Histologic characterization of regenerated tissues after pulp revascularization of immature dog teeth with apical periodontitis using tri-antibiotic paste and platelet-rich plasma

Publication date: November 2016
Source:Archives of Oral Biology, Volume 71
Author(s): Carlos Stambolsky, Soledad Rodríguez-Benítez, José Luis Gutiérrez-Pérez, Daniel Torres-Lagares, Jenifer Martín-González, Juan José Segura-Egea
IntroductionThis study evaluates histologically the efficacy of 4 revascularization protocols in necrotic-infected immature dog teeth with apical periodontitis (AP).MethodsForty double-rooted immature premolar teeth from 4 female Beagle dogs aged 5 months were used. Four teeth were left untouched as negative controls; the other 36 teeth were infected to develop pulp necrosis and AP. Four teeth were left untreated and assigned to the positive control group. The last 28 teeth were randomly assigned into four experimental groups of 8 teeth, each one treated with a different treatment protocol: A1, sodium hypochlorite (SH)+blood clot (BC); A2, SH+platelet-rich plasma (PRP); B1, SH+modified tri-antibiotic paste (mTAP)+BC; B2, SH+mTAP+PRP. The animals were sacrificed, histologic sections were prepared and three parameters were assessed: (1) presence or absence of new hard tissue on the internal root dentinal walls, (2) presence or absence of continued apical closure, and (3) presence or absence of vital tissue within the canal space.ResultsSignificant differences (p<0.05) between the four experimental groups were evident in the percentage of teeth showing histological apical closure (34.5%) and vital tissue within the canal space (68.8%). Group B2 showed the maximal improvement in the three variables assessed (p<0.05). Group A1 showed the minimum percentages in the three parameters assessed (p<0.05).ConclusionsThese results suggest that an intracanal dressing of mTAP, and the use of PRP as scaffold, improves the success rate of the revascularization procedure.



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Similar biological activity in skin prick test for Oralair® (8.200BAU) and Grazax®(6.200BAU) reinforces effective SLIT dosing level

Abstract

In Europe, allergen extracts are standardized based on skin-prick wheal-size in 20-30 allergic subjects. To understand the biologic activity of clinically effective SLIT, we used this method to determine the biologic activity of solution and tablet Timothy grass pollen (TIM) extracts, compared to an FDA approved extract (Reference) of 10.000BAU/mL.

Blinded, quadruplicate SPTs with concentrate and three serial half-log dilutions, allowed construction of a semi-logarithmic regression line per extract. BAU values were obtained from comparison with Reference.

Extracts and dilutions showed a neat linear dose-response (all: R²>0.98) in 33 rhinitis patients. Relative potencies: Staloral^® 12.000BAU/mL, Soluprick^® 10.300BAU/mL, Oralair^® 8.200BAU, Grazax^® 6.200BAU. Even though all extract concentrates differed in wheal-size (p= 0.01-0.001), Grazax^® producing a 25% smaller wheal-size than Oralair^®, the biological activity of these clinically effective TIM tablets led in the same range (6.200-8.200BAU; 0.92-1.23cm²). SLIT dose-finding studies for other pollens might start with allergen extracts producing 1.1cm² wheal surface.

This article is protected by copyright. All rights reserved.

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Similar biological activity in skin prick test for Oralair® (8.200BAU) and Grazax®(6.200BAU) reinforces effective SLIT dosing level

Abstract

In Europe, allergen extracts are standardized based on skin-prick wheal-size in 20-30 allergic subjects. To understand the biologic activity of clinically effective SLIT, we used this method to determine the biologic activity of solution and tablet Timothy grass pollen (TIM) extracts, compared to an FDA approved extract (Reference) of 10.000BAU/mL.

Blinded, quadruplicate SPTs with concentrate and three serial half-log dilutions, allowed construction of a semi-logarithmic regression line per extract. BAU values were obtained from comparison with Reference.

Extracts and dilutions showed a neat linear dose-response (all: R²>0.98) in 33 rhinitis patients. Relative potencies: Staloral^® 12.000BAU/mL, Soluprick^® 10.300BAU/mL, Oralair^® 8.200BAU, Grazax^® 6.200BAU. Even though all extract concentrates differed in wheal-size (p= 0.01-0.001), Grazax^® producing a 25% smaller wheal-size than Oralair^®, the biological activity of these clinically effective TIM tablets led in the same range (6.200-8.200BAU; 0.92-1.23cm²). SLIT dose-finding studies for other pollens might start with allergen extracts producing 1.1cm² wheal surface.

This article is protected by copyright. All rights reserved.

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The role of monocytes in ANCA-associated vasculitides

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Francesca Brunini, Theresa H. Page, Maurizio Gallieni, Charles D. Pusey
The anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are a heterogeneous group of diseases causing inflammation in small blood vessels and linked by the presence of circulating ANCA specific for proteinase 3 (PR3) or myeloperoxidase (MPO). These antigens are present both in the cytoplasmic granules and on the surface of neutrophils, and the effect of ANCA on neutrophil biology has been extensively studied. In contrast, less attention has been paid to the role of monocytes in AAV. These cells contain PR3 and MPO in lysosomes and can also express them at the cell surface. Monocytes respond to ANCA by producing pro-inflammatory and chemotactic cytokines, reactive-oxygen-species and by up-regulating CD14. Moreover, soluble and cell surface markers of monocyte activation are raised in AAV patients, suggesting an activated phenotype that may persist even during disease remission. The presence of monocyte-derived macrophages and giant cells within damaged renal and vascular tissue in AAV also attests to their role in pathogenesis. In particular, their presence in the tertiary lymphoid organ-like granulomas of AAV patients may generate an environment predisposed to maintaining autoimmunity. Here we discuss the evidence for a pathogenic role of monocytes in AAV, their role in granuloma formation and tissue damage, and their potential to both direct and maintain autoimmunity. ANCA-activation of monocytes may therefore provide an explanation for the relapsing-remitting course of disease and its links with infections. Monocytes may thus represent a promising target for the treatment of this group of life-threatening diseases.



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Pitfalls in Lupus

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): M. Schneider
"The objective of Pitfall!™ is to guide Harry through a maze of jungle scenes, jumping over or avoiding many deadly dangers… Harry has three lives in each game". If you exchange Harry's adventures with "Life with SLE", patients have to be guided through the jungle having just one life and the deadly dangers are flares, organ manifestations and e.g. consequences of immunosuppressive medications, especially glucocorticoids. Monitoring and treatment in line with recommendations and guidelines may be supportive to survive the first 3 to 5 levels in most cases, but for higher levels of the reality game creativity is needed and life becomes more risky. The aim of this reflection is to identify common pitfalls and to stimulate further research and collaboration in specific areas of the lupus jungle. Topics like "Hidden Power Unit", "Looks similar …", "Rev Meter for SLE", "Flare Prediction", "Level 2: Eminence Based", "Lupus=Lifelong Immunosuppression? !", "Glucocorticoids", "Antimalarials are Contraindicated", "It is all about immunosuppression", "Prediction of Damage" and "Patient Global Assessment (PGA) versus Physician Global Assessment (PhGA)" are addressed. Raised ideas and thoughts are by no means complete or exclusive, but if taken up they may hopefully lead to another approach in daily care and trials in SLE.



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Humoral and cellular autoimmunity in women with recurrent pregnancy losses and repeated implantation failures; a possible role of vitamin D

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Joanne Kwak-Kim, Annie Skariah, Li Wu, Dinorah Salazar, Nayoung Sung, Kuniaki Ota
Women with recurrent pregnancy losses (RPL) and repeated implantation failures (RIF) have auto- and cellular immune abnormalities. Approximately, 20% of women with RPL have autoimmune abnormalities, particularly antiphospholipid antibodies (APA). In addition, these women have a higher prevalence of antinuclear antibody, anti-thyroperoxidase and anti-thyroglobulin antibodies, and other non-organ specific autoantibodies. In women with RPL, presence of autoimmunity is often associated with cellular immune abnormalities, such as increased NK cell levels and Th1/Th2 cell ratios. Vitamin D (VD) plays a major role in regulation of auto- and cellular immune abnormalities. VD deficiency is prevalent in women with RPL, and women with VD deficiency have increased auto- and cellular immune abnormalities as compared with women with normal VD levels. VD has immune regulatory effects on various immune effectors including T, B and NK cells. Potential therapeutic application of VD for RPL and RIF with auto- and cellular immune abnormalities should be explored.



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The viral paradigm in type 1 diabetes: who are the main suspects?

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Teresa Rodriguez-Calvo, Somayeh Sabouri, Florence Anquetil, Matthias G. von Herrath
Type 1 diabetes (T1D) is an autoimmune disease characterized by the loss of pancreatic beta cells in the islets of Langerhans. Although genetic predisposition plays an important role in T1D development, studies of identical twins suggest that environmental factors such as viruses and other pathogens may be critical triggers either through direct cytolytic effect and gradual beta cell destruction, or by bystander activation of the immune system. In addition, viruses may circumvent the host immune response and have the capacity to establish chronic lifelong infections. The association of various viral infections with the induction of T1D has been extensively studied at the serological and epidemiological level. However, there is still little evidence from studies of human pancreas to confirm their presence or a causal role in disease pathogenesis. In this review, we identify possible suspects for viral triggers of disease and explain their potential roles in the "viral paradigm" of T1D.



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Fc-Gamma Receptors: Attractive Targets for Autoimmune Drug Discovery Searching for Intelligent Therapeutic Designs

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Carlos J. Bosques, Anthony M. Manning
Auto-antibody immune complexes (ICs) mediate pathogenesis in multiple autoimmune diseases direct interference with target function, complement fixation, and interaction with Fc-gamma receptors (FcγRs). Through high avidity interactions, ICs are able to crosslink low affinity FcγRs expressed on a wide variety of effector cells, leading to secretion of pro-inflammatory mediators and inducing cytotoxicity, ultimately resulting in tissue injury. Given their relevance in numerous autoimmune diseases, FcγRs have been considered as attractive therapeutic targets for the last three decades. However, a limited number of investigational drug candidates have been developed targeting FcγRs and only a few approved therapeutics have been associated with impacting FcγRs. This review provides a historical overview of the different therapeutic approaches used to target FcγRs for the treatment of autoimmune and inflammatory diseases.



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Anti-HMGCR antibodies as a biomarker for immune mediated necrotizing myopathies: A history of statins and experience from a large international multi-center study

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Lucile Musset, Yves Allenbach, Olivier Benveniste, Olivier Boyer, Xavier Bossuyt, Chelsea Bentow, Joe Phillips, Andrew Mammen, Philip Van Damme, René Westhovens, Anna Ghirardello, Andrea Doria, May E. Choi, Marvin J. Fritzler, Heinrike Schmeling, Yoshinao Muro, Ignacio García-De La Torre, Miguel A. Ortiz-Villalvazo, Nicola Bizzaro, Maria Infantino, Tiziana Imbastaro, Peng, Guochun Wang, Jiří Vencovský, Martin Klein, Olga Krystufkova, Franco Franceschini, Micaela Fredi, Sophie Hue, Thibaut Belmondo, Katalin Danko, Michael Mahler
In an effort to find natural occurring substances that reduced cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR), statins were first discovered by Endo in 1972. With the widespread prescription and use of statins to decrease morbidity from myocardial infarction and stroke, it was noted that approximately 5% of all statin users experience muscle pain and weakness during treatment. In a smaller proportion of patients the myopathy progresses to severe morbidity marked by proximal weakness and severe muscle wasting. Remarkably, Mammen and colleagues were the first to discover that the molecular target of statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is an autoantibody target in patients who develop an immune mediated necrotizing myopathy (IMNM). These observations have been confirmed in a number of studies, but until today a multi-center, international study of IMNM, related idiopathic inflammatory myopathies (IIM), other auto-inflammatory conditions and controls had not been published. Accordingly, an international, multi-center study investigated the utility of anti-HMGCR antibodies in the diagnosis of statin-associated IMNM in comparison to different forms of IIM and controls. This study included samples from patients with different forms of IIM (n=1250) and patients with other diseases (n=656) that were collected from twelve sites and tested for anti-HMGCR antibodies by ELISA. This study confirmed that anti-HMGCR autoantibodies, when found in conjunction with statin use, characterize a subset of IIM who are older and have necrosis on muscle biopsy. Taken together, the data to date indicates that testing for anti-HMGCR antibodies is important in the differential diagnosis of IIM and might be considered for future classification criteria.



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Multi-center harmonization of flow cytometers in the context of the European “PRECISESADS” project

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Christophe Jamin, Lucas Le Lann, Damiana Alvarez-Errico, Nuria Barbarroja, Tineke Cantaert, Julie Ducreux, Aleksandra Maria Dufour, Velia Gerl, Katja Kniesch, Esmeralda Neves, Elena Trombetta, Marta Alarcón-Riquelme, Concepción Marañon, Jacques-Olivier Pers
The innovative medicine initiative project called PRECISESADS will study 2.500 individuals affected by systemic autoimmune diseases (SADs) and controls. Among extensive OMICS approaches, multi-parameter flow cytometry analyses will be performed in eleven different centers. Therefore, the integration of all data in common bioinformatical and biostatistical investigations requires a fine mirroring of all instruments. We describe here the procedure elaborated to achieve this prerequisite. One flow cytometer chosen as reference instrument fixed the mean fluorescence intensities (MFIs) of 8 different fluorochrome-conjugated antibodies (Abs) using VersaComp Ab capture beads. The ten other centers adjusted their own PMT voltages to reach the same MFIs. Subsequently, all centers acquired Rainbow 8-peak beads data on a daily basis to follow the stability of their instrument overtime. One blood sample has been dispatched and concomitantly stained in all centers. Comparison of leukocytes frequencies and cell surface marker MFIs demonstrated the close sensitivity of all flow cytometers, allowing a multicenter analysis. The effective multi-center harmonization enables the constitution of a workable wide flow cytometry database for the identification of specific molecular signatures in individuals with SADs.



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Cardiovascular risk assessment in patients with rheumatoid arthritis: The relevance of clinical, genetic and serological markers

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Raquel López-Mejías, Santos Castañeda, Carlos González-Juanatey, Alfonso Corrales, Iván Ferraz-Amaro, Fernanda Genre, Sara Remuzgo-Martínez, Luis Rodriguez-Rodriguez, Ricardo Blanco, Javier Llorca, Javier Martín, Miguel A. González-Gay
Cardiovascular disease (CV) is the most common cause of premature mortality in patients with rheumatoid arthritis (RA). This is the result of an accelerated atherosclerotic process. Adequate CV risk stratification has special relevance in RA to identify patients at risk of CV disease. However, current CV risk screening and management strategies underestimate the actual CV risk in RA. Consequently, the search for additional tools that may help to identify those patients at high CV risk has become a key objective in the last years. In this regard, non-invasive surrogates, such as carotid ultrasonography, have been found to be excellent predictors of future CV events. In addition, several studies have revealed the relevance of a genetic component in the development of CV disease in RA patients. Besides an association with HLA-DRB1* shared epitope alleles other gene polymorphisms located inside and outside the HLA seem to influence the risk of cardiovascular disease in RA. Moreover, serum levels of some metabolic syndrome-related biomarkers, adipokines such as adiponectin and biomarkers of endothelial cell activation and inflammation such as Osteoprotegerin and Asymmetric dimethylarginine have recently been found useful for the prediction of CV disease in these patients. An update of the current knowledge on these potential markers, especially focused on new genetic and serological biomarkers is shown in this review.



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Critical review of the current recommendations for the treatment of systemic inflammatory rheumatic diseases during pregnancy and lactation

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Roger A. Levy, Guilherme R. de Jesús, Nilson R. de Jesús, Evandro M. Klumb
The crucial issue for a better pregnancy outcome in women with autoimmune rheumatic diseases is appropriate planning, with counseling of the ideal timing and treatment adaptation. Drugs used to treat rheumatic diseases may interfere with fertility or increase the risk of miscarriages and congenital abnormalities. MTX use post-conception is clearly linked to abortions as well as major birth defects, so it should be stopped 3months before conception. Leflunomide causes abnormalities in animals even in low doses. Although in humans, it does not seem to be as harmful as MTX, when pregnancy is detected in a patient on leflunomide, cholestyramine is given for washout. Sulfasalazine can be used safely and is an option for those patients who were on MTX or leflunomide. Azathioprine is generally the immunosuppressive of choice in many high-risk pregnancy centers because of the safety profile and its steroid-sparing property. Cyclosporine and tacrolimus can also be used as steroid-sparing agents, but experience is smaller. Although prednisone and prednisolone are inactivated in the placenta, we try to limit the dose to the minimal effective one, to prevent side effects. Antimalarials have been broadly studied and are safe during pregnancy and breastfeeding. Among biologic disease modifying anti-rheumatic agents (bDMARD), the anti-TNFs that have been used for longer are the ones with greater experience. The large monoclonal antibodies do not cross the placenta in the first trimester, and after conception, the decision to continue medication should be taken individually. The experience is larger in women with inflammatory bowel diseases, where anti-TNF is generally maintained at least until 30weeks to reduce fetal exposure. Live vaccines should not be administrated to the infant in the first 6months of life. Pregnancy data for rituximab, abatacept, anakinra, tocilizumab, ustekinumab, belimumab, and tofacitinib are limited and their use in pregnancy cannot currently be recommended.



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Multiparametric serological testing in autoimmune encephalitis using computer-aided immunofluorescence microscopy (CAIFM)

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Johanna Fraune, Stefan Gerlach, Kristin Rentzsch, Bianca Teegen, Sabine Lederer, Kai Affeldt, Kai Fechner, Maick Danckwardt, Jörn Voigt, Christian Probst, Lars Komorowski, Winfried Stöcker
Autoantibodies against neuronal cell surface antigens are tightly associated with immunotherapy-responsive autoimmune encephalitis, and a considerable number of corresponding autoantigens has been identified in recent years. Most patients initially present with overlapping symptoms, and a broad range of autoantibodies has to be considered to establish the correct diagnosis and initiate treatment as soon as possible to prevent irreversible and sometimes even life-threatening damage to the brain. Recombinant cell-based immunofluorescence allows to authentically present fragile membrane-associated surface antigens and, in combination with multiparametric analysis in the form of biochip mosaics, has turned out to be highly beneficial for parallel and prompt determination of anti-neuronal autoantibodies and comprehensive differential diagnostics. For the evaluation of recombinant cell-based IIFT, a semi-automated novel function was introduced into an established platform for computer-aided immunofluorescence microscopy. The system facilitates the microscopic analysis of the tests and supports the laboratory personnel in the rapid issuance of diagnostic findings, which is of major importance for autoimmune encephalitis patients since timely initiation of treatment may lead to their full recovery.



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From HBV to HPV: Designing vaccines for extensive and intensive vaccination campaigns worldwide

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Darja Kanduc, Yehuda Shoenfeld
HBsAg and HPV L1 proteins – the HBV and HPV antigens utilized in current vaccines – share amino acid sequences with human proteins such as cardiomyopathy-associated protein 5, titin, protein-arginine deiminase, E3 ubiquitin-protein ligase RNF19A, bassoon, G-protein coupled receptor for fatty acids, insulin isoform 2, and mitogen-activated protein kinase kinase kinase 10, inter alia. Many shared peptides are also part of immunopositive epitopes. The data 1) support the possibility of crossreactions between the two viral antigens and human proteins that, when altered, may associate with neuropsychiatric, cardiovascular and altered metabolic conditions such as multiple sclerosis, amyotrophic lateral sclerosis, diabetes, and sudden death; 2) confirm the concept that only vaccines based on sequences unique to pathogens might nullify potential crossreactivity risks in vaccination protocols.



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The in vitro generation of multi-tumor antigen-specific cytotoxic T cell clones: Candidates for leukemia adoptive immunotherapy following allogeneic stem cell transplantation

Publication date: September 2016
Source:Molecular Immunology, Volume 77
Author(s): Yehia S. Mohamed, Layla A. Bashawri, Chittibabu Vatte, Eman Y. Abu-rish, Cyril Cyrus, Wafaa S. Khalaf, Michael J. Browning
Adoptive T-cell immunotherapy is a promising approach to manage and maintain relapse-free survival of leukemia patients, especially following allogeneic stem cell transplantation. Post-transplant adoptive immunotherapy using cytotoxic T lymphocytes (CTLs) of the donor origin provide graft-versus-tumor effects, with or without graft–versus-host disease. Myeloid leukemias express immunogenic leukemia associated antigens (LAAs); such as WT-1, PRAME, MAGE, h-TERT and others, most of them are able to induce specific T cell responses whenever associated with the proper co-stimulation. We investigated the ability of a LAA-expressing hybridoma cell line to induce CTL clones in PBMCs of HLA-matched healthy donors in vitro. The CTL clones were induced by repetitive co-culture with LAAs-expressing, HLA-A*0201⁺ hybrid cell line, generated by fusion of leukemia blasts to human immortalized APC (EBV-sensitized B-lymphoblastoid cell line; HMy2). The induced cytotoxic T cell clones were phenotypically and functionally characterized by pentamer analysis, IFN-γ release ELISPOT and cellular cytotoxicity assays. All T cell lines showed robust peptide recognition and functional activity when sensitized with HLA-A*0201-restricted WT-1235–243, hTERT615–624 or PRAME100–108 peptides-pulsed T2 cells, in addition to partially HLA-matched leukemia blasts. This study demonstrates the feasibility of developing multi-tumor antigen-specific T cell lines in allogeneic PBMCs in vitro, using LAA-expressing tumor/HMy2 hybrid cell line model, for potential use in leukemia adoptive immunotherapy in partially matched donor-recipient setting.



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Familial C3 glomerulonephritis caused by a novel CFHR5-CFHR2 fusion gene

Publication date: September 2016
Source:Molecular Immunology, Volume 77
Author(s): Xue Xiao, Cybele Ghossein, Agustín Tortajadam, Yuzhou Zhang, Nicole Meyer, Michael Jones, Nicolo Ghiringhelli Borsa, Carla M. Nester, Christie P. Thomas, Santiago Rodríquez de Córdoba, Richard J.H. Smith
C3 glomerulopathy (C3G) is an ultra-rare complement-mediated renal disease characterized histologically by the predominance of C3 deposition within in the glomerulus. Familial cases of C3G are extremely uncommon and offer unique insight into the genetic drivers of complement dysregulation. In this report, we describe a patient who presented with C3G. Because a relative carried the same diagnosis, we sought an underlying genetic commonality to explain the phenotype. As part of a comprehension genetic screen, we completed multiplex ligation-dependent probe amplification across the complement factor H related region and identified amplification alterations consistent with a genomic rearrangement. Using comparative genomic hybridization, we narrowed and then cloned the rearrangement breakpoints thereby defining a novel fusion gene that is translated into a serum protein comprised of factor H related-5 (short consensus repeats 1 and 2) and factor H-related-2 (short consensus repeats 1–4). These data highlight the role of factor H related proteins in the control of complement activity and illustrate how perturbation of that control leads to C3G.



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Evidence of activity-dependent plasticity in the dorsal cochlear nucleus, in vivo, induced by brief sound exposure

Publication date: Available online 1 August 2016
Source:Hearing Research
Author(s): Y. Gao, N. Manzoor, J.A. Kaltenbach
The purpose of the present study was to investigate the immediate effects of acute exposure to intense sound on spontaneous and stimulus-driven activity in the dorsal cochlear nucleus (DCN). We examined the levels of multi- and single-unit spontaneous activity before and immediately following brief exposure (2 minutes) to tones at levels of either 109 or 85 dB SPL. Exposure frequency was selected to either correspond to the units' best frequency (BF) or fall within the borders of its inhibitory side band. The results demonstrate that these exposure conditions caused significant alterations in spontaneous activity and responses to BF tones. The induced changes have a fast onset (minutes) and are persistent for durations of at least 20 minutes. The directions of the change were found to depend on the frequency of exposure relative to BF. Transient decreases followed by more sustained increases in spontaneous activity were induced when the exposure frequency was at or near the units' BF, while sustained decreases of activity resulted when the exposure frequency fell inside the inhibitory side band. Follow-up studies at the single unit level revealed that the observed activity changes were found on unit types having properties which have previously been found to represent fusiform cells. The changes in spontaneous activity occurred despite only minor changes in response thresholds. Noteworthy changes also occurred in the strength of responses to BF tones, although these changes tended to be in the direction opposite those of the spontaneous rate changes. We discuss the possible role of activity-dependent plasticity as a mechanism underlying the rapid emergence of increased spontaneous activity after tone exposure and suggest that these changes may represent a neural correlate of acute noise-induced tinnitus.



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Motion of Tympanic Membrane in Guinea Pig Otitis Media Model Measured by Scanning Laser Doppler Vibrometry

Publication date: Available online 1 August 2016
Source:Hearing Research
Author(s): Xuelin Wang, Xiying Guan, Mario Pineda, Rong Z. Gan
Otitis media (OM) is an inflammatory or infectious disease of the middle ear. Acute otitis media (AOM) and otitis media with effusion (OME) are the two major types of OM. However, the tympanic membrane (TM) motion differences induced by AOM and OME have not been quantified in animal models in the literature. In this study, the guinea pig AOM and OME models were created by transbullar injection of Streptococcus pneumoniae type 3 and lipopolysaccharide, respectively. To explore the effects of OM on the entire TM vibration, the measurements of full-field TM motions were performed in the AOM, OME and untreated control ears by using scanning laser Doppler vibrometry (SLDV). The results showed that both AOM and OME generally reduced the displacement peak and produced the traveling-wave-like motions at relatively low frequencies. Compared with the normal ear, OME resulted in a significant change of the TM displacement mainly in the inferior portion of the TM, and AOM significantly affected the surface motion across four quadrants. The SLDV measurements provide more insight into sound-induced TM vibration in diseased ears.



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The role of monocytes in ANCA-associated vasculitides

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Francesca Brunini, Theresa H. Page, Maurizio Gallieni, Charles D. Pusey
The anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are a heterogeneous group of diseases causing inflammation in small blood vessels and linked by the presence of circulating ANCA specific for proteinase 3 (PR3) or myeloperoxidase (MPO). These antigens are present both in the cytoplasmic granules and on the surface of neutrophils, and the effect of ANCA on neutrophil biology has been extensively studied. In contrast, less attention has been paid to the role of monocytes in AAV. These cells contain PR3 and MPO in lysosomes and can also express them at the cell surface. Monocytes respond to ANCA by producing pro-inflammatory and chemotactic cytokines, reactive-oxygen-species and by up-regulating CD14. Moreover, soluble and cell surface markers of monocyte activation are raised in AAV patients, suggesting an activated phenotype that may persist even during disease remission. The presence of monocyte-derived macrophages and giant cells within damaged renal and vascular tissue in AAV also attests to their role in pathogenesis. In particular, their presence in the tertiary lymphoid organ-like granulomas of AAV patients may generate an environment predisposed to maintaining autoimmunity. Here we discuss the evidence for a pathogenic role of monocytes in AAV, their role in granuloma formation and tissue damage, and their potential to both direct and maintain autoimmunity. ANCA-activation of monocytes may therefore provide an explanation for the relapsing-remitting course of disease and its links with infections. Monocytes may thus represent a promising target for the treatment of this group of life-threatening diseases.



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Pitfalls in Lupus

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): M. Schneider
"The objective of Pitfall!™ is to guide Harry through a maze of jungle scenes, jumping over or avoiding many deadly dangers… Harry has three lives in each game". If you exchange Harry's adventures with "Life with SLE", patients have to be guided through the jungle having just one life and the deadly dangers are flares, organ manifestations and e.g. consequences of immunosuppressive medications, especially glucocorticoids. Monitoring and treatment in line with recommendations and guidelines may be supportive to survive the first 3 to 5 levels in most cases, but for higher levels of the reality game creativity is needed and life becomes more risky. The aim of this reflection is to identify common pitfalls and to stimulate further research and collaboration in specific areas of the lupus jungle. Topics like "Hidden Power Unit", "Looks similar …", "Rev Meter for SLE", "Flare Prediction", "Level 2: Eminence Based", "Lupus=Lifelong Immunosuppression? !", "Glucocorticoids", "Antimalarials are Contraindicated", "It is all about immunosuppression", "Prediction of Damage" and "Patient Global Assessment (PGA) versus Physician Global Assessment (PhGA)" are addressed. Raised ideas and thoughts are by no means complete or exclusive, but if taken up they may hopefully lead to another approach in daily care and trials in SLE.



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Humoral and cellular autoimmunity in women with recurrent pregnancy losses and repeated implantation failures; a possible role of vitamin D

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Joanne Kwak-Kim, Annie Skariah, Li Wu, Dinorah Salazar, Nayoung Sung, Kuniaki Ota
Women with recurrent pregnancy losses (RPL) and repeated implantation failures (RIF) have auto- and cellular immune abnormalities. Approximately, 20% of women with RPL have autoimmune abnormalities, particularly antiphospholipid antibodies (APA). In addition, these women have a higher prevalence of antinuclear antibody, anti-thyroperoxidase and anti-thyroglobulin antibodies, and other non-organ specific autoantibodies. In women with RPL, presence of autoimmunity is often associated with cellular immune abnormalities, such as increased NK cell levels and Th1/Th2 cell ratios. Vitamin D (VD) plays a major role in regulation of auto- and cellular immune abnormalities. VD deficiency is prevalent in women with RPL, and women with VD deficiency have increased auto- and cellular immune abnormalities as compared with women with normal VD levels. VD has immune regulatory effects on various immune effectors including T, B and NK cells. Potential therapeutic application of VD for RPL and RIF with auto- and cellular immune abnormalities should be explored.



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The viral paradigm in type 1 diabetes: who are the main suspects?

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Teresa Rodriguez-Calvo, Somayeh Sabouri, Florence Anquetil, Matthias G. von Herrath
Type 1 diabetes (T1D) is an autoimmune disease characterized by the loss of pancreatic beta cells in the islets of Langerhans. Although genetic predisposition plays an important role in T1D development, studies of identical twins suggest that environmental factors such as viruses and other pathogens may be critical triggers either through direct cytolytic effect and gradual beta cell destruction, or by bystander activation of the immune system. In addition, viruses may circumvent the host immune response and have the capacity to establish chronic lifelong infections. The association of various viral infections with the induction of T1D has been extensively studied at the serological and epidemiological level. However, there is still little evidence from studies of human pancreas to confirm their presence or a causal role in disease pathogenesis. In this review, we identify possible suspects for viral triggers of disease and explain their potential roles in the "viral paradigm" of T1D.



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Fc-Gamma Receptors: Attractive Targets for Autoimmune Drug Discovery Searching for Intelligent Therapeutic Designs

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Carlos J. Bosques, Anthony M. Manning
Auto-antibody immune complexes (ICs) mediate pathogenesis in multiple autoimmune diseases direct interference with target function, complement fixation, and interaction with Fc-gamma receptors (FcγRs). Through high avidity interactions, ICs are able to crosslink low affinity FcγRs expressed on a wide variety of effector cells, leading to secretion of pro-inflammatory mediators and inducing cytotoxicity, ultimately resulting in tissue injury. Given their relevance in numerous autoimmune diseases, FcγRs have been considered as attractive therapeutic targets for the last three decades. However, a limited number of investigational drug candidates have been developed targeting FcγRs and only a few approved therapeutics have been associated with impacting FcγRs. This review provides a historical overview of the different therapeutic approaches used to target FcγRs for the treatment of autoimmune and inflammatory diseases.



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Anti-HMGCR antibodies as a biomarker for immune mediated necrotizing myopathies: A history of statins and experience from a large international multi-center study

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Lucile Musset, Yves Allenbach, Olivier Benveniste, Olivier Boyer, Xavier Bossuyt, Chelsea Bentow, Joe Phillips, Andrew Mammen, Philip Van Damme, René Westhovens, Anna Ghirardello, Andrea Doria, May E. Choi, Marvin J. Fritzler, Heinrike Schmeling, Yoshinao Muro, Ignacio García-De La Torre, Miguel A. Ortiz-Villalvazo, Nicola Bizzaro, Maria Infantino, Tiziana Imbastaro, Peng, Guochun Wang, Jiří Vencovský, Martin Klein, Olga Krystufkova, Franco Franceschini, Micaela Fredi, Sophie Hue, Thibaut Belmondo, Katalin Danko, Michael Mahler
In an effort to find natural occurring substances that reduced cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR), statins were first discovered by Endo in 1972. With the widespread prescription and use of statins to decrease morbidity from myocardial infarction and stroke, it was noted that approximately 5% of all statin users experience muscle pain and weakness during treatment. In a smaller proportion of patients the myopathy progresses to severe morbidity marked by proximal weakness and severe muscle wasting. Remarkably, Mammen and colleagues were the first to discover that the molecular target of statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is an autoantibody target in patients who develop an immune mediated necrotizing myopathy (IMNM). These observations have been confirmed in a number of studies, but until today a multi-center, international study of IMNM, related idiopathic inflammatory myopathies (IIM), other auto-inflammatory conditions and controls had not been published. Accordingly, an international, multi-center study investigated the utility of anti-HMGCR antibodies in the diagnosis of statin-associated IMNM in comparison to different forms of IIM and controls. This study included samples from patients with different forms of IIM (n=1250) and patients with other diseases (n=656) that were collected from twelve sites and tested for anti-HMGCR antibodies by ELISA. This study confirmed that anti-HMGCR autoantibodies, when found in conjunction with statin use, characterize a subset of IIM who are older and have necrosis on muscle biopsy. Taken together, the data to date indicates that testing for anti-HMGCR antibodies is important in the differential diagnosis of IIM and might be considered for future classification criteria.



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Multi-center harmonization of flow cytometers in the context of the European “PRECISESADS” project

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Christophe Jamin, Lucas Le Lann, Damiana Alvarez-Errico, Nuria Barbarroja, Tineke Cantaert, Julie Ducreux, Aleksandra Maria Dufour, Velia Gerl, Katja Kniesch, Esmeralda Neves, Elena Trombetta, Marta Alarcón-Riquelme, Concepción Marañon, Jacques-Olivier Pers
The innovative medicine initiative project called PRECISESADS will study 2.500 individuals affected by systemic autoimmune diseases (SADs) and controls. Among extensive OMICS approaches, multi-parameter flow cytometry analyses will be performed in eleven different centers. Therefore, the integration of all data in common bioinformatical and biostatistical investigations requires a fine mirroring of all instruments. We describe here the procedure elaborated to achieve this prerequisite. One flow cytometer chosen as reference instrument fixed the mean fluorescence intensities (MFIs) of 8 different fluorochrome-conjugated antibodies (Abs) using VersaComp Ab capture beads. The ten other centers adjusted their own PMT voltages to reach the same MFIs. Subsequently, all centers acquired Rainbow 8-peak beads data on a daily basis to follow the stability of their instrument overtime. One blood sample has been dispatched and concomitantly stained in all centers. Comparison of leukocytes frequencies and cell surface marker MFIs demonstrated the close sensitivity of all flow cytometers, allowing a multicenter analysis. The effective multi-center harmonization enables the constitution of a workable wide flow cytometry database for the identification of specific molecular signatures in individuals with SADs.



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Cardiovascular risk assessment in patients with rheumatoid arthritis: The relevance of clinical, genetic and serological markers

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Raquel López-Mejías, Santos Castañeda, Carlos González-Juanatey, Alfonso Corrales, Iván Ferraz-Amaro, Fernanda Genre, Sara Remuzgo-Martínez, Luis Rodriguez-Rodriguez, Ricardo Blanco, Javier Llorca, Javier Martín, Miguel A. González-Gay
Cardiovascular disease (CV) is the most common cause of premature mortality in patients with rheumatoid arthritis (RA). This is the result of an accelerated atherosclerotic process. Adequate CV risk stratification has special relevance in RA to identify patients at risk of CV disease. However, current CV risk screening and management strategies underestimate the actual CV risk in RA. Consequently, the search for additional tools that may help to identify those patients at high CV risk has become a key objective in the last years. In this regard, non-invasive surrogates, such as carotid ultrasonography, have been found to be excellent predictors of future CV events. In addition, several studies have revealed the relevance of a genetic component in the development of CV disease in RA patients. Besides an association with HLA-DRB1* shared epitope alleles other gene polymorphisms located inside and outside the HLA seem to influence the risk of cardiovascular disease in RA. Moreover, serum levels of some metabolic syndrome-related biomarkers, adipokines such as adiponectin and biomarkers of endothelial cell activation and inflammation such as Osteoprotegerin and Asymmetric dimethylarginine have recently been found useful for the prediction of CV disease in these patients. An update of the current knowledge on these potential markers, especially focused on new genetic and serological biomarkers is shown in this review.



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Critical review of the current recommendations for the treatment of systemic inflammatory rheumatic diseases during pregnancy and lactation

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Roger A. Levy, Guilherme R. de Jesús, Nilson R. de Jesús, Evandro M. Klumb
The crucial issue for a better pregnancy outcome in women with autoimmune rheumatic diseases is appropriate planning, with counseling of the ideal timing and treatment adaptation. Drugs used to treat rheumatic diseases may interfere with fertility or increase the risk of miscarriages and congenital abnormalities. MTX use post-conception is clearly linked to abortions as well as major birth defects, so it should be stopped 3months before conception. Leflunomide causes abnormalities in animals even in low doses. Although in humans, it does not seem to be as harmful as MTX, when pregnancy is detected in a patient on leflunomide, cholestyramine is given for washout. Sulfasalazine can be used safely and is an option for those patients who were on MTX or leflunomide. Azathioprine is generally the immunosuppressive of choice in many high-risk pregnancy centers because of the safety profile and its steroid-sparing property. Cyclosporine and tacrolimus can also be used as steroid-sparing agents, but experience is smaller. Although prednisone and prednisolone are inactivated in the placenta, we try to limit the dose to the minimal effective one, to prevent side effects. Antimalarials have been broadly studied and are safe during pregnancy and breastfeeding. Among biologic disease modifying anti-rheumatic agents (bDMARD), the anti-TNFs that have been used for longer are the ones with greater experience. The large monoclonal antibodies do not cross the placenta in the first trimester, and after conception, the decision to continue medication should be taken individually. The experience is larger in women with inflammatory bowel diseases, where anti-TNF is generally maintained at least until 30weeks to reduce fetal exposure. Live vaccines should not be administrated to the infant in the first 6months of life. Pregnancy data for rituximab, abatacept, anakinra, tocilizumab, ustekinumab, belimumab, and tofacitinib are limited and their use in pregnancy cannot currently be recommended.



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Multiparametric serological testing in autoimmune encephalitis using computer-aided immunofluorescence microscopy (CAIFM)

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Johanna Fraune, Stefan Gerlach, Kristin Rentzsch, Bianca Teegen, Sabine Lederer, Kai Affeldt, Kai Fechner, Maick Danckwardt, Jörn Voigt, Christian Probst, Lars Komorowski, Winfried Stöcker
Autoantibodies against neuronal cell surface antigens are tightly associated with immunotherapy-responsive autoimmune encephalitis, and a considerable number of corresponding autoantigens has been identified in recent years. Most patients initially present with overlapping symptoms, and a broad range of autoantibodies has to be considered to establish the correct diagnosis and initiate treatment as soon as possible to prevent irreversible and sometimes even life-threatening damage to the brain. Recombinant cell-based immunofluorescence allows to authentically present fragile membrane-associated surface antigens and, in combination with multiparametric analysis in the form of biochip mosaics, has turned out to be highly beneficial for parallel and prompt determination of anti-neuronal autoantibodies and comprehensive differential diagnostics. For the evaluation of recombinant cell-based IIFT, a semi-automated novel function was introduced into an established platform for computer-aided immunofluorescence microscopy. The system facilitates the microscopic analysis of the tests and supports the laboratory personnel in the rapid issuance of diagnostic findings, which is of major importance for autoimmune encephalitis patients since timely initiation of treatment may lead to their full recovery.



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From HBV to HPV: Designing vaccines for extensive and intensive vaccination campaigns worldwide

Publication date: Available online 1 August 2016
Source:Autoimmunity Reviews
Author(s): Darja Kanduc, Yehuda Shoenfeld
HBsAg and HPV L1 proteins – the HBV and HPV antigens utilized in current vaccines – share amino acid sequences with human proteins such as cardiomyopathy-associated protein 5, titin, protein-arginine deiminase, E3 ubiquitin-protein ligase RNF19A, bassoon, G-protein coupled receptor for fatty acids, insulin isoform 2, and mitogen-activated protein kinase kinase kinase 10, inter alia. Many shared peptides are also part of immunopositive epitopes. The data 1) support the possibility of crossreactions between the two viral antigens and human proteins that, when altered, may associate with neuropsychiatric, cardiovascular and altered metabolic conditions such as multiple sclerosis, amyotrophic lateral sclerosis, diabetes, and sudden death; 2) confirm the concept that only vaccines based on sequences unique to pathogens might nullify potential crossreactivity risks in vaccination protocols.



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The in vitro generation of multi-tumor antigen-specific cytotoxic T cell clones: Candidates for leukemia adoptive immunotherapy following allogeneic stem cell transplantation

Publication date: September 2016
Source:Molecular Immunology, Volume 77
Author(s): Yehia S. Mohamed, Layla A. Bashawri, Chittibabu Vatte, Eman Y. Abu-rish, Cyril Cyrus, Wafaa S. Khalaf, Michael J. Browning
Adoptive T-cell immunotherapy is a promising approach to manage and maintain relapse-free survival of leukemia patients, especially following allogeneic stem cell transplantation. Post-transplant adoptive immunotherapy using cytotoxic T lymphocytes (CTLs) of the donor origin provide graft-versus-tumor effects, with or without graft–versus-host disease. Myeloid leukemias express immunogenic leukemia associated antigens (LAAs); such as WT-1, PRAME, MAGE, h-TERT and others, most of them are able to induce specific T cell responses whenever associated with the proper co-stimulation. We investigated the ability of a LAA-expressing hybridoma cell line to induce CTL clones in PBMCs of HLA-matched healthy donors in vitro. The CTL clones were induced by repetitive co-culture with LAAs-expressing, HLA-A*0201⁺ hybrid cell line, generated by fusion of leukemia blasts to human immortalized APC (EBV-sensitized B-lymphoblastoid cell line; HMy2). The induced cytotoxic T cell clones were phenotypically and functionally characterized by pentamer analysis, IFN-γ release ELISPOT and cellular cytotoxicity assays. All T cell lines showed robust peptide recognition and functional activity when sensitized with HLA-A*0201-restricted WT-1235–243, hTERT615–624 or PRAME100–108 peptides-pulsed T2 cells, in addition to partially HLA-matched leukemia blasts. This study demonstrates the feasibility of developing multi-tumor antigen-specific T cell lines in allogeneic PBMCs in vitro, using LAA-expressing tumor/HMy2 hybrid cell line model, for potential use in leukemia adoptive immunotherapy in partially matched donor-recipient setting.



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Familial C3 glomerulonephritis caused by a novel CFHR5-CFHR2 fusion gene

Publication date: September 2016
Source:Molecular Immunology, Volume 77
Author(s): Xue Xiao, Cybele Ghossein, Agustín Tortajadam, Yuzhou Zhang, Nicole Meyer, Michael Jones, Nicolo Ghiringhelli Borsa, Carla M. Nester, Christie P. Thomas, Santiago Rodríquez de Córdoba, Richard J.H. Smith
C3 glomerulopathy (C3G) is an ultra-rare complement-mediated renal disease characterized histologically by the predominance of C3 deposition within in the glomerulus. Familial cases of C3G are extremely uncommon and offer unique insight into the genetic drivers of complement dysregulation. In this report, we describe a patient who presented with C3G. Because a relative carried the same diagnosis, we sought an underlying genetic commonality to explain the phenotype. As part of a comprehension genetic screen, we completed multiplex ligation-dependent probe amplification across the complement factor H related region and identified amplification alterations consistent with a genomic rearrangement. Using comparative genomic hybridization, we narrowed and then cloned the rearrangement breakpoints thereby defining a novel fusion gene that is translated into a serum protein comprised of factor H related-5 (short consensus repeats 1 and 2) and factor H-related-2 (short consensus repeats 1–4). These data highlight the role of factor H related proteins in the control of complement activity and illustrate how perturbation of that control leads to C3G.



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Evidence of activity-dependent plasticity in the dorsal cochlear nucleus, in vivo, induced by brief sound exposure

Publication date: Available online 1 August 2016
Source:Hearing Research
Author(s): Y. Gao, N. Manzoor, J.A. Kaltenbach
The purpose of the present study was to investigate the immediate effects of acute exposure to intense sound on spontaneous and stimulus-driven activity in the dorsal cochlear nucleus (DCN). We examined the levels of multi- and single-unit spontaneous activity before and immediately following brief exposure (2 minutes) to tones at levels of either 109 or 85 dB SPL. Exposure frequency was selected to either correspond to the units' best frequency (BF) or fall within the borders of its inhibitory side band. The results demonstrate that these exposure conditions caused significant alterations in spontaneous activity and responses to BF tones. The induced changes have a fast onset (minutes) and are persistent for durations of at least 20 minutes. The directions of the change were found to depend on the frequency of exposure relative to BF. Transient decreases followed by more sustained increases in spontaneous activity were induced when the exposure frequency was at or near the units' BF, while sustained decreases of activity resulted when the exposure frequency fell inside the inhibitory side band. Follow-up studies at the single unit level revealed that the observed activity changes were found on unit types having properties which have previously been found to represent fusiform cells. The changes in spontaneous activity occurred despite only minor changes in response thresholds. Noteworthy changes also occurred in the strength of responses to BF tones, although these changes tended to be in the direction opposite those of the spontaneous rate changes. We discuss the possible role of activity-dependent plasticity as a mechanism underlying the rapid emergence of increased spontaneous activity after tone exposure and suggest that these changes may represent a neural correlate of acute noise-induced tinnitus.



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Motion of Tympanic Membrane in Guinea Pig Otitis Media Model Measured by Scanning Laser Doppler Vibrometry

Publication date: Available online 1 August 2016
Source:Hearing Research
Author(s): Xuelin Wang, Xiying Guan, Mario Pineda, Rong Z. Gan
Otitis media (OM) is an inflammatory or infectious disease of the middle ear. Acute otitis media (AOM) and otitis media with effusion (OME) are the two major types of OM. However, the tympanic membrane (TM) motion differences induced by AOM and OME have not been quantified in animal models in the literature. In this study, the guinea pig AOM and OME models were created by transbullar injection of Streptococcus pneumoniae type 3 and lipopolysaccharide, respectively. To explore the effects of OM on the entire TM vibration, the measurements of full-field TM motions were performed in the AOM, OME and untreated control ears by using scanning laser Doppler vibrometry (SLDV). The results showed that both AOM and OME generally reduced the displacement peak and produced the traveling-wave-like motions at relatively low frequencies. Compared with the normal ear, OME resulted in a significant change of the TM displacement mainly in the inferior portion of the TM, and AOM significantly affected the surface motion across four quadrants. The SLDV measurements provide more insight into sound-induced TM vibration in diseased ears.



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Tissue-resident Eomeshi T-betlo CD56bright NK cells with reduced pro-inflammatory potential are enriched in the human adult liver

The adult human liver is enriched with natural killer (NK) cells, accounting for 30–50% of hepatic lymphocytes which include tissue-resident hepatic NK-cell subpopulations, distinct from peripheral blood NK cells. In murine liver, a subset of liver-resident hepatic NK cells with altered expression of the two highly related T-box transcription factors, T-bet and Eomes. Here, we investigate the heterogeneity of T-bet and Eomes expression in NK cells from healthy adult human liver with a view to identifying human liver-resident populations. Hepatic NK cells were isolated from donor liver perfusates and biopsies obtained during orthotopic liver transplantation (N = 28). Hepatic CD56^bright NK cells were Eomes^hi T-bet^lo, a phenotype virtually absent from peripheral blood. These NK cells express the chemokine receptor CXCR6, a marker of tissue residency, which is absent from hepatic CD56^dim and blood NK cells. Compared to blood populations, these hepatic CD56^bright NK cells have increased expression of activatory receptors (NKp44, NKp46 and NKG2D). They show reduced ability to produce IFN-γ but enhanced degranulation in response to challenge with target cells. This functionally distinct population of hepatic NK cells constitutes 20–30% of the total hepatic lymphocyte repertoire and represents a tissue-resident immune cell population adapted to the tolerogenic liver microenvironment.

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Tissue-resident Eomeshi T-betlo CD56bright NK cells with reduced pro-inflammatory potential are enriched in the human adult liver

The adult human liver is enriched with natural killer (NK) cells, accounting for 30–50% of hepatic lymphocytes which include tissue-resident hepatic NK-cell subpopulations, distinct from peripheral blood NK cells. In murine liver, a subset of liver-resident hepatic NK cells with altered expression of the two highly related T-box transcription factors, T-bet and Eomes. Here, we investigate the heterogeneity of T-bet and Eomes expression in NK cells from healthy adult human liver with a view to identifying human liver-resident populations. Hepatic NK cells were isolated from donor liver perfusates and biopsies obtained during orthotopic liver transplantation (N = 28). Hepatic CD56^bright NK cells were Eomes^hi T-bet^lo, a phenotype virtually absent from peripheral blood. These NK cells express the chemokine receptor CXCR6, a marker of tissue residency, which is absent from hepatic CD56^dim and blood NK cells. Compared to blood populations, these hepatic CD56^bright NK cells have increased expression of activatory receptors (NKp44, NKp46 and NKG2D). They show reduced ability to produce IFN-γ but enhanced degranulation in response to challenge with target cells. This functionally distinct population of hepatic NK cells constitutes 20–30% of the total hepatic lymphocyte repertoire and represents a tissue-resident immune cell population adapted to the tolerogenic liver microenvironment.

This article is protected by copyright. All rights reserved

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Survival Impact of Initial Therapy in Patients with T1-T2 Glottic Squamous Cell Carcinoma

Objective

Laryngeal cancer most commonly arises from the glottis. Comparable outcomes in survival have been shown in patients with early glottic squamous cell carcinoma treated with either surgery or radiotherapy.

Study Design and Setting

Administrative database study.

Subjects and Methods

The US National Cancer Institute's SEER database (Surveillance, Epidemiology, and End Results) was queried for cases of early glottic cancer (T1-T2N0M0, 1988-2012). We identified 13,312 qualifying cases. Patient demographics, therapeutic measures, and survival outcomes were examined with appropriate univariate and multivariate analyses.

Results

Early glottic cancer has a mean age at diagnosis of 64.8 ± 11.6 years and a male:female ratio of 6.9:1. The most common treatment modality was radiotherapy alone (51.6%), followed by combination therapy with surgery first (31.5%). Overall, the 5-year disease-specific survival (DSS) rate was 88.4%. When stratified by treatment modality and stage, 5-year DSS for T1 tumors was 93.2% with surgery alone and 89.0% with radiation alone (P < .0001). With combination therapy, the 5-year DSS was 91.3% for surgery first and 84.9% for radiation first (P = .0239). In T2 tumors, 5-year DSS was improved with single-modality therapy versus multimodality therapy (81.1% vs 76.4; P = .0255).

Conclusion

In T1 disease, surgery alone shows improved 5-year DSS versus radiation alone, but this difference was not observed in T2 tumors. Additionally, surgery, rather than radiation, shows improved 5-year DSS when implemented as a first-line therapy. Combination therapy does not show improved 5-year DSS for early glottic cancer.

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Cochlear Implantation in Canal Wall Down Mastoid Cavities

Cochlear implantation in canal wall down mastoid (CWD) cavities is fraught with the issue of how best to manage the mastoid cavity. Decision points include whether the external auditory meatus should be overclosed, whether the implantation should be staged, or even if the eustachian tube should be plugged. Given these options, we sought to describe our experience of cochlear implantation in CWD cavities. Among evaluation of subjects ≥18 years of age, 9 had cochlear implants placed in CWD mastoid cavities, 7 of which had the external auditory meatus overclosed, while 2 maintained open cavities following implantation. With an average follow-up of 36.7 months (median, 22.8 months), 2 subjects who had overclosure developed meatal dehiscences requiring further intervention, while no complications were observed in the 2 patients who maintained open cavities.

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Laryngeal Preservation in Glottic Cancer: A Comparison of Hospital Charges and Morbidity among Treatment Options

Objective

When total laryngectomy is not required, organ preservation surgery or radiotherapy is considered the standard of care for primary glottic cancer. These accepted treatment options are available for early and advanced glottic cancers due to equivalent locoregional control and survival rates. However, in today's climate of accountable care, the financial burden of treatment choices continues to increase in significance. We therefore compared hospital charges and treatment-related morbidity between organ-preserving surgery and radiation with or without chemotherapy—herein, (chemo)radiation—in the primary treatment of glottic cancer.

Study Design

Nationwide Inpatient Sample Database was analyzed to assess clinical and financial information.

Setting

Population-based analysis.

Subjects

Patients (N = 5499) with primary glottic cancer undergoing treatment with laryngeal preservation strategies.

Methods

Patients were subdivided by ICD-9 codes into 3 treatment groups: endoscopic resection, open partial laryngectomy, and (chemo)radiation. Treatment-related outcomes, charges, and length of hospitalization were analyzed among treatment groups.

Results

When adjusting for sex, age, race, comorbidity, and primary payer, (chemo)radiotherapy was associated with increased direct charges (P < .001; coefficient, $23,658.99; 95% confidence interval [95% CI]: $10,227.15-$37,090.84) and length of hospitalization (P < .001; hazard ratio, 0.593; 95% CI: 0.502-0.702) when compared with endoscopic surgery. As compared with open surgery, endoscopic surgery was associated with reduced hospital charges (P = .012; coefficient, $11,967.01; 95% CI: $2,784.17-$21,249.85) and duration of hospitalization (P < .001; hazard ratio, 0.749; 95% CI: 0.641-0.876).

Conclusions

This analysis suggests that increased utilization of endoscopic surgery in patients with primary glottic cancer not requiring total laryngectomy may lead to reduced financial burden and duration of hospitalization when compared with open surgery or (chemo)radiation therapy.

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HMGB1 facilitates hypoxia-induced vWF upregulation through TLR2-MYD88-SP1 pathway

Increased plasma level of von Willebrand Factor (vWF) is associated with major cardiovascular diseases (CVDs). We previously reported that multimeric vWF binds to NO synthase (NOS) and inhibits insulin-induced production of NO, thus promoting insulin resistance (IR) during acute hypoxia (AH). However, the transcriptional regulation of vWF during AH is not clearly understood. Here, we investigated the mechanisms underlying the upregulation of vwf in mice. AH significantly upregulates the tlr2, tlr3, myd88, and vwf expression and phosphorylation of specificity protein 1 (SP1). Furthermore, AH significantly upregulates HMGB1 in a time-dependent manner. Moreover, a TLR2 agonist upregulates vWF but a TLR3 agonist does not. Pretreatment with an HMGB1 inhibitor, TLR2-immunoneutralizing antibody, or SP1 inhibitor significantly inhibits vWF expression. Furthermore, Tlr2 silencing completely inhibited MYD88, vWF expression and SP1 phosphorylation. However, pretreatment with glycyrrhizic acid (GA) or silencing of Tlr2 completely blocks binding of Sp1 to the Vwf promoter, thus inhibiting its expression, and enhances IR during AH. Patients with Type-2 DM also showed significantly elevated levels of HMGB1, TLR2, SP1, and vWF, thereby supporting the results of the murine model of AH. Taken together, HMGB1 upregulates vWF in vivo through the TLR2-MYD88-SP1 pathway in mice.

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Neural Mechanisms Contributing to Dysphagia in Mouse Models

Investigative research into curative treatments for dysphagia is hindered by our incomplete understanding of the neural mechanisms of swallowing in health and disease. Development of translational research models is essential to bridge this knowledge gap by fostering innovative methodology. Toward this goal, our laboratory has developed a translational research assessment tool to investigate the neural mechanistic control of swallowing in unrestrained, self-feeding mice. Here we describe our initial development of synchronous brainstem neural recordings with a videofluoroscopic swallow study assay in healthy mice across the life span. Refinement of this combined methodology is currently underway. Ultimately, we envision that this assessment tool will permit systematic analysis of therapeutic interventions for dysphagia in preclinical trials with numerous mouse models of human conditions that cause dysphagia, such as amyotrophic lateral sclerosis, Parkinson's disease, stroke, and advanced aging.

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Effects of Continuous Positive Airway Pressure on Middle Ear Pressure and Acoustic Stapedial Reflex

Objective

This study investigated the effects of continuous positive airway pressure (CPAP) on middle ear pressure and acoustic stapedial reflex and the correlation between CPAP and middle ear pressure.

Study Design

Prospective cohort study.

Setting

Tertiary hospitals.

Subjects and Methods

Fifty patients with obstructive sleep apnea-hypopnea syndrome were assigned to the study group, and 50 healthy volunteers were assigned to the control group. The subjects underwent standard tympanometry while wearing a CPAP device (ie, simulated CPAP treatment), which was set to 0, 5, 10, and 15 cm H₂O, respectively. Tympanometry was performed before and after swallowing at each pressure of CPAP treatment.

Results

The mean middle ear pressures were 21.2, 22.6, 22.7, and 23.4 daPa (before swallowing) and 21.6, 42.6, 81.4, and 118.6 daPa (after swallowing) in the study group and 17.6, 18.7, 19.5, and 20.8 daPa (before swallowing) and 17.7, 44.2, 85.6, and 120.5 daPa (after swallowing) in the control group at the CPAPs of 0, 5, 10, and 15 cm H₂O, respectively. While the CPAPs were at 0 and 15 cm H₂O, the stapedial muscle reflex at 1.0 kHz did not have a significant difference between the 2 groups (² = 0.521, P = .470). The Pearson correlation coefficient of the CPAP pressure and the middle ear pressure after swallowing was 0.812 (P < .001).

Conclusion

CPAP affected middle ear pressure and was directly proportional to the pressure of the CPAP. However, CPAP treatment had no significant effect on stapedial muscle reflex.

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Computer-Aided Design and 3D Printing to Produce a Costal Cartilage Model for Simulation of Auricular Reconstruction

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Peritonsillar Abscess: Complication of Acute Tonsillitis or Webers Glands Infection?

Objective

To review the literature concerning the 2 primary hypotheses put forth to explain the pathogenesis of peritonsillar abscess: "the acute tonsillitis hypothesis" (peritonsillar abscess is a complication of acute tonsillitis) and "the Weber gland hypothesis" (peritonsillar abscess is an infection of Weber's glands).

Data Sources

PubMed, EMBASE.

Review Methods

Data supporting or negating one hypothesis or the other were elicited from the literature.

Conclusions

Several findings support the acute tonsillitis hypothesis. First, the 2 main pathogens in peritonsillar abscess have been recovered from pus aspirates and bilateral tonsillar tissues with high concordance rates, suggesting that both tonsils are infected in patients with peritonsillar abscess. Second, studies report signs of acute tonsillitis in the days prior to and at the time of peritonsillar abscess. Third, antibiotic treatment reduces the risk of abscess development in patients with acute tonsillitis. However, some findings suggest involvement of the Weber's glands in peritonsillar abscess pathogenesis. First, high amylase levels have been found in peritonsillar pus. Second, the majority of peritonsillar abscesses are located at the superior tonsillar pole in proximity of the Weber's glands. We propose a unified hypothesis whereby bacteria initially infect the tonsillar mucosa and spread via the salivary duct system to the peritonsillar space, where an abscess is formed.

Implications for Practice

Our findings support the rationale for antibiotic treatment of patients with severe acute tonsillitis to reduce the risk of abscess development. Improved understanding of peritonsillar abscess pathogenesis is important for the development of efficient prevention strategies.

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Informed Consent in Pediatric Otolaryngology: What Risks and Benefits Do Parents Recall?

Objective

To evaluate parental recall of surgical risks and benefits in pediatric otolaryngology and to assess for factors that may influence recall.

Study Design

Prospective cohort study.

Setting

Academic pediatric otolaryngology clinic.

Subjects and Methods

Eighty-four parents of children <6 years of age who underwent consultation for adeno/tonsillectomy and/or tympanostomy tube insertion were prospectively enrolled. Consultation visits were video recorded and the benefits and risks of surgery documented. Two weeks following the consultation, parents were contacted for assessment of recall of information discussed during the consultation.

Results

Overall, parents recalled only one-third of the risks of surgery mentioned by the surgeons. Parents were significantly more likely to recall the benefits of surgery as opposed to the risks (P < .001). Nine parents (10.7%) reported that no benefits were discussed during the consultation, and 10 (11.9%) reported no mention of any risks. Inconsistencies were present in which risks and benefits were mentioned by the providers. Parents who decided to proceed with surgery (58.3%) were significantly less likely to recall the surgical risks than those who did not (P < .001). The specific surgeon involved, the number of caregivers present, parental education level, and prior surgical history did not influence recall.

Conclusion

Parental recall of benefits and risks associated with common pediatric otolaryngology procedures was poor. This information is important because a low rate of recall may influence parents' perspectives of the procedure and could alter their decision-making processes or expectations. Methods to improve parental recall should be further studied.

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Quality of Life in Children with Hearing Impairment: Systematic Review and Meta-analysis

Objective

To determine the impact of pediatric hearing loss (HL) on quality of life (QOL).

Data Sources

A qualified medical librarian conducted a literature search for relevant publications that evaluate QOL in school-aged children with HL.

Review Methods

Studies were assessed independently by 2 reviewers for inclusion in the systematic review and meta-analysis.

Results

From 979 abstracts, 69 were identified as relevant; ultimately, 40 articles were included in the systematic review. This review revealed that children with HL generally report a lower QOL than their normal-hearing peers and that QOL improves after interventions. The extent of these differences is variable among studies and depends on the QOL measure. Four studies using the Pediatric Quality of Life Inventory (PedsQL) had sufficient data for inclusion in a meta-analysis. After studies were pooled, statistically and clinically significant differences in PedsQL scores were found between children with normal hearing and those with HL, specifically in the social and school domains. Statistically significant differences were also noted in total scores for children with unilateral HL and in the physical domain for children with bilateral HL as compared with those having normal hearing; however, these differences were not clinically meaningful.

Conclusions

Our analysis reveals that decreased QOL in children with HL is detected in distinct domains of the PedsQL. These domains—school activities and social interactions—are especially important for development and learning. Future work should focus on these aspects of QOL when assessing HL in the pediatric population.

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Animal Model of Chronic Perforation Is Best for Eardrum Regeneration Using Biological Materials

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The Role of Surgery in Management of Samters Triad: A Systematic Review

Objective

Aspirin-exacerbated respiratory disease (AERD) represents a severe form of chronic rhinosinusitis (CRS) characterized by nasal polyposis, bronchial asthma, and aspirin intolerance. This syndrome, known as Samter's triad, is more difficult to manage than routine CRS and poses a challenge to the treating clinician. We performed a systematic review of the literature to determine the role of endoscopic sinus surgery in patients with AERD who are on adjuvant medical therapies.

Data Sources

PubMed, Embase, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Cochrane Technology Assessments, Cochrane Economic Evaluations, Cochrane Groups, and Clinicaltrials.gov.

Review Methods

A systematic review of the literature was performed using the 2009 PRISMA guidelines. Studies with both preoperative and postoperative data for patients with AERD who underwent sinus surgery were considered appropriate for inclusion. Publications were written in English, included patients aged 18 years or older, and had a minimum follow-up of 3 months.

Results

Eighteen studies met criteria for inclusion in our review. The primary outcome was change in symptom profile as measured by sinonasal and asthma symptom scores. Most studies demonstrated improvement in sinus- and asthma-related symptoms and quality-of-life measures after endoscopic sinus surgery.

Conclusion

This review, which did not exclude the use of concomitant medical therapy, suggests that surgery is beneficial in AERD management. Evidence demonstrates improvement in sinonasal and asthma symptom severity and frequency, radiographic and endoscopy scores, and quality of life after surgery.

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The Persistence of Tinnitus after Acoustic Neuroma Surgery

Objective

Examine possible prognostic factors for the persistence of tinnitus after acoustic neuroma resection.

Study Design

Case series with chart review.

Setting

Tertiary academic medical center.

Subjects and Methods

The records of 166 patients who underwent acoustic neuroma resection from 2009 to 2014 were reviewed. Patients were asked to complete a survey, including the Tinnitus Handicap Inventory, 1 to 6 years postoperatively.

Results

Of the 53 patients who completed the survey, 17% reported that their tinnitus resolved; 9% reported improvement; 23% reported no change; 43% reported that their tinnitus worsened; and 8% were unsure. Respondents ≥50 years old and those with nonserviceable hearing preoperatively were more likely to report that their tinnitus resolved or improved (P < .01 and P = .02, respectively). Respondents <50 years old and those with serviceable hearing preoperatively were more likely to report that their tinnitus was the same or worse (P < .001 and P = .036, respectively). Respondents with age <50 years, serviceable hearing preoperatively, and residual tumor had a higher average Tinnitus Handicap Inventory score (P = .016, P = .048, and P = .047, respectively). Sex, tumor size, surgical approach, hearing preservation, and cochlear nerve status did not correlate with the prognosis of tinnitus postoperatively. Respondents whose tinnitus resolved postoperatively were more likely to report being "very satisfied" with their care (P = .012).

Conclusion

In this study, 83% of respondents had persistent tinnitus after acoustic neuroma resection. The prognosis of tinnitus was worse for younger respondents, those with serviceable hearing preoperatively, and those with residual tumor postoperatively. Respondents' satisfaction was higher if their tinnitus resolved.

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Analysis of Outcome Domains in Adult Cochlear Implantation: A Systematic Review

Objectives

To determine the breadth of outcome domains used in the reporting of adult cochlear implant surgery for the purpose of registry and quality measure development.

Data Sources

Systematic review of randomized controlled trials.

Review Methods

In consultation with a medical librarian, search strategies were constructed to identify randomized controlled trials studying adults undergoing cochlear implantation. MEDLINE, EMBASE, Scopus, CINAHL, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and the Database of Abstracts of Reviews of Effects were searched from database inception to July 2015. Studies were evaluated for level of evidence and risk of bias with the Cochrane Collaboration's Risk of Bias Tool, and outcome domains were extracted from each study.

Results

Of 4473 unique citations found, 8 studies were included in this review. All 8 trials were evidence level 1B. Risk of bias was low in 2 trials and high in the other 6. Reported outcome domains included speech perception in quiet and noise, speech tracking, quality of life, timbre perception, hearing preservation, vestibular function, electrode insertion technique, functional measures, functional imaging, fitting time, and tinnitus.

Conclusions

An analysis of randomized controlled trials studying cochlear implantation in adults yielded a wide spectrum of outcome domains. This is the first study to comprehensively describe the breadth of outcome domains in adult cochlear implantation. Validated instruments from these domains could be considered for potential inclusion as quality measures and registry use.

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Effects of Nasal Septum Deviation and Septoplasty on Cardiac Arrhythmia Risk

Objective

Upper airway obstruction (UAO) can result in cardiac complications, including arrhythmias and sudden cardiac death. Nasal septum deviation (NSD) is a common cause of UAO. The aim of this study was to assess the risk of cardiac arrhythmias in patients with NSD. To assess this risk, we measured noninvasive indicators of atrial arrhythmia (P-wave dispersion [Pd]) and ventricular arrhythmia (corrected QT dispersion [QTcd]) and compared these values between NSD patients and healthy subjects.

Study Design

Prospective study.

Settings

Tertiary referral center.

Subjects and Methods

This study included 53 consecutive patients who had underwent septoplasty due to marked NSD. Electrocardiographic records were used to determine Pd and QTcd values preoperatively and 6 months postoperatively. Fifty-three consecutive age- and sex-matched subjects without any UAO were also examined as a control group.

Results

Preoperative Pd and QTcd values were significantly higher in NSD patients than in the control group (Pd: 57.40 ± 14.21 vs 34.11 ± 7.12 milliseconds, P < .001; QTcd: 81.77 ± 16.39 vs 50.25 ± 11.51 milliseconds, P < .001, respectively). In addition, Pd and QTcd values were significantly greater in preoperative NSD patients when compared with the same patients postoperatively (Pd: 57.40 ± 14.21 vs 36.32 ± 8.9 milliseconds, P = .013; QTcd: 81.77 ± 16.39 vs 55.76 ± 11.4 milliseconds, P = .012, respectively).

Conclusion

In conclusion, NSD patients are at risk for both atrial and ventricular cardiac arrhythmias; however, septoplasty in these patients can relieve UAO and reduce the risk of arrhythmias.

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Impact of Sensory and Motor Defects on Oral Function in an Animal Model

Objective

To evaluate the combined functional impact on swallowing of tongue sensory and motor loss using a rat model.

Study Design

Rats underwent selective neurectomies with transection of the motor (hypoglossal) nerve or motor and sensory (lingual) nerves. Postoperative functional parameters were followed for 2 weeks.

Setting

Translational research.

Subjects and Methods

Thirty-six adolescent male Wistar rats were divided into 4 groups: anesthetic (n = 6), sham surgery (n = 8), hypoglossal transection (n = 10), and hypoglossal and lingual transection (n = 12). Each morning on postoperative days 1 to 14, the water and food intake were quantified and the animal weighed. Two-way analyses of variance (SigmaPlot; SYSTAT, San Jose, California) were performed with factors of "group" and "postoperative day" (POD) to analyze whether a significant difference existed between water intake, pellet consumption, and weight change.

Results

The hypoglossal and lingual group consumed significantly less water during PODs 1 to 2 and significantly less food during PODs 1 to 3 than any other group. This established a significant difference in body weight between the hypoglossal and lingual group and all other groups for the duration of the study. Measured parameters in the hypoglossal group better approximated those of the control anesthetic and sham groups.

Conclusions

The addition of a sensory loss to a motor deficit involving the oral tongue results in a measurably significant difference in weight gain, a marker of function, compared with rats with only a motor deficit. Additional studies are needed to determine if there would be similar findings in a model of sensate vs asensate oral tongue reconstruction.

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MRI- and CT-Compatible Polymer Laryngoscope: A Step toward Image-Guided Transoral Surgery

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A Low-Cost Method of Ciliary Beat Frequency Measurement Using iPhone and MATLAB: Rabbit Study

Objectives

(1) To determine ciliary beat frequency (CBF) using a consumer-grade cellphone camera and MATLAB and (2) to evaluate the effectiveness and accuracy of the proposed method.

Study Design

Prospective animal study.

Setting

Academic otolaryngology department research laboratory.

Methods

Five ex vivo tracheal samples were extracted from 3 freshly euthanized (<3 hours postmortem) New Zealand white rabbits and incubated for 30 minutes in buffer at 23°C, buffer at 37°C, or 10% formalin at 23°C. Samples were sectioned transversely and observed under a phase-contrast microscope. Cilia movement was recorded through the eyepiece using an iPhone 6 at 240 frames per second (fps). Through MATLAB programming, the video of the 23°C sample was downsampled to 120, 60, and 30 fps, and Fourier analysis was performed on videos of all frame rates and conditions to determine CBF. CBF of the 23°C sample was also calculated manually frame by frame for verification.

Results

Recorded at 240 fps, the CBF at 23°C was 5.03 ± 0.4 Hz, and the CBF at 37°C was 9.08 ± 0.49 Hz (P < .001). The sample with 10% formalin did not display any data beyond DC noise. Compared with 240 fps, the means of other frame rates/methods (120, 60, 30 fps; manual counting) at 23°C all showed no statistical difference (P > .05).

Conclusion

There is no significant difference between CBF measured via visual inspection and that analyzed by the developed program. Furthermore, all tested acquisition rates are shown to be effective, providing a fast and inexpensive alternative to current CBF measurement protocols.

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Response to "Animal Model of Chronic Perforation Is Best for Eardrum Regeneration Using Biological Materials"

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Survival Impact of Initial Therapy in Patients with T1-T2 Glottic Squamous Cell Carcinoma

Objective

Laryngeal cancer most commonly arises from the glottis. Comparable outcomes in survival have been shown in patients with early glottic squamous cell carcinoma treated with either surgery or radiotherapy.

Study Design and Setting

Administrative database study.

Subjects and Methods

The US National Cancer Institute's SEER database (Surveillance, Epidemiology, and End Results) was queried for cases of early glottic cancer (T1-T2N0M0, 1988-2012). We identified 13,312 qualifying cases. Patient demographics, therapeutic measures, and survival outcomes were examined with appropriate univariate and multivariate analyses.

Results

Early glottic cancer has a mean age at diagnosis of 64.8 ± 11.6 years and a male:female ratio of 6.9:1. The most common treatment modality was radiotherapy alone (51.6%), followed by combination therapy with surgery first (31.5%). Overall, the 5-year disease-specific survival (DSS) rate was 88.4%. When stratified by treatment modality and stage, 5-year DSS for T1 tumors was 93.2% with surgery alone and 89.0% with radiation alone (P < .0001). With combination therapy, the 5-year DSS was 91.3% for surgery first and 84.9% for radiation first (P = .0239). In T2 tumors, 5-year DSS was improved with single-modality therapy versus multimodality therapy (81.1% vs 76.4; P = .0255).

Conclusion

In T1 disease, surgery alone shows improved 5-year DSS versus radiation alone, but this difference was not observed in T2 tumors. Additionally, surgery, rather than radiation, shows improved 5-year DSS when implemented as a first-line therapy. Combination therapy does not show improved 5-year DSS for early glottic cancer.

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Cochlear Implantation in Canal Wall Down Mastoid Cavities

Cochlear implantation in canal wall down mastoid (CWD) cavities is fraught with the issue of how best to manage the mastoid cavity. Decision points include whether the external auditory meatus should be overclosed, whether the implantation should be staged, or even if the eustachian tube should be plugged. Given these options, we sought to describe our experience of cochlear implantation in CWD cavities. Among evaluation of subjects ≥18 years of age, 9 had cochlear implants placed in CWD mastoid cavities, 7 of which had the external auditory meatus overclosed, while 2 maintained open cavities following implantation. With an average follow-up of 36.7 months (median, 22.8 months), 2 subjects who had overclosure developed meatal dehiscences requiring further intervention, while no complications were observed in the 2 patients who maintained open cavities.

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Laryngeal Preservation in Glottic Cancer: A Comparison of Hospital Charges and Morbidity among Treatment Options

Objective

When total laryngectomy is not required, organ preservation surgery or radiotherapy is considered the standard of care for primary glottic cancer. These accepted treatment options are available for early and advanced glottic cancers due to equivalent locoregional control and survival rates. However, in today's climate of accountable care, the financial burden of treatment choices continues to increase in significance. We therefore compared hospital charges and treatment-related morbidity between organ-preserving surgery and radiation with or without chemotherapy—herein, (chemo)radiation—in the primary treatment of glottic cancer.

Study Design

Nationwide Inpatient Sample Database was analyzed to assess clinical and financial information.

Setting

Population-based analysis.

Subjects

Patients (N = 5499) with primary glottic cancer undergoing treatment with laryngeal preservation strategies.

Methods

Patients were subdivided by ICD-9 codes into 3 treatment groups: endoscopic resection, open partial laryngectomy, and (chemo)radiation. Treatment-related outcomes, charges, and length of hospitalization were analyzed among treatment groups.

Results

When adjusting for sex, age, race, comorbidity, and primary payer, (chemo)radiotherapy was associated with increased direct charges (P < .001; coefficient, $23,658.99; 95% confidence interval [95% CI]: $10,227.15-$37,090.84) and length of hospitalization (P < .001; hazard ratio, 0.593; 95% CI: 0.502-0.702) when compared with endoscopic surgery. As compared with open surgery, endoscopic surgery was associated with reduced hospital charges (P = .012; coefficient, $11,967.01; 95% CI: $2,784.17-$21,249.85) and duration of hospitalization (P < .001; hazard ratio, 0.749; 95% CI: 0.641-0.876).

Conclusions

This analysis suggests that increased utilization of endoscopic surgery in patients with primary glottic cancer not requiring total laryngectomy may lead to reduced financial burden and duration of hospitalization when compared with open surgery or (chemo)radiation therapy.

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Phase 3 Trials of Thermosensitive Ciprofloxacin Gel for Middle Ear Effusion in Children with Tubes

Objective

To investigate the efficacy, safety, and microbiology of a thermosensitive otic suspension of ciprofloxacin (OTO-201) in children with bilateral middle ear effusion undergoing tympanostomy tube placement.

Study Design

Two randomized, double-blind, sham-controlled phase 3 trials. Patients were randomized to intratympanic OTO-201 or sham.

Setting

Children with bilateral middle ear effusion undergoing tympanostomy tube placement.

Subjects/Methods

Studies evaluated 532 patients (6 months to 17 years old) in a combined analysis of efficacy (treatment failure: presence of otorrhea, otic or systemic antibiotic use, lost to follow-up, missed visits), safety (audiometry, otoscopy, tympanometry), and microbiology.

Results

There was a lower cumulative proportion of treatment failures in patients receiving OTO-201 vs tympanostomy tubes alone (1) on days 4, 8, 15, and 29; (2) on day 15, primary end point (23.0% vs 45.1%; age-adjusted odds ratio, 0.341; P < .001; reduction in relative risk, 49%); and (3) on day 15, blinded-assessor otorrhea treatment failure (7.0% vs 19.4%; age-adjusted odds ratio, 0.303; P < .001; reduction in relative risk, 64%). Per-protocol and subgroup analyses (baseline demographics, pathogen type, culture status, effusion type, microbiologic response) supported these findings. There were no drug-related serious adverse events; the most frequent treatment-emergent adverse events in both groups were pyrexia, postoperative pain, nasopharyngitis, cough, and upper respiratory tract infection. OTO-201 administration had no evidence of increased tube occlusion and no negative effect on audiometry, tympanometry, or otoscopy.

Conclusions

Combined analysis of 2 phase 3 trials demonstrated a lower cumulative proportion of treatment failures through day 15 compared with TT alone when OTO-201 was administered intratympanically for otitis media with bilateral middle ear effusion at time of tympanostomy tube placement.

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The Role of Epstein-Barr Virus DNA Load and Serology as Screening Tools for Nasopharyngeal Carcinoma

Objective

Screening for nasopharyngeal carcinoma (NPC) among family members has been advocated in endemic populations in view of significantly increased risks. We aimed to compare the role of Epstein-Barr virus (EBV) DNA load and EBV IgA serology as tools for screening patients with a first-degree family history of NPC.

Study Design

Case-control study.

Setting

Tertiary referral center.

Subjects and Methods

Serum samples were compared from 293 newly diagnosed NPC patients and 475 individuals with a first-degree family history of NPC. EBV DNA load was measured by real-time quantitative polymerase chain reaction, while EBV viral capsid antigen (VCA) IgA and EBV early antigen (EA) IgA titers were measured by immunofluorescence assays.

Results

NPC patients had a significantly higher median EBV DNA load as compared with unaffected family members (835.4 vs 18.8 copies/mL; P < .001). At 100 copies/mL, EBV DNA load demonstrated a sensitivity of 76.8% and a specificity of 85.6%. A positive EBV-EA IgA titer (≥1:10) gave a sensitivity of 85.0% and a specificity of 96.4%. There was good correlation between EBV DNA load and EBV serology titers (Spearman's = .536 and .594 for EBV-VCA IgA and EBV-EA IgA, respectively; P < .001). Receiver operating characteristic analysis demonstrated that EBV-VCA IgA and EBV-EA IgA were better classifiers than EBV DNA load (areas under the curve: 0.942, 0.926, and 0.880, respectively) in distinguishing NPC patients and unaffected family members.

Conclusion

EBV DNA load and EBV IgA serology demonstrate good sensitivity and specificity as screening tools. EBV-EA IgA gave the best sensitivity and specificity profile as a screening tool for NPC among high-risk family members.

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Cyclooxygenase inhibitors as a new therapeutic strategy in small bowel transplantation.

BACKGROUND: The long-term outcome of intestinal transplantations is still not favorable, which is partly due to the intestinal susceptibility to ischemia. There are several indications that the inflammatory response to ischemia-reperfusion injury is mediated by cyclooxygenases and that their inhibition may be associated with improved organ function. The aim of this study was to analyze if COX inhibitors could improve the early posttransplant outcome after orthotopic small bowel transplantation (SBTx). METHODS: SBTx was performed between rats to test the impact of non-selective (Piroxicam), preferential (Meloxicam) and selective COX-2 inhibitors (Parecoxib). The donor intestines were either perfused and stored with inhibitor or had inhibitor administered intravenously after transplantation. RESULTS: Using COX inhibitors, a sequential increase of posttransplantation intestinal integrity could be shown, with Parecoxib the least effective and Meloxicam the most effective treatment. These differences were in line with the downregulation of COX-2 activity by the inhibitors. Functionally, the same tendency could be seen in diminished expression of proinflammatory molecules, decreased leucocyte inflammation and significantly improved graft microcirculation. In most cases, the intravenous administration was more effective. However, the COX inhibitors used were shown to cause relevant hepatotoxicity under nearly all conditions, but particularly under intravenous administration. Only Meloxicam in HTK was demonstrated to be a safe drug without hepatotoxic side effects. CONCLUSIONS: The activity of COX contributes to ischemia-reperfusion injury after intestinal transplantation. In this comparative study, the administration of the preferential COX-2 inhibitor Meloxicam via HTK showed the best graft-protective attributes and the lowest hepatotoxic side effects. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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