:Impaired kidney function is an established predictor of mortality after acute nonvariceal upper gastrointestinal bleeding (ANVUGIB); however, which factors are associated with mortality after ANVUGIB among patients undergoing dialysis is unknown. We examined the associations among demographic characteristics, dialysis-specific features, and comorbid conditions with short-term mortality after ANVUGIB among patients on dialysis.

METHODS:Design: Retrospective cohort study. Setting: United States Renal Data System

(USRDS), a nation-wide registry of patients with end-stage renal disease. Participants: All

ANVUGIB episodes identified by validated algorithms in Medicare-covered patients between

2003 and 2007. Measurements: Demographic characteristics and comorbid conditions from 1 year of billing claims prior to each bleeding event. We used logistic regression extended with generalized estimating equations methods to model the associations among risk factors and 30day mortality following ANVUGIB events.

RESULTS:From 2003 to 2007, we identified 40,016 eligible patients with 50,497 episodes of

ANVUGIB. Overall 30-day mortality was 10.7% (95% CI: 10.4-11.0). Older age, white race, longer dialysis vintage, peritoneal dialysis (vs. hemodialysis), and hospitalized (vs. outpatient) episodes were independently associated with a higher risk of 30-day mortality. Most but not all comorbid conditions were associated with death after ANVUGIB. The joint ability of all factors captured to discriminate mortality was modest (c=0.68).

CONCLUSIONS:We identified a profile of risk factors for 30-day mortality after ANVUGIB among patients on dialysis that was distinct from what had been reported in non-dialysis populations. Specifically, peritoneal dialysis and more years since initiation of dialysis were independently associated with short-term death after ANVUGIB.


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63)Pain. 2013 Jun;154(6):776-81. doi: 10.1016/j.pain.2012.11.008. Epub 2012 Nov 23.

Functional magnetic resonance imaging identifies somatotopic organization of nociception in the human spinal cord.

Nash P, Wiley K, Brown J, Shinaman R, Ludlow D, Sawyer AM, Glover G, Mackey S.

Functional magnetic resonance imaging (fMRI) is a technique that uses blood oxygen-leveldependent (BOLD) signals to elucidate discrete areas of neuronal activity. Despite the significant number of fMRI human brain studies, few researchers have applied fMRI technology to investigating neuronal activity within the human spinal cord. Our study goals were to demonstrate that fMRI could reveal the following: (i) appropriate somatotopic activations in response to noxious stimuli in the deep and superficial dorsal horn of the human cervical spinal cord, and (ii) lateralization of fMRI activations in response to noxious stimulation in the right and left upper extremity. We subjected healthy participants to noxious stimulation during fMRI scans. Using a spiral in-out image sequence and retrospective correction for physiologic noise, we demonstrated that fMRI can create high-resolution, neuronal activation maps of the human cervical spinal cord. During nociceptive stimulation of all 4 sites (left deltoid, right deltoid, left thenar eminence and right thenar eminence), we found ipsilateral dorsal horn activation.

Stimulation of the deltoid activated C5, whereas stimulation of the thenar eminence activated C6.

Our study contributes to creating an objective analysis of pain transmission; other investigators can use these results to further study central nervous system changes that occur in patients with acute and chronic pain. Copyright © 2012. Published by Elsevier B.V.

Comment in Somatotopy of nociceptive responses in the human spinal cord. [Pain. 2013]

Response to: Letter from Paul Eugene Summers, Federico Giove, and Carlo Adolfo Porro.

[Pain. 2013]


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64)J Rheumatol. 2013 Jun;40(6):768-80. doi: 10.3899/jrheum.120687. Epub 2013 Mar 1.

Longterm safety and efficacy of tocilizumab in patients with rheumatoid arthritis: a cumulative analysis of up to 4.6 years of exposure.

Genovese MC, Rubbert-Roth A, Smolen JS, Kremer J, Khraishi M, Gómez-Reino J, Sebba A,

Pilson R, Williams S, Van Vollenhoven R.

OBJECTIVE:To assess the longterm safety and efficacy of tocilizumab (TCZ) in patients with moderate to severe rheumatoid arthritis (RA).

METHODS:Patient data were from 5 randomized controlled TCZ trials (n = 4211), their openlabel extension phases (n = 3512), and a drug interaction study (n = 23). All randomly assigned patients, regardless of previous RA treatment, were analyzed. Measures of safety included number of adverse events (AE), serious AE (SAE), AE leading to treatment discontinuation, laboratory tests, and deaths. Efficacy measures included American College of Rheumatology

(ACR) 20/50/70 responses, tender joint count (TJC), swollen joint count (SJC), ACR core set components, and low disease activity (LDA) or Disease Activity Score in 28 joints (DAS28) remission. ACR/European League Against Rheumatism (EULAR) disease remission was a posthoc exploratory analysis.

RESULTS:Total duration of observation was 12,293 patient-years (PY). No new safety signals were identified; infections were the most common AE and SAE. The rate of serious infections was 4.5/100 PY. Improvements from baseline in clinical efficacy, measured as ACR20/50/70 responses, TJC, SJC, ACR core set components, and LDA and DAS28 remission, were generally sustained through at least 216 weeks of followup. ACR/EULAR disease remission was attained by 16.5% (Boolean) and 22.7% (index) of patients at Week 216.

CONCLUSION:TCZ has to date been studied for up to 4.6 years (240 weeks) of treatment in patients with RA. Our analysis reveals a longer-term safety profile consistent with previous observations, no new safety signals, and durable efficacy of TCZ in a large clinical trial program.

KEYWORDS:RHEUMATOID ARTHRITIS, SAFETY, TOCILIZUMAB, TREATMENT

EFFICACY


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65)Sci Transl Med. 2013 Feb 6;5(171):171ra19. doi: 10.1126/scitranslmed.3004794.

Lineage structure of the human antibody repertoire in response to influenza vaccination.

Jiang N, He J, Weinstein JA, Penland L, Sasaki S, He XS, Dekker CL, Zheng NY, Huang M,

Sullivan M, Wilson PC, Greenberg HB, Davis MM, Fisher DS, Quake SR.

The human antibody repertoire is one of the most important defenses against infectious disease, and the development of vaccines has enabled the conferral of targeted protection to specific pathogens. However, there are many challenges to measuring and analyzing the immunoglobulin sequence repertoire, including that each B cell's genome encodes a distinct antibody sequence, that the antibody repertoire changes over time, and the high similarity between antibody sequences. We have addressed these challenges by using high-throughput long read sequencing to perform immunogenomic characterization of expressed human antibody repertoires in the context of influenza vaccination. Informatic analysis of 5 million antibody heavy chain sequences from healthy individuals allowed us to perform global characterizations of isotype distributions, determine the lineage structure of the repertoire, and measure age- and antigenrelated mutational activity. Our analysis of the clonal structure and mutational distribution of individuals' repertoires shows that elderly subjects have a decreased number of lineages but an increased prevaccination mutation load in their repertoire and that some of these subjects have an oligoclonal character to their repertoire in which the diversity of the lineages is greatly reduced relative to younger subjects. We have thus shown that global analysis of the immune system's clonal structure provides direct insight into the effects of vaccination and provides a detailed molecular portrait of age-related effects.PMID: 23390249 [PubMed - indexed for

MEDLINE] PMCID: PMC3699344

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66)Mucosal Immunol. 2013 Jul;6(4):847-56. doi: 10.1038/mi.2012.123. Epub 2012 Dec 12.

Retinoic acid regulates the development of a gut-homing precursor for intestinal dendritic cells.

Zeng R, Oderup C, Yuan R, Lee M, Habtezion A, Hadeiba H, Butcher EC.

The vitamin A metabolite retinoic acid (RA) regulates intestinal immune responses through immunomodulatory actions on intestinal dendritic cells (DCs) and lymphocytes. Here, we show that RA also controls the generation of gut-tropic migratory DC precursors, referred to as premucosal DCs (pre-μDCs). Pre-μDCs express the gut trafficking receptor α4β7 and home preferentially to the intestines. They develop in the bone marrow (BM), can differentiate into

CCR9 ⁺ plasmacytoid DCs as well as conventional DCs (cDCs), but preferentially give rise to

CD103 ⁺ intestinal cDCs. Generation of pre-μDCs in vivo in the BM or in vitro is regulated by

RA and RA receptor α (RARα) signaling. The frequency of pre-μDCs is reduced in vitamin Adeficient animals and in animals treated with RAR inhibitors. The results define a novel vitamin

A-dependent, RA-regulated developmental sequence for DCs and identify a targeted precursor for CD103 ⁺ cDCs in the gut.PMID: 23235743 [PubMed - indexed for MEDLINE]

PMCID: PMC3612556

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67)Cardiovasc Intervent Radiol. 2013 Jun;36(3):690-8. doi: 10.1007/s00270-012-0490-1. Epub

2012 Oct 16.

N-butyl cyanoacrylate glue embolization of arterial networks to facilitate hepatic arterial skeletonization before radioembolization.

Samuelson SD, Louie JD, Sze DY.

PURPOSE:Avoidance of nontarget microsphere deposition via hepatoenteric anastomoses is essential to the safety of yttrium-90 radioembolization (RE). The hepatic hilar arterial network may remain partially patent after coil embolization of major arteries, resulting in persistent risk.

We retrospectively reviewed cases where n-butyl cyanoacrylate (n-BCA) glue embolization was used to facilitate endovascular hepatic arterial skeletonization before RE.

METHODS:A total of 543 RE procedures performed between June 2004 and March 2012 were reviewed, and 10 were identified where n-BCA was used to embolize hepatoenteric anastomoses.

Arterial anatomy, prior coil embolization, and technical details were recorded. Outcomes were reviewed to identify subsequent complications of n-BCA embolization or nontarget RE.

RESULTS:The rate of complete technical success was 80 % and partial success 20 %, with one nontarget embolization complication resulting in a minor change in treatment plan. No evidence of gastrointestinal or biliary ischemia or infarction was identified, and no microsphere-related gastroduodenal ulcerations or other evidence of nontarget RE were seen. Median volume of n-

BCA used was <0.1 ml.

CONCLUSION:n-BCA glue embolization is useful to eliminate hepatoenteric networks that may result in nontarget RE, especially in those that persist after coil embolization of major vessels such as the gastroduodenal and right gastric arteries.


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