Antigen-Specific Immune Modulation Targets mTORC1 Function To Drive Chemokine Receptor-Mediated T Cell Tolerance [IMMUNE REGULATION]

To contain autoimmunity, pathogenic T cells must be eliminated or diverted from reaching the target organ. Recently, we defined a novel form of T cell tolerance whereby treatment with Ag downregulates expression of the chemokine receptor CXCR3 and prevents diabetogenic Th1 cells from reaching the pancreas, leading to suppression of type 1 diabetes (T1D). This report defines the signaling events underlying Ag-induced chemokine receptor-mediated tolerance. Specifically, we show that the mammalian target of rapamycin complex 1 (mTORC1) is a major target for induction of CXCR3 downregulation and crippling of Th1 cells. Indeed, Ag administration induces upregulation of programmed death-ligand 1 on dendritic cells in a T cell–dependent manner. In return, programmed death-ligand 1 interacts with the constitutively expressed programmed death-1 on the target T cells and stimulates docking of Src homology 2 domain-containing tyrosine phosphatase 2 phosphatase to the cytoplasmic tail of programmed death-1. Active Src homology 2 domain-containing tyrosine phosphatase 2 impairs the signaling function of the PI3K/protein kinase B (AKT) pathway, leading to functional defect of mTORC1, downregulation of CXCR3 expression, and suppression of T1D. Thus, mTORC1 component of the metabolic pathway serves as a target for chemokine receptor-mediated T cell tolerance and suppression of T1D.

http://ift.tt/2erWbA6

Accumulation of CD11c+CD163+ Adipose Tissue Macrophages through Upregulation of Intracellular 11{beta}-HSD1 in Human Obesity [TUMOR IMMUNOLOGY]

Adipose tissue (AT) macrophages (ATMs) are key players for regulation of AT homeostasis and obesity-related metabolic disorders. However, the phenotypes of human ATMs and regulatory mechanisms of their polarization have not been clearly described. In this study, we investigated human ATMs in both abdominal visceral AT and s.c. AT and proposed an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)–glucocorticoid receptor regulatory axis that might dictate M1/M2 polarization in ATMs. The accumulation of CD11c⁺CD163⁺ ATMs in both visceral AT and s.c. AT of obese individuals was confirmed at the cellular level and was found to be clearly correlated with body mass index and production of reactive oxygen species. Using our in vitro system where human peripheral blood monocytes (hPBMs) were cocultured with Simpson–Golabi–Behmel syndrome adipocytes, M1/M2 polarization was found to be dependent on 11β-HSD1, an intracellular glucocorticoid reactivating enzyme. Exposure of hPBMs to cortisol-induced expression of CD163 and RU-486, a glucocorticoid receptor antagonist, significantly abrogated CD163 expression through coculture of mature adipocytes with hPBMs. Moreover, 11β-HSD1 was expressed in crown ATMs in obese AT. Importantly, conditioned medium from coculture of adipocytes with hPBMs enhanced proliferation of human breast cancer MCF7 and MDA-MB-231 cells. In summary, the phenotypic switch of ATMs from M2 to mixed M1/M2 phenotype occurred through differentiation of adipocytes in obese individuals, and upregulation of intracellular 11β-HSD1 might play a role in the process.

http://ift.tt/2eg12sX

G-CSF-Induced Suppressor IL-10+ Neutrophils Promote Regulatory T Cells That Inhibit Graft-Versus-Host Disease in a Long-Lasting and Specific Way [TRANSPLANTATION]

Acute graft-versus-host disease (aGVHD) is the main complication of allogeneic hematopoietic stem cell transplantation, and many efforts have been made to overcome this important limitation. We showed previously that G-CSF treatment generates low-density splenic granulocytes that inhibit experimental aGVHD. In this article, we show that aGVHD protection relies on incoming IL-10⁺ neutrophils from G-CSF–treated donor spleen (G-Neutrophils). These G-Neutrophils have high phagocytic capacity, high peroxide production, low myeloperoxidase activity, and low cytoplasmic granule content, which accounts for their low density. Furthermore, they have low expression of MHC class II, costimulatory molecules, and low arginase1 expression. Also, they have low IFN-, IL-17F, IL-2, and IL-12 levels, with increased IL-10 production and NO synthase 2 expression. These features are in accordance with the modulatory capacity of G-Neutrophils on regulatory T cell (Treg) generation. In vivo, CD25⁺ Treg depletion shortly after transplantation with splenic cells from G-CSF–treated donors blocks suppression of aGVHD, suggesting Treg involvement in the protection induced by the G-Neutrophils. The immunocompetence and specificity of the semiallogeneic T cells, long-term after the bone marrow transplant using G-Neutrophils, were confirmed by third-party skin graft rejection; importantly, a graft-versus-leukemia assay showed that T cell activity was maintained, and all of the leukemic cells were eliminated. We conclude that G-CSF treatment generates a population of activated and suppressive G-Neutrophils that reduces aGVHD in an IL-10– and Treg-dependent manner, while maintaining immunocompetence and the graft versus leukemia effect.

http://ift.tt/2erWfji

Humoral Immunity Provides Resident Intestinal Eosinophils Access to Luminal Antigen via Eosinophil-Expressed Low-Affinity Fc{gamma} Receptors [MUCOSAL IMMUNOLOGY]

Eosinophils are native to the healthy gastrointestinal tract and are associated with inflammatory diseases likely triggered by exposure to food allergens (e.g., food allergies and eosinophilic gastrointestinal disorders). In models of allergic respiratory diseases and in vitro studies, direct Ag engagement elicits eosinophil effector functions, including degranulation and Ag presentation. However, it was not known whether intestinal tissue eosinophils that are separated from luminal food Ags by a columnar epithelium might similarly engage food Ags. Using an intestinal ligated loop model in mice, in this study we determined that resident intestinal eosinophils acquire Ag from the lumen of Ag-sensitized but not naive mice in vivo. Ag acquisition was Ig-dependent; intestinal eosinophils were unable to acquire Ag in sensitized Ig-deficient mice, and passive immunization with immune serum or Ag-specific IgG was sufficient to enable intestinal eosinophils in otherwise naive mice to acquire Ag in vivo. Intestinal eosinophils expressed low-affinity IgG receptors, and the activating receptor FcRIII was necessary for Ig-mediated acquisition of Ags by isolated intestinal eosinophils in vitro. Our combined data suggest that intestinal eosinophils acquire lumen-derived food Ags in sensitized mice via FcRIII Ag focusing and that they may therefore participate in Ag-driven secondary immune responses to oral Ags.

http://ift.tt/2eg4Z0S

Circulating Soluble IL-6R but Not ADAM17 Activation Drives Mononuclear Cell Migration in Tissue Inflammation [INNATE IMMUNITY AND INFLAMMATION]

Neutrophil and mononuclear cell infiltration during inflammatory processes is highly regulated. The first cells at the site of infection or inflammation are neutrophils, followed by mononuclear cells. IL-6 plays an important role during inflammatory states. It has been shown in several models that the soluble form of IL-6R (sIL-6R) is involved in the recruitment of mononuclear cells by a mechanism called IL-6 trans-signaling. It had been speculated that sIL-6R was generated at the site of inflammation by shedding from neutrophils via activation of the metalloprotease ADAM17. Attempts to genetically delete the floxed ADAM17 gene selectively in myeloid cells infiltrating an air pouch cavity upon injection of carrageenan failed because in transgenic mice, LysM^cre did not lead to appreciable loss of the ADAM17 protein in these cells. We therefore used ADAM17 hypomorphic mice, which only express ~5% of ADAM17 wild-type levels in all tissues and show virtually no shedding of all tested ADAM17 substrates, to clarify the role of ADAM17 during local inflammation in the murine air pouch model. In the present study, we demonstrate that although IL-6 and the trans-signaling mechanism is mandatory for cellular infiltration in this model, it is not ADAM17-mediated shedding of IL-6R within the pouch that orchestrates this inflammatory process. Instead, we demonstrate that sIL-6R is infiltrating from the circulation in an ADAM17-independent process. Our data suggest that this infiltrating sIL-6R, which is needed for IL-6 trans-signaling, is involved in the controlled resolution of an acute inflammatory episode.

http://ift.tt/2erW3jZ

JAK2 Disease-Risk Variants Are Gain of Function and JAK Signaling Threshold Determines Innate Receptor-Induced Proinflammatory Cytokine Secretion in Macrophages [INNATE IMMUNITY AND INFLAMMATION]

JAK2 genetic variants are associated with inflammatory bowel disease (IBD) and JAK inhibitors are being evaluated for therapy targeting immune-mediated diseases, including IBD. As JAK pathway-mediated cytokine regulation varies across cell types and stimulation conditions, we examined how JAK signaling and IBD-associated JAK2 variants regulate distinct acute and chronic microbial product exposure outcomes in human myeloid cells, consistent with the conditions of initial entry and ongoing intestinal tissue residence, respectively. Macrophages from controls and ulcerative colitis patients carrying the IBD-risk rs10758669 CC genotype showed increased JAK2 expression and nucleotide-binding oligomerization domain 2-induced JAK2 phosphorylation relative to AA carriers. Interestingly, the threshold of JAK2 expression and signaling determined pattern-recognition receptor (PRR)-induced outcomes; whereas anti-inflammatory cytokines progressively decreased with lower JAK2 expression, proinflammatory cytokines switched from decreased to increased secretion below a certain JAK2 expression threshold. Low JAK2-expressing rs10758669 AA macrophages were above this threshold; consequently, both PRR-induced pro- and anti-inflammatory cytokines were decreased. However, relative to rs10758669 CC risk carriers, AA carrier macrophages switched to increased nucleotide-binding oligomerization domain 2-induced proinflammatory cytokines at lower therapeutically used JAK inhibitor doses. Importantly, JAK inhibitors increased proinflammatory cytokines secreted by peripheral macrophages following chronic PRR stimulation and by human intestinal myeloid cells following exposure to intestinal pathogens. Mechanistically, the decreased response to and secretion of autocrine/paracrine IL-10, IL-4, IL-22 and thymic stromal lymphopoietin regulated these JAK-dependent outcomes in myeloid cells. Taken together, the JAK signaling threshold determines whether PRR-induced pro- and anti-inflammatory cytokines are reciprocally regulated in myeloid cells; consideration of JAK2 genotype and targeting of specific cell types might improve JAK-targeted therapy in immune-mediated diseases.

http://ift.tt/2eg5M1z

Dok-1 and Dok-2 Regulate the Formation of Memory CD8+ T Cells [INFECTIOUS DISEASE AND HOST RESPONSE]

Diverse signals received by CD8⁺ T cells are integrated to achieve the required magnitude of cell expansion and the appropriate balance of effector/memory CD8⁺ T cell generation. Notably, the strength and nature of TCR signaling influence the differentiation and functional capacity of effector and memory CD8⁺ T cells. Dok-1 and Dok-2, the two members of the Dok family expressed in T cells, negatively regulate TCR signaling in vitro. However, the role of Dok proteins in modulating T cell function in vivo has not yet studied. We studied the function of Dok-1 and Dok-2 proteins in the regulation of the CD8⁺ T cell response to vaccinia virus infection. Comparison of responses to vaccinia virus expressing OVA peptide SIINFEKL by wild-type and Dok-1/2^–/– CD8⁺ OT-I cells showed that the absence of Dok-1 and Dok-2 slightly reduced the magnitude of virus-specific effector CD8⁺ T cell expansion. This was not due to reduced proliferation or enhanced apoptosis of effector CD8⁺ T cells. Dok-1/2–deficient effector CD8⁺ T cells showed increased cell surface TCR expression following virus infection in vivo and increased expression of granzyme B and TNF upon stimulation with peptide Ag ex vivo. Finally, Dok-1/2–deficient effector CD8⁺ T had a severe defect in survival that resulted in impaired generation of memory CD8⁺ T cells. These results reveal the critical involvement of Dok-1 and Dok-2 in a negative-feedback loop that prevents overactivation of CD8⁺ T cells and promotes memory formation.

http://ift.tt/2erVwig

Antigen Targeting to Human HLA Class II Molecules Increases Efficacy of DNA Vaccination [IMMUNOTHERAPY AND VACCINES]

It has been difficult to translate promising results from DNA vaccination in mice to larger animals and humans. Previously, DNA vaccines encoding proteins that target Ag to MHC class II (MHC-II) molecules on APCs have been shown to induce rapid, enhanced, and long-lasting Ag-specific Ab titers in mice. In this study, we describe two novel DNA vaccines that as proteins target HLA class II (HLA-II) molecules. These vaccine proteins cross-react with MHC-II molecules in several species of larger mammals. When tested in ferrets and pigs, a single DNA delivery with low doses of the HLA-II–targeted vaccines resulted in rapid and increased Ab responses. Importantly, painless intradermal jet delivery of DNA was as effective as delivery by needle injection followed by electroporation. As an indication that the vaccines could also be useful for human application, HLA-II–targeted vaccine proteins were found to increase human CD4⁺ T cell responses by a factor of x10³ in vitro. Thus, targeting of Ag to MHC-II molecules may represent an attractive strategy for increasing efficacy of DNA vaccines in larger animals and humans.

http://ift.tt/2erVc2W

Inositol-Triphosphate 3-Kinase C Mediates Inflammasome Activation and Treatment Response in Kawasaki Disease [CLINICAL AND HUMAN IMMUNOLOGY]

Kawasaki disease (KD) is a multisystem vasculitis that predominantly targets the coronary arteries in children. Phenotypic similarities between KD and recurrent fever syndromes point to the potential role of inflammasome activation in KD. Mutations in NLRP3 are associated with recurrent fever/autoinflammatory syndromes. We show that the KD-associated genetic polymorphism in inositol-triphosphate 3-kinase C (ITPKC) (rs28493229) has important functional consequences, governing ITPKC protein levels and thereby intracellular calcium, which in turn regulates NLRP3 expression and production of IL-1β and IL-18. Analysis of transcript abundance, protein levels, and cellular response profiles from matched, serial biospecimens from a cohort of genotyped KD subjects points to the critical role of ITPKC in mediating NLRP3 inflammasome activation. Treatment failure in those with the high-risk ITPKC genotype was associated with the highest basal and stimulated intracellular calcium levels and with increased cellular production of IL-1β and IL-18 and higher circulating levels of both cytokines. Mechanistic studies using Itpkc-deficient mice in a disease model support the genomic, cellular, and clinical findings in affected children. Our findings provide the mechanism behind the observed efficacy of rescue therapy with IL-1 blockade in recalcitrant KD, and we identify that regulation of calcium mobilization is fundamental to the underlying immunobiology in KD.

http://ift.tt/2eg6I6e

MK2/3 Are Pivotal for IL-33-Induced and Mast Cell-Dependent Leukocyte Recruitment and the Resulting Skin Inflammation [INNATE IMMUNITY AND INFLAMMATION]

The IL-1R family member IL-33R mediates Fc-receptor-I (FcRI)-independent activation of mast cells leading to NF-B activation and consequently the production of cytokines. IL-33 also induces the activation of MAPKs, such as p38. We aimed to define the relevance of the p38-targets, the MAPK-activated protein kinases 2 and 3 (MK2 and MK3) in IL-33-induced signaling and the resulting mast cell effector functions in vitro and in vivo. We demonstrate that the IL-33-induced IL-6 and IL-13 production strongly depends on the MK2/3-mediated activation of ERK1/2 and PI3K signaling. Furthermore, in the presence of the stem cell factors, IL-33 did induce an MK2/3-, ERK1/2- and PI3K-dependent production of TNF-α. In vivo, the loss of MK2/3 in mast cells decreased the IL-33-induced leukocyte recruitment and the resulting skin inflammation. Therefore, the MK2/3-dependent signaling in mast cells is essential to mediate IL-33-induced inflammatory responses. Thus, MK2/3 are potential therapeutic targets for suppression of IL-33-induced inflammation skin diseases such as psoriasis.

http://ift.tt/2erUUJg

Upregulation of IFN-Inducible and Damage-Response Pathways in Chronic Graft-versus-Host Disease [CLINICAL AND HUMAN IMMUNOLOGY]

Although chronic graft-versus-host disease (CGVHD) is the primary nonrelapse complication of allogeneic transplantation, understanding of its pathogenesis is limited. To identify the main operant pathways across the spectrum of CGVHD, we analyzed gene expression in circulating monocytes, chosen as in situ systemic reporter cells. Microarrays identified two interrelated pathways: 1) IFN-inducible genes, and 2) innate receptors for cellular damage. Corroborating these with multiplex RNA quantitation, we found that multiple IFN-inducible genes (affecting lymphocyte trafficking, differentiation, and Ag presentation) were concurrently upregulated in CGVHD monocytes compared with normal subjects and non-CGVHD control patients. IFN-inducible chemokines were elevated in both lichenoid and sclerotic CGHVD plasma and were linked to CXCR3⁺ lymphocyte trafficking. Furthermore, the levels of the IFN-inducible genes CXCL10 and TNFSF13B (BAFF) were correlated at both the gene and the plasma levels, implicating IFN induction as a factor in elevated BAFF levels in CGVHD. In the second pathway, damage-/pathogen-associated molecular pattern receptor genes capable of inducing type I IFN were upregulated. Type I IFN-inducible MxA was expressed in proportion to CGVHD activity in skin, mucosa, and glands, and expression of TLR7 and DDX58 receptor genes correlated with upregulation of type I IFN-inducible genes in monocytes. Finally, in serial analyses after transplant, IFN-inducible and damage-response genes were upregulated in monocytes at CGVHD onset and declined upon therapy and resolution in both lichenoid and sclerotic CGVHD patients. This interlocking analysis of IFN-inducible genes, plasma analytes, and tissue immunohistochemistry strongly supports a unifying hypothesis of induction of IFN by innate response to cellular damage as a mechanism for initiation and persistence of CGVHD.

http://ift.tt/2es0485

A Tetravalent Formulation Based on Recombinant Nucleocapsid-like Particles from Dengue Viruses Induces a Functional Immune Response in Mice and Monkeys [IMMUNOTHERAPY AND VACCINES]

Despite the considerable effort that has been invested in elucidating the mechanisms of protection and immunopathogenesis associated with dengue virus infections, a reliable correlate of protection against the disease remains to be found. Neutralizing Abs, long considered the prime component of a protective response, can exacerbate disease severity when present at subprotective levels, and a growing body of data is challenging the notion that their titers are positively correlated with disease protection. Consequently, the protective role of cell-mediated immunity in the control of dengue infections has begun to be studied. Although earlier research implicated cellular immunity in dengue immunopathogenesis, a wealth of newer data demonstrated that multifunctional CD8⁺ T cell responses are instrumental for avoiding the more severe manifestations of dengue disease. In this article, we describe a new tetravalent vaccine candidate based on recombinant dengue virus capsid proteins, efficiently produced in Escherichia coli and purified using a single ion-exchange chromatography step. After aggregation to form nucleocapsid-like particles upon incubation with an oligodeoxynucleotide containing immunostimulatory CpG motifs, these Ags induce, in mice and monkeys, an IFN-–secreting cell response that significantly reduces viral load after challenge without the contribution of antiviral Abs. Therefore, this new vaccine candidate may not carry the risk for disease enhancement associated with Ab-based formulations.

http://ift.tt/2es03Rz

Antibody Binding to CD4 Induces Rac GTPase Activation and Alters T Cell Migration [IMMUNE REGULATION]

The use of nondepleting Abs specific for CD4 and CD8 is an effective strategy to tolerize CD4⁺ and CD8⁺ T cells in a tissue-specific manner. We reported that coreceptor therapy reverses diabetes in new onset NOD mice. A striking feature of coreceptor-induced remission is the purging of T cells from the pancreatic lymph nodes (PLN) and islets of NOD mice. Evidence indicates that Abs binding to the coreceptors promotes T cell egress from these tissues. The present study examined how coreceptor therapy affects the migration of CD4⁺ T cells residing in the PLN of NOD mice. Anti-CD4 Ab treatment resulted in an increased frequency of PLN but not splenic CD4⁺ T cells that exhibited a polarized morphology consistent with a migratory phenotype. Furthermore, PLN CD4⁺ T cells isolated from anti-CD4 versus control Ab-treated animals displayed increased in vitro chemotaxis to chemoattractants such as sphingosine-1-phosphate and CXCL12. Notably, the latter was dependent on activation of the small Rho GTPases Rac1 and Rac2. Rac1 and Rac2 activation was increased in Ab-bound CD4⁺ T cells from the PLN but not the spleen, and knockdown of Rac expression blocked the heightened reactivity of Ab-bound PLN CD4⁺ T cells to CXCL12. Interestingly, Rac1 and Rac2 activation was independent of Rac guanine nucleotide exchange factors known to regulate T cell activity. Therefore, Ab binding to CD4 initiates a novel pathway that involves inflammation-dependent activation of Rac and establishment of altered T cell migratory properties.

http://ift.tt/2eg5KHi

HIF-2{alpha} in Resting Macrophages Tempers Mitochondrial Reactive Oxygen Species To Selectively Repress MARCO-Dependent Phagocytosis [INNATE IMMUNITY AND INFLAMMATION]

Hypoxia-inducible factor (HIF)-α isoforms regulate key macrophage (M) functions during ischemic inflammation. HIF-2α drives proinflammatory cytokine production; however, the requirements for HIF-2α during other key M functions, including phagocytosis, are unknown. In contrast to HIF-1α, HIF-2α was not required for hypoxic phagocytic uptake. Surprisingly, basal HIF-2α levels under nonhypoxic conditions were necessary and sufficient to suppress phagocytosis. Screening approaches revealed selective induction of the scavenger receptor MARCO, which was required for enhanced engulfment. Chromatin immunoprecipitation identified the antioxidant NRF2 as being directly responsible for inducing Marco. Concordantly, Hif-2α^–/– Ms exhibited reduced antioxidant gene expression, and inhibition of mitochondrial reactive oxygen species suppressed Marco expression and phagocytic uptake. Ex vivo findings were recapitulated in vivo; the enhanced engulfment phenotype resulted in increased bacterial clearance and cytokine suppression. Importantly, natural induction of Hif-2α by IL-4 also suppressed MARCO-dependent phagocytosis. Thus, unlike most characterized prophagocytic regulators, HIF-2α can act as a phagocytic repressor. Interestingly, this occurs in resting Ms through tempering of steady-state mitochondrial reactive oxygen species. In turn, HIF-2α promotes M quiescence by blocking a MARCO bacterial-response pathway. IL-4 also drives HIF-2α suppression of MARCO, leading to compromised bacterial immunosurveillance in vivo.

http://ift.tt/2erWw5R

Antigen-Specific Development of Mucosal Foxp3+ROR{gamma}t+ T Cells from Regulatory T Cell Precursors [IMMUNE REGULATION]

Foxp3⁺retinoic acid–related orphan receptor (ROR)t⁺ T cells have recently been characterized as an immunoregulatory population highly enriched in the colon lamina propria. However, their developmental origin and relationship to RORt^– regulatory T and Th17 cells remain unclear. In this study, we use a fixed TCRβ system to show that the TCR repertoire of the Foxp3⁺RORt⁺ population is mostly distinct compared with other colonic T cell subsets. However, of these TCRs, a fraction is also found in the Th17 subset, suggesting that TCR repertoire overlap may contribute to the reported ability of Foxp3⁺RORt⁺ cells to regulate Th17 immunity. Naive transgenic T cells expressing a Foxp3⁺RORt⁺-restricted TCR first acquire a Foxp3⁺RORt^– phenotype before coexpressing RORt, suggesting that Foxp3⁺RORt⁺ cell development can occur via an RORt^– regulatory T cell intermediate.

http://ift.tt/2erXHST

Von Willebrand Factor Interacts with Surface-Bound C1q and Induces Platelet Rolling [INNATE IMMUNITY AND INFLAMMATION]

Premature atherosclerosis and thrombotic complications are major causes of morbidity and mortality in patients with systemic lupus erythematosus (SLE). However, the high incidence of these complications cannot be explained by traditional risk factors alone, suggesting direct effects of an activated immune system on hemostasis. The unexpected nucleotide sequence homology between SLE patient–derived autoantibodies against complement C1q (Fab anti-C1q) and von Willebrand factor (VWF) led us to investigate a potential interaction between the complement and hemostatic systems on the level of initiating molecules. VWF was found to bind to surface-bound C1q under static conditions. The binding could specifically be inhibited by Fab anti-C1q and C1q-derived peptides. Under shear stress the C1q–VWF interaction was enhanced, resembling the binding of VWF to collagen I. Additionally, we could show that C1q–VWF complexes induced platelet rolling and firm adhesion. Furthermore, we observed VWF binding to C1q-positive apoptotic microparticles and cholesterol crystals, as well as increased VWF deposition in C1q-positive glomeruli of SLE patients compared with control nephropathy. We show, to our knowledge for the first time, binding of VWF to C1q and thus a direct interaction between starter molecules of hemostasis and the classical pathway of complement. This direct interaction might contribute to the pathogenic mechanisms in complement-mediated, inflammatory diseases.

http://ift.tt/2eg5LuQ

CD4-Transgenic Zebrafish Reveal Tissue-Resident Th2- and Regulatory T Cell-like Populations and Diverse Mononuclear Phagocytes [IMMUNE REGULATION]

CD4⁺ T cells are at the nexus of the innate and adaptive arms of the immune system. However, little is known about the evolutionary history of CD4⁺ T cells, and it is unclear whether their differentiation into specialized subsets is conserved in early vertebrates. In this study, we have created transgenic zebrafish with vibrantly labeled CD4⁺ cells allowing us to scrutinize the development and specialization of teleost CD4⁺ leukocytes in vivo. We provide further evidence that CD4⁺ macrophages have an ancient origin and had already emerged in bony fish. We demonstrate the utility of this zebrafish resource for interrogating the complex behavior of immune cells at cellular resolution by the imaging of intimate contacts between teleost CD4⁺ T cells and mononuclear phagocytes. Most importantly, we reveal the conserved subspecialization of teleost CD4⁺ T cells in vivo. We demonstrate that the ancient and specialized tissues of the gills contain a resident population of il-4/13b–expressing Th2-like cells, which do not coexpress il-4/13a. Additionally, we identify a contrasting population of regulatory T cell–like cells resident in the zebrafish gut mucosa, in marked similarity to that found in the intestine of mammals. Finally, we show that, as in mammals, zebrafish CD4⁺ T cells will infiltrate melanoma tumors and obtain a phenotype consistent with a type 2 immune microenvironment. We anticipate that this unique resource will prove invaluable for future investigation of T cell function in biomedical research, the development of vaccination and health management in aquaculture, and for further research into the evolution of adaptive immunity.

http://ift.tt/2eg3gbH

High Doses of GM-CSF Inhibit Antibody Responses in Rectal Secretions and Diminish Modified Vaccinia Ankara/Simian Immunodeficiency Virus Vaccine Protection in TRIM5{alpha}-Restrictive Macaques [IMMUNOTHERAPY AND VACCINES]

We tested, in rhesus macaques, the effects of a 500-fold range of an admixed recombinant modified vaccinia Ankara (MVA) expressing rhesus GM-CSF (MVA/GM-CSF) on the immunogenicity and protection elicited by an MVA/SIV macaque 239 vaccine. High doses of MVA/GM-CSF did not affect the levels of systemic envelope (Env)-specific Ab, but it did decrease the expression of the gut-homing receptor α4β7 on plasmacytoid dendritic cells (p < 0.01) and the magnitudes of Env-specific IgA (p = 0.01) and IgG (p < 0.05) in rectal secretions. The protective effect of the vaccine was evaluated using 12 weekly rectal challenges in rhesus macaques subgrouped by tripartite motif-containing protein 5α (TRIM5α) genotypes that are restrictive or permissive for infection by the challenge virus SIVsmE660. Eight of nine TRIM5α-restrictive animals receiving no or the lowest dose (1 x 10⁵ PFU) of MVA/GM-CSF resisted all 12 challenges. In the comparable TRIM5α-permissive group, only 1 of 12 animals resisted all 12 challenges. In the TRIM5α-restrictive animals, but not in the TRIM5α-permissive animals, the number of challenges to infection directly correlated with the magnitudes of Env-specific rectal IgG (r = +0.6) and IgA (r = +0.6), the avidity of Env-specific serum IgG (r = +0.5), and Ab dependent cell-mediated virus inhibition (r = +0.6). Titers of neutralizing Ab did not correlate with protection. We conclude that 1) protection elicited by MVA/SIVmac239 is strongly dependent on the presence of TRIM5α restriction, 2) nonneutralizing Ab responses contribute to protection against SIVsmE660 in TRIM5α-restrictive animals, and 3) high doses of codelivered MVA/GM-CSF inhibit mucosal Ab responses and the protection elicited by MVA expressing noninfectious SIV macaque 239 virus-like particles.

http://ift.tt/2eg3jEG

Chemotaxis and Immunoregulatory Function of Cardiac {gamma}{delta} T Cells in Dystrophin-Deficient Mice [IMMUNE REGULATION]

Duchenne muscular dystrophy (DMD) is a fatal X-linked disorder caused by mutations in the dystrophin gene that lead to degeneration of skeletal and cardiac muscles and to chronic inflammation. Despite the importance of T cells in many diseases, this cellular subpopulation has not been described in DMD patients or in mdx mice, a widely used mouse model for studying DMD. Therefore, in this study, we aimed to evaluate the migration of T cells to the cardiac muscle of mdx mice and to characterize their phenotype and functional activity. We observed no migration of T cells to skeletal muscles, but these cells were found in the hearts of mdx mice during the study period, reaching a peak in 12-wk-old mice. These cells migrate primarily owing to CCL2 and CCL5 chemokines produced by cardiac tissue, and they are V1⁺/CD27⁺ and thus produce high levels of IFN-. In vivo depletion of the T cells revealed T cell–dependent cardiac inflammatory immunoregulation, with increased numbers of CD3⁺CD4⁺, CD3⁺CD8⁺, and, in particular, F4/80⁺ cells in the heart and increased cardiac damage in mdx mice. We also observed in vitro that purified cardiac T cells are cytotoxic against adherent endomysial cardiac cells, mostly macrophages, but not against peritoneal cells, in a perforin/granzyme–dependent manner. Our present data indicate that T cells exert protective effects on the hearts of mdx mice, possibly by selectively killing pathogenic macrophages, and this function may be important for the late onset of cardiac damage in DMD.

http://ift.tt/2erXhfl

Papillary Thyroid Carcinoma Cervical Lymph Node Metastasis with Cystic Change Differentiated from Congenital Cystic Lesions with the Assistance of Immunohistochemistry: A Case Study

Abstract

Diagnosis of cystic papillary thyroid carcinoma (PTC) lymph node metastasis at head neck region can be a challenge in the absence of known PTC history. The congenital cystic lesions of head neck, especially thyroglossal duct cyst (TGDC) and branchial cleft cyst (BCC), are major differential diagnoses in this clinicopathological scenario. The location of cyst and morphology of lining epithelium are critical clues for reaching correct diagnosis. However it is not uncommon that the flattened bland epithelial lining can be seen in both cystic metastases and congenital cystic lesions. Given that Pax8 and TTF-1 are common markers in thyroid follicular epithelium; we applied immunohistochemical stains of those two markers on aforementioned cystic lesions. Here we reported a case of cystic PTC metastasis to lymph node without prior malignancy history and cases of TGDC and BCC. Both Pax8 and TTF-1 stainings highlighted the cyst lining in PTC metastatic lymph node, while they were negative in the lining of TGDC and BCC. Collectively, Pax8 and TTF-1 immunohistochemical studies are very helpful tools for making correct diagnosis of head neck cystic lesions in the challenging clinical cases.

http://ift.tt/2dtYA0p

Papillary Thyroid Carcinoma Cervical Lymph Node Metastasis with Cystic Change Differentiated from Congenital Cystic Lesions with the Assistance of Immunohistochemistry: A Case Study

Abstract

Diagnosis of cystic papillary thyroid carcinoma (PTC) lymph node metastasis at head neck region can be a challenge in the absence of known PTC history. The congenital cystic lesions of head neck, especially thyroglossal duct cyst (TGDC) and branchial cleft cyst (BCC), are major differential diagnoses in this clinicopathological scenario. The location of cyst and morphology of lining epithelium are critical clues for reaching correct diagnosis. However it is not uncommon that the flattened bland epithelial lining can be seen in both cystic metastases and congenital cystic lesions. Given that Pax8 and TTF-1 are common markers in thyroid follicular epithelium; we applied immunohistochemical stains of those two markers on aforementioned cystic lesions. Here we reported a case of cystic PTC metastasis to lymph node without prior malignancy history and cases of TGDC and BCC. Both Pax8 and TTF-1 stainings highlighted the cyst lining in PTC metastatic lymph node, while they were negative in the lining of TGDC and BCC. Collectively, Pax8 and TTF-1 immunohistochemical studies are very helpful tools for making correct diagnosis of head neck cystic lesions in the challenging clinical cases.

http://ift.tt/2dtYA0p

Heterogeneity of CD8 + tumor-infiltrating lymphocytes in non-small-cell lung cancer: impact on patient prognostic assessments and comparison of quantification by different sampling strategies

Abstract

Introduction

Infiltration of non-small-cell lung cancer (NSCLC) by CD8⁺ T lymphocytes predicts improved patient survival; however, heterogeneity of intratumoral localization complicates this assessment. Strategies for tumor sampling may not accurately represent the whole tumor. We hypothesized that sampling strategies may alter the identification of tumors with high CD8 density and affect the prognostic significance.

Patients and methods

Twenty-three primary NSCLC tumors were immunohistochemically stained for CD8 and were assessed using automated software with eight different sampling strategies or the whole tumor. Results of all sampling strategies were compared to the whole tumor counts (paired t tests, Pearson's r). Associations between CD8 densities and overall survival were assessed (log-rank test).

Results

Counts from all eight sampling strategies significantly correlated with whole tumor counts (p ≤ 0.001). However, the magnitude of CD8⁺ cell counts and categorization into high vs low infiltrate groups were affected by the sampling strategy. The most concordant values were derived from random sampling of 20 % of the tumor, a simulated core biopsy, or from sampling the tumor center. TIL infiltration was associated with survival when sampling the center (p = 0.038), but not the invasive margin (p > 0.2) or other strategies.

Conclusion

Different tumor sampling strategies may yield discordant TIL density results and different stratification for risk assessment. Small biopsies may be particularly unrepresentative. Random sampling of larger tumor areas is recommended. Enumerating CD8⁺ T cells in the tumor center may have prognostic value.

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Threshold dose distribution and eliciting dose of cashew nut allergy

Publication date: Available online 20 October 2016
Source:Annals of Allergy, Asthma & Immunology
Author(s): Johanna P.M. van der Valk, Roy Gerth van Wijk, J.L. Baumert, J.A. Nordlee, Berber J. Vlieg-Boerstra, Hans de Groot, Anthony E.J. Dubois, Nicolette W. de Jong




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Resolution of Pulsatile Tinnitus after Venous Sinus Stenting in Patients with Idiopathic Intracranial Hypertension

by Srikanth Boddu, Marc Dinkin, Maria Suurna, Kelly Hannsgen, Xem Bui, Athos Patsalides

Objective

Evaluate the role of venous sinus stenting in the treatment of pulsatile tinnitus among patients with Idiopathic Intracranial Hypertension (IIH) and significant venous sinus stenosis.

Subjects and Methods

A written informed consent approved by the Weill Cornell institutional review board was signed and obtained from the study participants. Thirty-seven consecutive patients with IIH and venous sinus stenosis who were treated with venous sinus stenting between Jan.2012-Jan.2016 were prospectively evaluated. Patients without pulsatile tinnitus were excluded. Tinnitus severity was categorized based on "Tinnitus Handicap Inventory" (THI) at pre-stent, day-0, 1-month, 3-month, 6-month, 12-month, 18-month and 2-year follow-up. Demographics, body-mass index (BMI), pre and post VSS trans-stenotic pressure gradient were documented. Statistical analysis performed using Pearson's correlation, Chi-square analysis and Fischer's exact test.

Results

29 patients with a mean age of 29.5±8.5 years M:F = 1:28. Median (mean) THI pre and post stenting were: 4 (3.7) and 1 (1) respectively. Median time of tinnitus resolution post VSS was 0-days. There was significant improvement of THI (Δ Mean: 2.7 THI [95% CI: 2.3–3.1 THI], p Conclusion

Venous sinus stenting is an effective treatment for pulsatile tinnitus in patients with IIH and venous sinus stenosis.

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Erratum to: Remifentanil for labor analgesia: a comprehensive review

http://ift.tt/2eBqrc8

Rare case of type I hypersensitivity reaction to sodium hypochlorite solution in a healthcare setting

Sodium hypochlorite is a clear yellowish solution with a characteristic odour of chlorine and is commonly used as a disinfectant and a bleaching agent. It is used in various healthcare settings for its fast-acting and broad-spectrum antimicrobial activity. It is a known irritant and there are some reports that it can also cause allergic contact dermatitis of type IV hypersensitivity. We report a case of work-related type I hypersensitivity to sodium hypochlorite, presenting with recurrent urticarial rash and a positive prick test reaction to this chemical. He was subsequently excused from further exposure with no further recurrences of the urticarial rash. To the best of our knowledge, this is the first such reported case due to work in the healthcare setting.

http://ift.tt/2erhXE5

Two tunnels for one peritoneal dialysis catheter: a case for caution

Description

Catheter tunnel infection (CTI) is a known cause of adverse outcomes in peritoneal dialysis (PD)-related peritonitis. Extension of exit site infection is the most common reported reason for CTI. We report a case of PD-related peritonitis due to a delayed surgical complication.

A man aged 54 years with a history of end-stage renal disease due to polycystic kidney disease, on continuous cycling PD for the past 5 years, presented with fever, abdominal pain and cloudy PD effluent. His abdomen was diffusely tender. Except for extruded external cuff, the PD catheter exit site was unremarkable. Serous drainage was noted 1 inch from the exit site where the surgical trocar had been inserted for laparoscopic PD catheter placement. The patient reported increasing drainage for 4 weeks prior to presentation. Laboratory studies were consistent with PD-related peritonitis with PD fluid white cell count of 470/mm³ and 64% neutrophils. Broad-spectrum antibiotics were initiated. The...

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Rare cause of massive haemoptysis in pulmonary tuberculosis: Rasmussen's aneurysm

Description

A woman aged 48 years presented to the accident and emergency department with three episodes of massive haemoptysis of ~500 mL. On examination, her vitals were stable. She had a history of pulmonary tuberculosis 2 years prior to this episode for which she had taken a complete course of antituberculous drugs for 9 months and was symptom-free and sputum culture-negative at the end of treatment. Her blood routines showed leucocytosis and raised inflammatory markers (ESR). Sputum and bronchoalveolar lavage specimens were smear positive for acid-fast bacilli, thus she was diagnosed to have a relapse with active tuberculosis.

Imaging evaluation included a chest radiograph which showed cavitatory lesions with air fluid levels in bilateral lung fields with surrounding air space shadowing (figure 1). A plain multidetector CT (MDCT) was performed, which revealed multiple discrete cavities randomly distributed throughout both lungs (figure 2) and the largest cavity was...

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Mediastinal osteosarcoma metastasis causing right heart failure due to pulmonary trunk compression

Description

We present the case of a woman aged 27 years with a background of operated femoral osteosarcoma 9 months ago. She was transferred to our hospital with worsening shortness of breath and signs of decompensated heart failure, haemodynamic instability and suspicion of pericardial effusion. Her transthoracic echocardiogram ruled out a pericardial collection but revealed severe tricuspid regurgitation and right ventricular dilation (figure 1A). A chest CT scan demonstrated an anterior mediastinal mass causing pulmonary trunk compression with subsequent right heart strain and bilateral congestive pleural effusions (figure 1B,C). Haemodynamic instability dictated urgent palliative surgical debulking that was performed under local anaesthesia and sedation via an anterior mediastinotomy approach, due to anaesthetic concerns (figure 2A). This resulted in decompression of the pulmonary trunk and improvement in the patient condition to allow further oncological treatment. The subsequent histopathological examination confirmed osteosarcoma metastasis. Following oncological medical...

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Rare case of T-cell lymphoma presenting as acute myelopathy

Acute myelopathy is a rare presentation of systemic T-cell lymphoma. We present the case of a man aged 68 years with a diffuse erythematous maculopapular rash, followed by lower extremity paresthesias and progressive lower extremity weakness. Spinal MRI showed longitudinally extensive T2 hyperintensity with diffuse contrast enhancement. An atypical clonal T-lymphocyte population was identified in cerebrospinal fluid, peripheral blood and bone marrow aspirate, indicating a malignant T-cell lymphoproliferative disorder. The patient was treated with intrathecal and systemic chemotherapy. Unfortunately, he was not responsive to chemotherapy.

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Total recovery of optic nerve sheath meningioma

We reported the case of a 43-year-old woman with a rapid progressive visual loss. The diagnosis of primary optic nerve sheath meningioma was made thanks to atypia evolution, clinical and radiological findings. The patient was treated with an intensity-modulated radiotherapy of 50.4 Gy in 28 fractions 2 months after the diagnosis. Visual acuity and visual field were completely recovered after 2 years of follow-up. No late side effects of irradiation were recorded.

http://ift.tt/2efrfYs

Infant bald patch: ultrasonographic diagnosis of aplasia cutis congenita

Abstract

Aplasia cutis congenita (ACC) is a rare congenital disorder characterized by the absence of skin at birth, typically involving the midline of the scalp. This is the first case report to highlight the usefulness of precise ultrasonography for diagnosing mild ACC. A 1-month-old boy was referred to our hospital for assessment of a bald patch found at birth. He was born to nonconsanguineous parents in spontaneous vaginal delivery with a vacuum extractor because of fetal distress and anomaly of rotation at 40 weeks of gestation.

This article is protected by copyright. All rights reserved.

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The efficacy and safety of apremilast, etanercept, and placebo, in patients with moderate to severe plaque psoriasis: 52-week results from a phase 3b, randomized, placebo-controlled trial (LIBERATE)

Abstract

Background

Apremilast, an oral, small-molecule phosphodiesterase 4 inhibitor, has demonstrated efficacy in patients with moderate to severe psoriasis.

Objective

Evaluate efficacy and safety of apremilast vs. placebo in biologic-naive patients with moderate to severe plaque psoriasis and safety of switching from etanercept to apremilast in a phase IIIb, randomized, double-blind, placebo-controlled study (NCT01690299).

Methods

250 patients were randomized to placebo (n=84), apremilast 30 mg BID (n=83) or etanercept 50 mg QW (n=83) through Week 16; thereafter, all patients continued or switched to apremilast through Week 104. The primary efficacy endpoint was achievement of PASI-75 at Week 16 with apremilast vs. placebo. Secondary endpoints included achievement of PASI-75 at Week 16 with etanercept vs. placebo and improvements in other clinical endpoints vs. placebo at Week 16. Outcomes were assessed through Week 52. This study was not designed for apremilast vs. etanercept comparisons.

Results

At Week 16, PASI-75 achievement was greater with apremilast (39.8%) vs. placebo (11.9%; P<0.0001); 48.2% of patients achieved PASI-75 with etanercept (P<0.0001 vs. placebo). PASI-75 response was maintained in 47.3% (apremilast/apremilast), 49.4% (etanercept/apremilast), and 47.9% (placebo/apremilast) of patients at Week 52. Most common adverse events (≥5%) with apremilast, including nausea, diarrhoea, upper respiratory tract infection, nasopharyngitis, tension headache and headache, were mild or moderate in severity; diarrhoea and nausea generally resolved in the first month. No new safety or tolerability issues were observed through Week 52 with apremilast.

Conclusion

Apremilast demonstrated significant efficacy vs. placebo at Week 16 in biologic-naive patients with psoriasis, which was sustained over 52 weeks, and demonstrated safety consistent with the known safety profile of apremilast. Switching from etanercept to apremilast did not result in any new or clinically significant safety findings, and efficacy was maintained with apremilast through Week 52.

This article is protected by copyright. All rights reserved.

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Factors associated with combined hand and foot eczema Associations between foot and hand eczema

Abstract

Background

As for hand eczema, the etiology of foot eczema is multifactorial, and not very well understood. The aim of the present study was to identify factors associated with foot eczema in a cohort of hand eczema patients being classified into different subgroups.

Methods

Associations between foot and hand eczema was studied in a cross sectional design in a cohort of hand eczema patients. Consecutive patients were recruited from 9 different European Centres during the period October 2011 – September 2012. Data on demographic factors, presence of foot eczema, hand eczema duration and severity, and whether the hand eczema was work-related or not were available, as well as patch-test results.

Results

Of a total of 427 hand eczema patients identified, information on foot eczema was available in 419 patients who were included in the present study. 125 patients (29.8 %) had concomitant foot and hand eczema. It was found more often in association with hyperkeratotic hand eczema (p=0.007), and was less often associated with irritant hand eczema (p<0.001). However, foot eczema was nevertheless found in 18% of patient with irritant hand eczema and in 25% of patients with occupational hand eczema. Combined foot and hand eczema was associated with more severe and long standing hand eczema (p< 0.001 and p=0.004, respectively). Contact allergy was found in 51.8 % with no difference between patients with combined foot and hand-eczema and patients with hand eczema only.

Conclusion

Occurrence of combined foot and hand eczema is a common finding and not restricted to endogenous hand eczema.

This article is protected by copyright. All rights reserved.

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Update HNO

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TPC vs PF as Induction Chemotherapy Combined With CCRT for Stage IVa-b Nasopharyngeal Carcinoma

Condition:   Nasopharyngeal Carcinoma
Interventions:   Other: Drug: Taxol,cisplatin and capecitabine;   Other: Drug: Cisplatin and 5-Fluorouracil
Sponsor:   Sun Yat-sen University
Recruiting - verified October 2016

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Transoral Robotic Surgery in Treating Patients With Benign or Malignant Tumors of the Head and Neck

Conditions:   Recurrent Adenoid Cystic Carcinoma of the Oral Cavity;   Recurrent Mucoepidermoid Carcinoma of the Oral Cavity;   Recurrent Squamous Cell Carcinoma of the Hypopharynx;   Recurrent Squamous Cell Carcinoma of the Larynx;   Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity;   Recurrent Verrucous Carcinoma of the Larynx;   Recurrent Verrucous Carcinoma of the Oral Cavity;   Stage 0 Hypopharyngeal Cancer;   Stage 0 Laryngeal Cancer;   Stage 0 Lip and Oral Cavity Cancer;   Stage I Adenoid Cystic Carcinoma of the Oral Cavity;   Stage I Mucoepidermoid Carcinoma of the Oral Cavity;   Stage I Squamous Cell Carcinoma of the Hypopharynx;   Stage I Squamous Cell Carcinoma of the Larynx;   Stage I Squamous Cell Carcinoma of the Lip and Oral Cavity;   Stage I Verrucous Carcinoma of the Larynx;   Stage I Verrucous Carcinoma of the Oral Cavity;   Stage II Adenoid Cystic Carcinoma of the Oral Cavity;   Stage II Mucoepidermoid Carcinoma of the Oral Cavity;   Stage II Squamous Cell Carcinoma of the Hypopharynx;   Stage II Squamous Cell Carcinoma of the Larynx;   Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity;   Stage II Verrucous Carcinoma of the Larynx;   Stage II Verrucous Carcinoma of the Oral Cavity;   Stage III Adenoid Cystic Carcinoma of the Oral Cavity;   Stage III Mucoepidermoid Carcinoma of the Oral Cavity;   Stage III Squamous Cell Carcinoma of the Hypopharynx;   Stage III Squamous Cell Carcinoma of the Larynx;   Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity;   Stage III Verrucous Carcinoma of the Larynx;   Stage III Verrucous Carcinoma of the Oral Cavity;   Stage IV Squamous Cell Carcinoma of the Hypopharynx;   Stage IVA Adenoid Cystic Carcinoma of the Oral Cavity;   Stage IVA Mucoepidermoid Carcinoma of the Oral Cavity;   Stage IVA Squamous Cell Carcinoma of the Larynx;   Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity;   Stage IVA Verrucous Carcinoma of the Larynx;   Stage IVA Verrucous Carcinoma of the Oral Cavity;   Stage IVB Adenoid Cystic Carcinoma of the Oral Cavity;   Stage IVB Mucoepidermoid Carcinoma of the Oral Cavity;   Stage IVB Squamous Cell Carcinoma of the Larynx;   Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity;   Stage IVB Verrucous Carcinoma of the Larynx;   Stage IVB Verrucous Carcinoma of the Oral Cavity;   Stage IVC Adenoid Cystic Carcinoma of the Oral Cavity;   Stage IVC Mucoepidermoid Carcinoma of the Oral Cavity;   Stage IVC Squamous Cell Carcinoma of the Larynx;   Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity;   Stage IVC Verrucous Carcinoma of the Larynx;   Stage IVC Verrucous Carcinoma of the Oral Cavity;   Tongue Cancer
Interventions:   Procedure: transoral robotic surgery;   Procedure: quality of life assessment
Sponsor:   Enver Ozer
Recruiting - verified October 2016

http://ift.tt/2edl455

Epidermale Barrierestörung bei Dermatosen

Zusammenfassung

Die Permeabilitätsbarriere spielt bei zahlreichen Hauterkrankungen eine Rolle. Besonders gut aufgeklärt ist die Bedeutung der Barriere bei ekzematösen Erkrankungen. Bei einem irritativ-toxischen Kontaktekzem ist die Störung der Permeabilitätsbarriere durch irritativ-toxische Noxen der erste Schritt in der Pathogenese. Nur nach Schädigung der Barriere können Irritanzien und Allergene in die lebende Epidermis eindringen. Beim atopischen Ekzem penetrieren aufgrund der gestörten Barriere Typ-I-Allergene aus der Umwelt in die Haut und verursachen oder verschlimmern das Ekzem. Bei der anderen häufigen chronisch entzündlichen Dermatose, der Psoriasis, ist die Rolle der Permeabilitätsbarriere nur teilweise bekannt. Bei einem Exanthem verursachen Infektionserreger oder Medikamente eine systemische Entzündung, wobei der Inflammation der Haut eine Barrierestörung folgt. Prinzipiell liegt bei allen entzündlichen Erkrankungen eine gestörte Permeabilitätsbarriere der Haut vor.

http://ift.tt/2dUzuUC

Flüchtlingswelle als Herausforderung für europäische Dermatologinnen und Dermatologen

Zusammenfassung

Die Zunahme der Anzahl der Asylsuchenden in den letzten Monaten konfrontiert die europäischen Dermatologen mit bisher in unseren Breiten eher selten beobachteten Hauterkrankungen und einer Zunahme oder ungewöhnlichen Ausprägung infektiöser Hauterkrankungen. Sorgfältige Anamneseerhebung – auch der Reiserouten und des Herkunftslandes der Patienten –, ausführliche klinische und labortechnische Untersuchungsmethoden und ggf. Zuweisung an Spezialzentren ermöglichen eine rasche und zielgerichtete Behandlung.

http://ift.tt/2enJ9X7

Squamous cell carcinoma of the penis successfully treated with imiquimod 5% cream in a porphyria cutanea tarda patient

http://ift.tt/2dFXs8a

In response to “Asbestos exposure and laryngeal cancer mortality”

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Applicant characteristics associated with successful matching into otolaryngology

Objective

To identify resident applicant characteristics that increase the odds of matching to otolaryngology residency.

Study Design

Cross-sectional analysis.

Methods

Residency applications to our institution from 2009 through 2013 were reviewed. The available data represented 81.1% of applicants to otolaryngology programs nationwide. Online public records were searched to determine whether an applicant matched to an otolaryngology residency position. Factors that were significantly associated with the odds of matching were determined using logistic regression.

Results

A total of 1,479 unique applications were analyzed. On univariate analysis, 27 demographic, academic, personal, medical school, prior training, and application-specific factors were associated with the odds of matching into otolaryngology. On multivariate analysis, indicators of academic achievement, such as Alpha Omega Alpha Honor Medical Society (AOA) status, whether applicant received awards, and publications, were significantly associated with the odds of matching (odds ratio [OR] 2.03, 1.39, 1.66, respectively). The odds of matching increased with increasing step 1 scores (P < 0.001). Attending a medical school ranked by the U.S. News & World Report and being a U.S. citizen born in the United States significantly increased the odds of matching (OR 1.55 and 2.04, respectively), whereas being a non-U.S. senior medical student significantly decreased the odds of matching (OR 0.33).

Conclusion

Multiple factors are associated with successfully matching into an otolaryngology residency. Although this information allows medical students to determine the strength of their application, these criteria have not been correlated with resident success. We urge selection committees to begin identifying applicant selection methods that reflect the values we want to cultivate in our future colleagues.

Level of Evidence

N/A. Laryngoscope, 2016

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Systematic review for surgical treatment of adult and adolescent laryngotracheal stenosis

Objectives/Hypothesis

To determine if open surgical treatment options for adult and adolescent laryngotracheal stenosis are more successful than endoscopic procedures.

Study Design

Systematic review.

Methods

Embase and MEDLINE were searched for publications on adult and adolescent patients (>13 years old) with laryngotracheal stenosis. Cause of stenosis (intubation, idiopathic, or trauma) and treatments (open laryngotracheal resection with anastomosis, open laryngotracheal reconstruction with expansion grafting, or endoscopic procedures) were included. Primary outcomes are decreased additional surgery performed and success of decannulation, if previously tracheostomy.

Results

There were 297 abstracts reviewed, 104 articles selected for full-text review, and 39 articles, with 834 pooled patients, included in the analysis. Patients who had an open procedure (resection with anastomosis or reconstruction with expansion grafting) had significantly different outcomes rates; 32% versus 38% (P <.001) received additional surgery and 89%and 83% (P <.001) were decannulated, respectively. For patients who had endoscopic repair, 44% received additional surgery, and 63% were decannulated. Patients with idiopathic stenosis were more likely to receive additional surgery than those with traumatic (54% vs. 25%) and intubation/tracheostomy etiologies (54% vs. 35%). Etiology of stenosis did affect decannulation rates, patients with intubation/tracheostomy etiology had decannulation rates of 88%, compared to traumatic etiologies (78%, P <.001) and idiopathic stenosis (63%, P <.001). Risk of bias did not impact study results and was assessed using a validated instrument, Methodological Index for Non-randomized Studies criteria.

Conclusions

Patients with adult laryngotracheal stenosis who undergo laryngotracheal resection with anastomosis receive less surgery compared to those who undergo endoscopic treatment or laryngotracheal reconstruction with augmentation/grafting. Patients with idiopathic stenosis are less likely to receive further surgery compared to those from trauma or intubation/tracheostomy, but have the lowest rate of decannulation.

Level of Evidence

3 Laryngoscope, 2016

http://ift.tt/2eYpw8O

Cataract Surgery with a New Fluidics Control Phacoemulsification System in Nanophthalmic Eyes

Purpose: To report visual outcomes and complications after cataract surgery in nanophthalmic eyes with a phacoemulsification system using the active fluidics control strategy. Methods: This is a retrospective case series. All eyes with an axial length of less than 20 mm that underwent cataract surgery or refractive lens exchange using the Centurion Vision System (Alcon Laboratories Inc.) in Hong Kong Sanatorium and Hospital were evaluated. The visual acuity and intraoperative and postoperative complications were reported. Prior approval from the Hospital Research Committee has been granted. Results: Five eyes of 3 patients were included. The mean follow-up period was 10.2 ± 5.3 months (range, 4–18). Two eyes (40%) had a one-line loss of corrected distance visual acuity. No uveal effusion and posterior capsular tear developed. An optic crack and haptic breakage in the intraocular lens developed in 1 eye (20%) and 2 eyes (40%), respectively. Additional surgeries to treat high postoperative intraocular pressure were required in 1 eye (20%). Conclusion: The use of a new phacoemulsification system, which actively monitors and maintains the intraoperative pressure, facilitated anterior chamber stability during cataract surgery in nanophthalmic eyes. This minimized the risk of major complications related to unstable anterior chambers such as uveal effusion and posterior capsular tear. Development of intraoperative crack/breakage in a high-power intraocular lens was common.
Case Rep Ophthalmol 2016;7:218–226

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Modified anastomotic technique for thoracolaparoscopic Ivor Lewis esophagectomy: early outcomes and technical details

Summary

Thoracoscopic intrathoracic esophagogastrostomy is a technically demanding operation; these technical requirements restrict the extensive application of minimally invasive Ivor Lewis esophagectomy. In an attempt to reduce the difficulty of this surgical procedure, we developed a modified anastomotic technique for thoracolaparoscopic Ivor Lewis esophagectomy. During the entirety of this modified approach, neither technically challenging operations such as intrathoracic suturing, or knotting, nor special instruments such as an OrVil system or a reverse-puncture head are required. Between Octomber 2015 and January 2016, 15 consecutive patients with cancer in the distal third of the esophagus or the gastric cardia underwent this modified surgical procedure. The good short-term outcomes that were achieved suggest that the modified anastomotic technique is safe and feasible for thoracolaparoscopic Ivor Lewis esophagectomy.

http://ift.tt/2dTTgzH

Perfusion of the gastric conduit during esophagectomy

Summary

In esophageal cancer surgery, perfusion of the gastric conduit is a critical issue. Measurement of gastric intramucosal pH (pH_i) is a method to identify anaerobic metabolism as a sign of impaired perfusion. In this study we aimed to monitor changes in the perfusion of the gastric conduit at key steps during and after esophagectomy. pH_i was measured per- and postoperatively using intermittent gastric tonometry in 32 patients undergoing open, 65%, or video-assisted thoracoscopic esophagectomy for esophageal cancer. Measurements focused on the surgical steps when the vascular supply to the gastric conduit was altered. A tonometry catheter was successfully placed in all patients and a decrease in pH_i (mean ± SD) was observed from baseline to after the division of the short gastric vessels (7.33 ± 0.07 to 7.29 ±  0.07, P  = 0.005). A further reduction after the ligation of the left gastric artery (7.26 ± 0.08, P  < 0.001) and after final linear stapling the gastric conduit (7.15 ± 0.13, P  < 0.001) was observed. Two hours after surgery, pH_i increased (7.24 ± 0.09, P  = 0.002). In contrast to open surgery, a trend towards less reduction in pH_i was seen in thoracoscopic surgery. Patients with anastomotic leaks had lower pH_i on the first postoperative day (7.12 ± 0.05 vs. 7.27 ± 0.08, P  = 0.040). It can be concluded that each surgical step altering the vascular supply to the gastric conduit resulted in detectable changes, however transient, in pH_i. Patients with low pH_i on the first postoperative day were more prone to have clinically relevant anastomotic leaks.

http://ift.tt/2en2nfK

Effect of neoadjuvant chemoradiotherapy on perioperative immune function of patients with locally advanced esophageal cancer

Summary

This study aims to evaluate the effect of neoadjuvant chemoradiotherapy (NCRT) on perioperative immune function during surgery to treat resectable locally advanced esophageal cancer. Records were retrospectively analyzed for 220 patients with locally advanced esophageal cancer, of whom 112 received surgery alone and 98 received neoadjuvant NCRT plus surgery. The two groups were compared in terms of proportions of CD3⁺, CD4⁺, CD8⁺, and natural kill (NK) cells, as well as the ratio of CD4⁺ to CD8⁺ cells. These measurements were made using flow cytometry on preoperative day 1 and on postoperative days 1 and 7. Subgroup analysis were performed in terms of degrees of pathological response of NCRT. When the entire NCRT and no-NCRT (surgery alone) cohorts were compared, no significant differences in propocrtions of CD3⁺, CD4⁺, CD8⁺, or NK cells or in the CD4⁺/CD8⁺ ratio occurred at any of the three time points. Similar results were obtained using the subgroup of NCRT patients who were NCRT-sensitive, but the subgroup of NCRT-insensitive patients showed significantly lower CD4⁺ and NK proportions and lower CD4⁺/CD8⁺ ratio than the no-NCRT group. Our findings suggest that NCRT does not affect perioperative immune function in patients who are NCRT-sensitive, but it does significantly reduce such function in patients who are NCRT-insensitive.

http://ift.tt/2dTSnH4

Definitive chemoradiation for locoregional recurrences of esophageal cancer after primary curative treatment

Summary

The aim of this study was to determine the outcome of salvage definitive chemoradiation (dCRT) for a locoregional recurrence after any prior curative treatment outside previously irradiated areas. Thirty-nine patients treated between January 2005 and December 2014 were reviewed for locoregional recurrent esophageal cancer outside previously irradiated areas. All patients received salvage treatment with external beam radiotherapy (50.4 Gy in 28 fractions) combined with weekly concurrent paclitaxel and carboplatin. The median follow-up period was 15 months (range 1.7–120). The median overall survival (OS) for all patients after salvage dCRT was 22 months (95% CI 6.2–37.6). The 1-, 3-, and 5-year OS was 72%, 31%, and 28%, respectively. Median survival after salvage dCRT for a regional lymph node recurrence was 33 months (95% CI 5.8–60.3) versus 14 months (95% CI 6.8–21.6) for a recurrence at the anastomosis (P = 0.022, logrank). Median OS was 35 months for the squamous cell carcinoma group and 19 months for the adenocarcinoma group (P = 0.67). Sixteen of 39 patients developed a locoregional recurrence after salvaged dCRT. The median locoregional recurrence-free survival (LRFS) was 24 months. The 1-, 3-, and 5-year LRFS was 79%, 36%, and 36%, respectively. Median disease-free survival (DFS) was 15 months. The 1-, 3-, and 5-year DFS was 66%, 27%, and 27%, respectively. Of 16 patients, 8 (50%) with a primary failure at the site of the anastomosis developed a local recurrence after salvaged dCRT compared to 7 of 22 patients (32%) with a primary recurrence in a lymph node. Definitive chemoradiation is a feasible and effective treatment for locoregional recurrent esophageal cancer outside a previously irradiated area, and should be given with a curative intent. This holds true for recurrence of both squamous cell carcinoma and adenocarcinoma. Lymph node recurrences have a markedly better prognosis than recurrences at the site of the anastomosis.

http://ift.tt/2en3J9W

Quality of life and fear of cancer recurrence after endoscopic treatment for early Barrett's neoplasia: a prospective study

Summary

Endoscopic therapy is the treatment of choice for high grade intraepithelial neoplasia (HGIN) or early cancer (≤T1sm1) in Barrett's esophagus (BE). We prospectively evaluated the effect of endoscopic treatment on quality of life (QOL) and fear of cancer (recurrence) and compared this with the effect of Barrett's surveillance or surgery. Patients treated endoscopically for early Barrett's neoplasia (n = 42, HGIN – T1sm1N0M0) were compared with three groups: patients with non-dysplastic BE undergoing surveillance (n = 44); patients treated surgically for early BE neoplasia (HGIN – T2N0M0, n = 21); patients treated surgically for advanced BE cancer (T1N1M0 – T3N1M0, n = 19). QOL (SF-36; EORTC-QLQ-C30; EORTC-QLQ-OES18) and fear of cancer recurrence (Worry of Cancer Scale [WOCS] and the Hospital Anxiety and Depression Scale [HADS]) were measured at baseline, 2 and 6 months after treatment. The endoscopic treatment group reported significantly better QOL in both physical and mental scales of SF-36 and EORTC-QLQ-C30 and less esophageal cancer related symptoms compared to both surgical groups. The endoscopic treatment group reported significant more worry for cancer recurrence (WOCS) compared to the early surgical group. Their scores on the WOCS were comparable with the scores of the advanced surgical group. Endoscopic treatment of early esophageal cancer has less negative impact on QOL and esophageal cancer symptoms than surgery. However, endoscopically treated patients worry as much about cancer recurrence as patients treated surgically for advanced cancer.

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Neurofibroma with naevus of Ota

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