Role of Adenoid-Nasopharyngeal Ratio in Assessing Adenoid Hypertrophy

Abstract

Most of the time, pediatrician is the first to see children with adenotonsillar hypertrophy (AH) and they mostly rely on clinical assessment with or without some investigation to refer these children to otorhinolaryngologist. Numerous methods have been described for evaluation of AH, but many of these methods are not possible to follow in busy pediatric outpatient unit either because of lack of cooperation from child or due to limited availability of test or due to cost constraints. This study has been conducted to determine the diagnostic accuracy of lateral neck X-ray (LNX) for assessing AH and to assess the correlation between adenoid size in LNX and clinical symptoms in a pediatric unit. Prospective study conducted in Department of ENT, Pathmavathy Medical Foundation, Kollam, Kerala, India from January 2015 to March 2016. 60 consecutive children of both genders, between the age group of 5 to 14 years, attending Department of Pediatrics with a provisional diagnosis of AH were included in the study. The symptom scores, radiographic ratio of adenoid to nasopharynx and endoscopic scorings were calculated. Lateral neck X-ray with calculation of adenoid-to-nasopharynx ratio is found to have significant correlation with patient reported symptoms and findings in nasal endoscopic examination (NE). LNX can be considered as a useful objective tool in evaluation of children with adenoid hypertrophy. Primary care physicians or pediatricians can confidently use lateral neck X-ray for making clinical decisions and can consider nasopharyngoscopy when clinical picture remains unclear or more evaluation is needed.

https://ift.tt/2Jm7WGW

Laryngectomy With or Without Partial Pharyngectomy: A Systematic Review

Abstract

Complications following the total laryngectomy with or without partial pharyngectomy with neck dissection for laryngeal and pyriform fossa malignancies like aspiration, pharyngocutaneous fistula wound infection, flap necrosis, haematoma, chyle fistula and carotid blowout can cause serious implication on the final outcome of the treatment, which leads to increased postoperative morbidity, hospital stay and hospital cost. A prospective study in the Department of Otolaryngology and Head–Neck Surgery, JSS Hospital, Mysore, from November 2014 to July 2016. 30 patients undergoing Total laryngectomy with or without partial pharyngectomy for laryngeal and pyriform fossa were included in this study. The presentation, diagnosis, and management of the complications that were occurred, were discussed. The age of the patients vary between 32 and 76. Also, male preponderance was seen with approximately M:F ratio 3:1. Out of these 30 patients, 6 patients developed complications. The most common complication was pharyngocutaneous fistula (2 patients, 6%), which was developed after the 7th day. It was managed conservatively in both patients, wound infection was a second complication (2, 6%). Other complications were drain failure (1, 3%) and chylous fistula (1, 3%). The Most common complications after total laryngectomy with or without partial pharyngectomy with neck dissection in our study were wound infection and pharyngocutaneous fistula. Assessment of risk factors, early recognition of complications per operative protocols with improvised techniques are necessary to reduce incidence of complication after total laryngectomy with or without partial pharyngectomy with neck dissection.

https://ift.tt/2HKFnWl

Barbed Reposition Pharyngoplasty in Indian Population: A New Palatal Surgery for OSAS

Abstract

Obstructive sleep apnoea (OSA) is a common problem affecting almost 4% of the population. Although continuous positive airway pressure (CPAP) is considered the standard of care, the patient compliance for long term use is poor. Clinicians have explored surgical options for cure with varying success. Uvulopalatopharyngoplasty was considered as a standard of surgical care but long-term results were not satisfactory. Surgical researchers have explored newer techniques to improve outcomes in the past decade with less morbidity and better quality of life outcomes. One of such development is Barbed Reposition Pharyngoplasty (BRP). We would like to discuss the technique of BRP for OSA patients step by step.

https://ift.tt/2Jk2CDR

Role of Adenoid-Nasopharyngeal Ratio in Assessing Adenoid Hypertrophy

Abstract

Most of the time, pediatrician is the first to see children with adenotonsillar hypertrophy (AH) and they mostly rely on clinical assessment with or without some investigation to refer these children to otorhinolaryngologist. Numerous methods have been described for evaluation of AH, but many of these methods are not possible to follow in busy pediatric outpatient unit either because of lack of cooperation from child or due to limited availability of test or due to cost constraints. This study has been conducted to determine the diagnostic accuracy of lateral neck X-ray (LNX) for assessing AH and to assess the correlation between adenoid size in LNX and clinical symptoms in a pediatric unit. Prospective study conducted in Department of ENT, Pathmavathy Medical Foundation, Kollam, Kerala, India from January 2015 to March 2016. 60 consecutive children of both genders, between the age group of 5 to 14 years, attending Department of Pediatrics with a provisional diagnosis of AH were included in the study. The symptom scores, radiographic ratio of adenoid to nasopharynx and endoscopic scorings were calculated. Lateral neck X-ray with calculation of adenoid-to-nasopharynx ratio is found to have significant correlation with patient reported symptoms and findings in nasal endoscopic examination (NE). LNX can be considered as a useful objective tool in evaluation of children with adenoid hypertrophy. Primary care physicians or pediatricians can confidently use lateral neck X-ray for making clinical decisions and can consider nasopharyngoscopy when clinical picture remains unclear or more evaluation is needed.

https://ift.tt/2Jm7WGW

Laryngectomy With or Without Partial Pharyngectomy: A Systematic Review

Abstract

Complications following the total laryngectomy with or without partial pharyngectomy with neck dissection for laryngeal and pyriform fossa malignancies like aspiration, pharyngocutaneous fistula wound infection, flap necrosis, haematoma, chyle fistula and carotid blowout can cause serious implication on the final outcome of the treatment, which leads to increased postoperative morbidity, hospital stay and hospital cost. A prospective study in the Department of Otolaryngology and Head–Neck Surgery, JSS Hospital, Mysore, from November 2014 to July 2016. 30 patients undergoing Total laryngectomy with or without partial pharyngectomy for laryngeal and pyriform fossa were included in this study. The presentation, diagnosis, and management of the complications that were occurred, were discussed. The age of the patients vary between 32 and 76. Also, male preponderance was seen with approximately M:F ratio 3:1. Out of these 30 patients, 6 patients developed complications. The most common complication was pharyngocutaneous fistula (2 patients, 6%), which was developed after the 7th day. It was managed conservatively in both patients, wound infection was a second complication (2, 6%). Other complications were drain failure (1, 3%) and chylous fistula (1, 3%). The Most common complications after total laryngectomy with or without partial pharyngectomy with neck dissection in our study were wound infection and pharyngocutaneous fistula. Assessment of risk factors, early recognition of complications per operative protocols with improvised techniques are necessary to reduce incidence of complication after total laryngectomy with or without partial pharyngectomy with neck dissection.

https://ift.tt/2HKFnWl

Barbed Reposition Pharyngoplasty in Indian Population: A New Palatal Surgery for OSAS

Abstract

Obstructive sleep apnoea (OSA) is a common problem affecting almost 4% of the population. Although continuous positive airway pressure (CPAP) is considered the standard of care, the patient compliance for long term use is poor. Clinicians have explored surgical options for cure with varying success. Uvulopalatopharyngoplasty was considered as a standard of surgical care but long-term results were not satisfactory. Surgical researchers have explored newer techniques to improve outcomes in the past decade with less morbidity and better quality of life outcomes. One of such development is Barbed Reposition Pharyngoplasty (BRP). We would like to discuss the technique of BRP for OSA patients step by step.

https://ift.tt/2Jk2CDR

Feasibility of 3D UV-C treatment to reduce fungal growth and mycotoxin loads on maize and wheat kernels

Abstract

Fungal disease of grain crops is a concern for the agricultural industry, resulting in economic losses. Aside from severe yield losses, mycotoxigenic fungi such as Penicillium and Fusarium can produce harmful mycotoxins, including deoxynivalenol (DON), zearalenone (ZEN), and ochratoxin A (OTA). This proof-of-concept study explored the feasibility and effects of ultraviolet (UV) C light at 253.7 nm to reduce fungal and mycotoxin loads on model surfaces as well as on maize and wheat kernels using benchtop 2D and 3D illumination strategies. Reduction of Penicillium verrucosum (98.6%) and Fusarium graminearum (88.8%) on agar was achieved using a UV-C dose of 100 mJ cm⁻². Naturally occurring fungal growth resembling P. verrucosum on maize was reduced by 79% after exposure to 5000 mJ cm⁻². Similarly, fungal growth resembling F. graminearum on maize was reduced by 60% with 1000 mJ cm⁻². On wheat, significant reduction of fungal growth was not observed. Maximal reduction of DON (97.3%), ZEN (75.4%), and OTA (91.2%) on filter paper was obtained using 15,000 mJ cm⁻². The overall reduction of DON (30%; 14%), ZEN (52%; 42%), and OTA (17%; 6%) on maize and wheat, respectively, was lower than on filter paper. Moisture and crude protein content as well as percent germination of maize kernels were not affected by UV-C treatment up to 5000 mJ cm⁻². This study has shown that 3D UV-C treatment is a feasible option for reducing Fusarium and Penicillium growth on maize kernels and, at higher doses, decreasing ZEN by ~ 50%.

https://ift.tt/2I0k7df

Transcriptome Network Analysis Reveals Aging-Related Mitochondrial and Proteasomal Dysfunction and Immune Activation in Human Thyroid

Thyroid, Ahead of Print.


https://ift.tt/2HpwL8s

Blimp-1 prolongs allograft survival without regimen via influencing T cell development in favor of regulatory T cells while suppressing Th1

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Aline Yen Ling Wang, Charles Yuen Yung Loh, Shyi-Jou Chen, Huang-Kai Kao, Cheng-Hung Lin, Sheng-Hao Chuang, Chin-Ming Lee, Huey-Kang Sytwu, Fu-Chan Wei
BackgroundB lymphocyte-induced maturation protein 1 (Blimp-1) transcription factor is expressed in multiple cell lineages and in particular, T cells. However, the role of Blimp-1 in T cell-mediated allograft tolerance is still unknown.MethodsThis study is the first to investigate transplanted skin allograft survival using transgenic (Tg) mice with T cell overexpression of Blimp-1.ResultsWithout any immunosuppression, fully MHC-mismatched skin allografts on Tg(+) mice had a significantly prolonged survival rate and partial tolerance at 90 days. Allograft lymphocytic infiltration was decreased in Tg(+) mice and a dampened donor-stimulated alloimmune response was seen. An absolute cell number ratio of inflammatory Th1 and Th17 cells against anti-inflammatory regulatory T (Treg) and IL-10-producing T cells, as well as cytolytic proteins, were significantly decreased in lymphoid organs and allograft. Blimp-1 transgenic T cells displayed an increased Treg differentiation capability and enhanced suppression of T cell proliferation. Overexpression of Blimp-1 in T cells promoted the formation of an anti-inflammatory cell-cytokine composition, both systemically and locally via transcription factor modulation such as T-bet downregulation and FoxP3 upregulation.DiscussionAs such, allograft survival was made possible due to Th1 suppression and Treg amplification with the creation of an 'allograft protective microenvironment'.



https://ift.tt/2HMqYZZ

Assessing the carcinogenic potential of E-cigarette

Past decade has seen a significant rise in the use of E-cigarette especially among youngsters. The increasing popularity of E-cigarette is largely due to its marketing as a safe alternative to conventional smoking. Recent studies have shown that the health hazards posed by e-cigarette are comparable to that of conventional smoking. Studies have also shown the presence of several potential carcinogens including tobacco-specific nitrosamines, carbonyls (formaldehyde, acetaldehyde) in e-cigarettes [1].

https://ift.tt/2HlL3mp

Thyroid® High-Impact Articles

FREE ACCESS through May 7, 2018.
Read now:

Latest Impact Factor: 5.515
The Official Journal of: American Thyroid Association^®

 Seasonal Changes in Serum Thyrotropin Concentrations Observed from Big Data Obtained During Six Consecutive Years from 2010 to 2015 at a Single Hospital in Japan 
Ai Yoshihara, Jaeduk Yoshimura Noh, Natsuko Watanabe, Kenji Iwaku, Yo Kunii, Hidemi Ohye, Miho Suzuki, Masako Matsumoto, Nami Suzuki, Kiminori Sugino, Linda M. Thienpont, Akira Hishinuma, Koichi Ito  

Hypothyroidism During Tyrosine Kinase Inhibitor Therapy Is Associated with Longer Survival in Patients with Advanced Nonthyroidal Cancers
Melissa G. Lechner, Chirag M. Vyas, Ole-Petter R. Hamnvik, Erik K. Alexander, P. Reed Larsen, Toni K. Choueiri, Trevor E. Angell  

Quantitative Analysis of the Benefits and Risk of Thyroid Nodule Evaluation in Patients ≥70 Years Old
Zhihong Wang, Chirag M. Vyas, Olivia Van Benschoten, Matt A. Nehs, Francis D. Moore, Jr., Ellen Marqusee, Jeffrey F. Krane, Matthew I. Kim, Howard T. Heller, Atul A. Gawande, Mary C. Frates, Peter M. Doubilet, Gerard M. Doherty, Nancy L. Cho, Edmund S. Cibas, Carol B. Benson, Justine A. Barletta, Ann Marie Zavacki, P. Reed Larsen, Erik K. Alexander, Trevor E. Angell

Occurrence of Endocrine and Thyroid Cancers Among Alaska Native People, 1969-2013
Sarah H. Nash, Anne P. Lanier, Molly B. Southworth  

Subclassification of Bethesda Atypical and Follicular Neoplasm Categories According to Nuclear and Architectural Atypia Improves Discrimination of Thyroid Malignancy Risk
Joel Xue Yi Lim, Min En Nga, Dedrick Kok Hong Chan, Wee Boon Tan,Rajeev Parameswaran, Kee Yuan Ngiam

The post <i>Thyroid^®</i> High-Impact Articles appeared first on American Thyroid Association.

https://ift.tt/2K7fHBI

Mechanism Underlying the Effects of Estrogen Deficiency on Otoconia

Abstract

Otoconia-related vertigo and balance deficits, particularly benign paroxysmal positional vertigo (BPPV), are common. Our recent studies in humans show that, while BPPV prevalence greatly increases with age in both genders, peri-menopausal women are especially susceptible. In the present study, we show that bilateral ovariectomized (OVX) mice have significant balance behavioral deficits, and that estrogen deficiency compromises otoconia maintenance and anchoring by reducing the expression of otoconial component and anchoring proteins. There is ectopic debris formation in the ampulla under estrogen deficiency due to aberrant matrix protein expression. Furthermore, phytoestrogen is effective in rescuing the otoconia abnormalities. By comparing the expression levels of known estrogen receptor (Esr) subtypes, and by examining the otoconia phenotypes of null mice for selected receptors, we postulate that Esr2 may be critical in mediating the effects of estrogen in otoconia maintenance.

https://ift.tt/2qUon6s

Lipocalin 2 Plays an Important Role in Regulating Inflammation in Retinal Degeneration [IMMUNE REGULATION]

It has become increasingly important to understand how retinal inflammation is regulated because inflammation plays a role in retinal degenerative diseases. Lipocalin 2 (LCN2), an acute stress response protein with multiple innate immune functions, is increased in ATP-binding cassette subfamily A member 4 (Abca4)^–/– retinol dehydrogenase 8 (Rdh8)^–/– double-knockout mice, an animal model for Stargardt disease and age-related macular degeneration (AMD). To examine roles of LCN2 in retinal inflammation and degeneration, Lcn2^–/–Abca4^–/–Rdh8^–/– triple-knockout mice were generated. Exacerbated inflammation following light exposure was observed in Lcn2^–/–Abca4^–/–Rdh8^–/– mice as compared with Abca4^–/–Rdh8^–/– mice, with upregulation of proinflammatory genes and microglial activation. RNA array analyses revealed an increase in immune response molecules such as Ccl8, Ccl2, and Cxcl10. To further probe a possible regulatory role for LCN2 in retinal inflammation, we examined the in vitro effects of LCN2 on NF-B signaling in human retinal pigmented epithelial (RPE) cells differentiated from induced pluripotent stem cells derived from healthy donors. We found that LCN2 induced expression of antioxidant enzymes heme oxygenase 1 and superoxide dismutase 2 in these RPE cells and could inhibit the cytotoxic effects of H₂O₂ and LPS. ELISA revealed increased LCN2 levels in plasma of patients with Stargardt disease, retinitis pigmentosa, and age-related macular degeneration as compared with healthy controls. Finally, overexpression of LCN2 in RPE cells displayed protection from cell death. Overall these results suggest that LCN2 is involved in prosurvival responses during cell stress and plays an important role in regulating inflammation during retinal degeneration.

https://ift.tt/2Jk1mRa

Occupational dermatitis: how to identify the exposures, make the diagnosis, and treat the disease.

Key messages:

https://ift.tt/2HmlYI4

Red meat and processed meat intake and risk of cutaneous melanoma in white women and men: Two prospective cohort studies

Epidemiological studies investigating red and processed meat intake and melanoma have been limited and inconclusive., We found an inverse association between red and processed meat intake and melanoma., Because processed meat and potentially red meat may contain carcinogens, our findings need to be replicated in other populations.

https://ift.tt/2vEUnjL

Subcutaneous Infiltration of Carbon Dioxide (Carboxytherapy) for Abdominal Fat Reduction: A Randomized Clinical Trial

Patients have shown an increasing preference for more non-invasive fat reduction options. Five weeks after study initiation and one week after the fifth treatment session, carboxytherapy reduced abdominal fat more than sham treatment, but there was no difference at 28 weeks. This study showed only a transient benefit for carboxytherapy.

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In This Issue [IN THIS ISSUE]

https://ift.tt/2FbUVNx

IFN Regulatory Factor 2 Inhibits Expression of Glycolytic Genes and Lipopolysaccharide-Induced Proinflammatory Responses in Macrophages [INNATE IMMUNITY AND INFLAMMATION]

Rapid initiation and timely resolution of inflammatory response in macrophages are synergistic events that are known to be equally critical to optimal host defense against pathogen infections. However, the regulation of these processes, in particular by a specific cellular metabolic program, has not been well understood. In this study, we found that IFN regulatory factor 2 (IRF2) underwent an early degradation in a proteasome-mediated pathway in LPS-treated mouse macrophages, followed by a later recovery of the expression via transactivation. We showed that IRF2 was anti-inflammatory in that knockdown of this protein promoted the production of LPS-induced proinflammatory mediators. Mechanistically, although IRF2 apparently did not target the proximal cytoplasmic signaling events upon LPS engagements, it inhibited HIF-1α–dependent expression of glycolytic genes and thereby cellular glycolysis, sequential events necessary for the IRF2 anti-inflammatory activity. We found that macrophages in endotoxin tolerant state demonstrated deficiency in LPS-augmented glycolysis, which was likely caused by failed downregulation of IRF2 and the ensuing upregulation of the glycolytic genes in these cells. In contrast to observations with LPS, knockdown of IRF2 decreased IL-4–induced macrophage alternative activation. The pro–IL-4 activity of IRF2 was dependent on KLF4, a key mediator of the alternative activation, which was transcriptionally induced by IRF2. In conclusion, our data suggest that IRF2 is an important regulator of the proinflammatory response in macrophages by controlling HIF-1α–dependent glycolytic gene expression and glycolysis. This study also indicates IRF2 as a novel therapeutic target to treat inflammatory disorders associated with dysregulations of macrophage activations.

https://ift.tt/2FamZ47

Comment on "Therapeutic Application of an Extract of Helicobacter pylori Ameliorates the Development of Allergic Airway Disease" [LETTERS TO THE EDITOR]

https://ift.tt/2KaGsVR

Local Stimulation of Liver Sinusoidal Endothelial Cells with a NOD1 Agonist Activates T Cells and Suppresses Hepatitis B Virus Replication in Mice [INFECTIOUS DISEASE AND HOST RESPONSE]

Functional maturation of liver sinusoidal endothelial cells (LSECs) induced by a NOD1 ligand (diaminopimelic acid [DAP]) during viral infection has not been well defined. Thus, we investigated the role of DAP-stimulated LSEC maturation during hepatitis B virus (HBV) infection and its potential mechanism in a hydrodynamic injection (HI) mouse model. Primary LSECs were isolated from wild-type C57BL/6 mice and stimulated with DAP in vitro and in vivo and assessed for the expression of surface markers as well as for their ability to promote T cell responses via flow cytometry. The effects of LSEC maturation on HBV replication and expression and the role of LSECs in the regulation of other immune cells were also investigated. Pretreatment of LSECs with DAP induced T cell activation in vitro. HI-administered DAP induced LSEC maturation and subsequently enhanced T cell responses, which was accompanied by an increased production of intrahepatic cytokines, chemokines, and T cell markers in the liver. The HI of DAP significantly reduced the HBsAg and HBV DNA levels in the mice. Importantly, the DAP-induced anti-HBV effect was impaired in the LSEC-depleted mice, which indicated that LSEC activation and T cell recruitment into the liver were essential for the antiviral function mediated by DAP application. Taken together, the results showed that the Ag-presenting ability of LSECs was enhanced by DAP application, which resulted in enhanced T cell responses and inhibited HBV replication in a mouse model.

https://ift.tt/2FaWo6Q

Response to Comment on "Therapeutic Application of an Extract of Helicobacter pylori Ameliorates the Development of Allergic Airway Disease" [LETTERS TO THE EDITOR]

https://ift.tt/2Jk1wYM

Mitocryptides from Human Mitochondrial DNA-Encoded Proteins Activate Neutrophil Formyl Peptide Receptors: Receptor Preference and Signaling Properties [INNATE IMMUNITY AND INFLAMMATION]

Phagocytic neutrophils express formyl peptide receptors (FPRs; FPR1 and FPR2) that distinctly recognize peptides starting with an N-formylated methionine (fMet). This is a hallmark of bacterial metabolism; similar to prokaryotes, the starting amino acid in synthesis of mitochondrial DNA–encoded proteins is an fMet. Mitochondrial cryptic peptides (mitocryptides; MCTs) with an N-terminal fMet could be identified by our innate immune system; however, in contrast to our knowledge about bacterial metabolites, very little is known about the recognition profiles of MCTs. In this study, we determined the neutrophil-recognition profiles and functional output of putative MCTs originating from the N termini of the 13 human mitochondrial DNA–encoded proteins. Six of the thirteen MCTs potently activated neutrophils with distinct FPR-recognition profiles: MCTs from ND3 and ND6 have a receptor preference for FPR1; MCTs from the proteins ND4, ND5, and cytochrome b prefer FPR2; and MCT-COX1 is a dual FPR1/FPR2 agonist. MCTs derived from ND2 and ND4L are very weak neutrophil activators, whereas MCTs from ND1, ATP6, ATP8, COX2, and COX3, do not exert agonistic or antagonistic FPR effects. In addition, the activating MCTs heterologously desensitized IL-8R but primed the response to the platelet-activating factor receptor agonist. More importantly, our data suggest that MCTs have biased signaling properties in favor of activation of the superoxide-generating NADPH oxidase or recruitment of β-arrestin. In summary, we identify several novel FPR-activating peptides with sequences present in the N termini of mitochondrial DNA–encoded proteins, and our data elucidate the molecular basis of neutrophil activation by MCTs.

https://ift.tt/2FcxHa2

Specialized Antitumor Functions for Skin {gamma}{delta} T Cells [PILLARS OF IMMUNOLOGY]

https://ift.tt/2K7Vgog

Microcrystalline Tyrosine and Aluminum as Adjuvants in Allergen-Specific Immunotherapy Protect from IgE-Mediated Reactivity in Mouse Models and Act Independently of Inflammasome and TLR Signaling [IMMUNOTHERAPY AND VACCINES]

Allergen immunotherapy (AIT) is the only modality that can modify immune responses to allergen exposure, but therapeutic coverage is low. One strategy to improve AIT safety and efficacy is the use of new or improved adjuvants. This study investigates immune responses produced by microcrystalline tyrosine (MCT)–based vaccines as compared with conventional aluminum hydroxide (alum). Wild-type, immune-signaling–deficient, and TCR-transgenic mice were treated with different Ags (e.g., OVA and cat dander Fel d 1), plus MCT or alum as depot adjuvants. Specific Ab responses in serum were measured by ELISA, whereas cytokine secretion was measured both in culture supernatants by ELISA or by flow cytometry of spleen cells. Upon initiation of AIT in allergic mice, body temperature and further clinical signs were used as indicators for anaphylaxis. Overall, MCT and alum induced comparable B and T cell responses, which were independent of TLR signaling. Alum induced stronger IgE and IL-4 secretion than MCT. MCT and alum induced caspase-dependent IL-1β secretion in human monocytes in vitro, but inflammasome activation had no functional effect on inflammatory and Ab responses measured in vivo. In sensitized mice, AIT with MCT-adjuvanted allergens caused fewer anaphylactic reactions compared with alum-adjuvanted allergens. As depot adjuvants, MCT and alum are comparably effective in strength and mechanism of Ag-specific IgG induction and induction of T cell responses. The biocompatible and biodegradable MCT seems therefore a suitable alternative adjuvant to alum-based vaccines and AIT.

https://ift.tt/2F8B81G

Pillars Article: Regulation of Cutaneous Malignancy by {gamma}{delta} T Cells. Science. 2001. 294: 605-609 [PILLARS OF IMMUNOLOGY]

https://ift.tt/2JjEAck

S100A8/A9 Drives Neuroinflammatory Priming and Protects against Anxiety-like Behavior after Sepsis [INNATE IMMUNITY AND INFLAMMATION]

Sepsis commonly results in acute and chronic brain dysfunction, which dramatically increases the morbidity associated with this common disease. Chronic brain dysfunction in animal models of sepsis survival is linked to persistent neuroinflammation and expression of multiple cytokines. However, we have found previously that microglia predominantly upregulate the damage associated molecule S100A8/A9 after sepsis. In this article, we show that S100A8/A9 is increased in the brains of patients who died of sepsis and that S100A8 is expressed in astrocytes and myeloid cells. Using a mouse model of sepsis survival, we show that S100A8/A9 is persistently expressed in the brain after sepsis. S100A9 expression is necessary for recruitment of neutrophils to the brain and for priming production of reactive oxygen species and TNF-α secretion in microglia and macrophages. However, despite improving these indices of chronic inflammation, S100A9 deficiency results in worsened anxiety-like behavior 2 wk after sepsis. Taken together, these results indicate that S100A8/A9 contributes to several facets of neuroinflammation in sepsis survivor mice, including granulocyte recruitment and priming of microglial-reactive oxygen species and cytokine production, and that these processes may be protective against anxiety behavior in sepsis survivors.

https://ift.tt/2FbvDz8

Contribution of the Immune Response to Phage Therapy [BRIEF REVIEWS]

Therapeutic phages are being employed for vaccination and treatment of cancer and bacterial infections. Their natural immunogenicity triggers intertwined interactions with innate and adaptive immune cells that might influence therapy. Phage- and bactierial-derived pathogen-associated molecular patterns released after bacterial lysis have been proposed to stimulate local innate immune responses, which could promote antitumor immunity or bacterial clearance. Conversely, immunogenicity of phages induces phage-specific humoral memory, which can hamper therapeutic success. This review outlines the current knowledge on the different types of immune responses elicited by phages and their potential benefits and adverse side effects, when applied therapeutically. This review further summarizes the knowledge gaps and defines the key immunological questions that need to be addressed regarding the clinical application of antibacterial phage therapy.

https://ift.tt/2KaDil6

Mycobacterium tuberculosis Transfer RNA Induces IL-12p70 via Synergistic Activation of Pattern Recognition Receptors within a Cell Network [INNATE IMMUNITY AND INFLAMMATION]

Upon recognition of a microbial pathogen, the innate and adaptive immune systems are linked to generate a cell-mediated immune response against the foreign invader. The culture filtrate of Mycobacterium tuberculosis contains ligands, such as M. tuberculosis tRNA, that activate the innate immune response and secreted Ags recognized by T cells to drive adaptive immune responses. In this study, bioinformatics analysis of gene-expression profiles derived from human PBMCs treated with distinct microbial ligands identified a mycobacterial tRNA-induced innate immune network resulting in the robust production of IL-12p70, a cytokine required to instruct an adaptive Th1 response for host defense against intracellular bacteria. As validated by functional studies, this pathway contained a feed-forward loop, whereby the early production of IL-18, type I IFNs, and IL-12p70 primed NK cells to respond to IL-18 and produce IFN-, enhancing further production of IL-12p70. Mechanistically, tRNA activates TLR3 and TLR8, and this synergistic induction of IL-12p70 was recapitulated by the addition of a specific TLR8 agonist with a TLR3 ligand to PBMCs. These data indicate that M. tuberculosis tRNA activates a gene network involving the integration of multiple innate signals, including types I and II IFNs, as well as distinct cell types to induce IL-12p70.

https://ift.tt/2Jk1gcg

Cutting Edge: Mitochondrial Assembly of the NLRP3 Inflammasome Complex Is Initiated at Priming [CUTTING EDGE]

The NLRP3 inflammasome is activated in response to microbial and danger signals, resulting in caspase-1–dependent secretion of the proinflammatory cytokines IL-1β and IL-18. Canonical NLRP3 inflammasome activation is a two-step process requiring both priming and activation signals. During inflammasome activation, NLRP3 associates with mitochondria; however, the role for this interaction is unclear. In this article, we show that mouse NLRP3 and caspase-1 independently interact with the mitochondrial lipid cardiolipin, which is externalized to the outer mitochondrial membrane at priming in response to reactive oxygen species. An NLRP3 activation signal is then required for the calcium-dependent association of the adaptor molecule ASC with NLRP3 on the mitochondrial surface, resulting in inflammasome complex assembly and activation. These findings demonstrate a novel lipid interaction for caspase-1 and identify a role for mitochondria as supramolecular organizing centers in the assembly and activation of the NLRP3 inflammasome.

https://ift.tt/2Jlcopo

Deregulated Mucosal Immune Surveillance through Gut-Associated Regulatory T Cells and PD-1+ T Cells in Human Colorectal Cancer [TUMOR IMMUNOLOGY]

Disturbed balance between immune surveillance and tolerance may lead to poor clinical outcomes in some malignancies. In paired analyses of adenocarcinoma and normal mucosa from 142 patients, we found a significant increase of the CD4/CD8 ratio and accumulation of regulatory T cells (Tregs) within the adenocarcinoma. The increased frequency of Tregs correlated with the local infiltration and extension of the tumor. There was concurrent maturation arrest, upregulation of programmed death-1 expression, and functional impairment in CD8⁺ T cells (CTLs) isolated from the adenocarcinoma. Adenocarcinoma-associated Tregs directly inhibit the function of normal human CTLs in vitro. With histopathological analysis, Foxp3⁺ Tregs were preferentially located in stroma. Concurrent transcriptome analysis of epithelial cells, stromal cells, and T cell subsets obtained from carcinomatous and normal intestinal samples from patients revealed a distinct gene expression signature in colorectal adenocarcinoma–associated Tregs, with overexpression of CCR1, CCR8, and TNFRSF9, whereas their ligands CCL4 and TNFSF9 were found upregulated in cancerous epithelium. Overexpression of WNT2 and CADM1, associated with carcinogenesis and metastasis, in cancer-associated stromal cells suggests that both cancer cells and stromal cells play important roles in the development and progression of colorectal cancer through the formation of a tumor microenvironment. The identification of CTL anergy by Tregs and the unique gene expression signature of human Tregs and stromal cells in colorectal cancer patients may facilitate the development of new therapeutics against malignancies.

https://ift.tt/2Jk1boY

Characterization of the Antigenic Heterogeneity of Lipoarabinomannan, the Major Surface Glycolipid of Mycobacterium tuberculosis, and Complexity of Antibody Specificities toward This Antigen [ANTIGEN RECOGNITION AND RESPONSES]

Lipoarabinomannan (LAM), the major antigenic glycolipid of Mycobacterium tuberculosis, is an important immunodiagnostic target for detecting tuberculosis (TB) infection in HIV-1–coinfected patients, and is believed to mediate a number of functions that promote infection and disease development. To probe the human humoral response against LAM during TB infection, several novel LAM-specific human mAbs were molecularly cloned from memory B cells isolated from infected patients and grown in vitro. The fine epitope specificities of these Abs, along with those of a panel of previously described murine and phage-derived LAM-specific mAbs, were mapped using binding assays against LAM Ags from several mycobacterial species and a panel of synthetic glycans and glycoconjugates that represented diverse carbohydrate structures present in LAM. Multiple reactivity patterns were seen that differed in their specificity for LAM from different species, as well as in their dependence on arabinofuranoside branching and nature of capping at the nonreducing termini. Competition studies with mAbs and soluble glycans further defined these epitope specificities and guided the design of highly sensitive immunodetection assays capable of detecting LAM in urine of TB patients, even in the absence of HIV-1 coinfection. These results highlighted the complexity of the antigenic structure of LAM and the diversity of the natural Ab response against this target. The information and novel reagents described in this study will allow further optimization of diagnostic assays for LAM and may facilitate the development of potential immunotherapeutic approaches to inhibit the functional activities of specific structural motifs in LAM.

https://ift.tt/2K72N6K

Elastin Shapes Small Molecule Distribution in Lymph Node Conduits [IMMUNOGENETICS]

The spatial and temporal Ag distribution determines the subsequent T cell and B cell activation at the distinct anatomical locations in the lymph node (LN). It is well known that LN conduits facilitate small Ag distribution in the LN, but the mechanism of how Ags travel along LN conduits remains poorly understood. In C57BL/6J mice, using FITC as a fluorescent tracer to study lymph distribution in the LN, we found that FITC preferentially colocalized with LN capsule–associated (LNC) conduits. Images generated using a transmission electron microscope showed that LNC conduits are composed of solid collagen fibers and are wrapped with fibroblastic cells. Superresolution images revealed that high-intensity FITC is typically colocalized with elastin fibers inside the LNC conduits. Whereas tetramethylrhodamine isothiocyanate appears to enter LNC conduits as effectively as FITC, fluorescently-labeled Alexa-555–conjugated OVA labels significantly fewer LNC conduits. Importantly, injection of Alexa-555–conjugated OVA with LPS substantially increases OVA distribution along elastin fibers in LNC conduits, indicating immune stimulation is required for effective OVA traveling along elastin in LN conduits. Finally, elastin fibers preferentially surround lymphatic vessels in the skin and likely guide fluid flow to the lymphatic vessels. Our studies demonstrate that fluid or small molecules are preferentially colocalized with elastin fibers. Although the exact mechanism of how elastin fibers regulate Ag trafficking remains to be explored, our results suggest that elastin can be a potentially new target to direct Ag distribution in the LN during vaccine design.

https://ift.tt/2K8vErp

ICOS Signaling Controls Induction and Maintenance of Collagen-Induced Arthritis [AUTOIMMUNITY]

ICOS is a key costimulatory receptor facilitating differentiation and function of follicular helper T cells and inflammatory T cells. Rheumatoid arthritis patients were shown to have elevated levels of ICOS⁺ T cells in the synovial fluid, suggesting a potential role of ICOS-mediated T cell costimulation in autoimmune joint inflammation. In this study, using ICOS knockout and knockin mouse models, we found that ICOS signaling is required for the induction and maintenance of collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis. For the initiation of CIA, the Tyr¹⁸¹-based SH2-binding motif of ICOS that is known to activate PI3K was critical for Ab production and expansion of inflammatory T cells. Furthermore, we found that Tyr¹⁸¹-dependent ICOS signaling is important for maintenance of CIA in an Ab-independent manner. Importantly, we found that a small molecule inhibitor of glycolysis, 3-bromopyruvate, ameliorates established CIA, suggesting an overlap between ICOS signaling, PI3K signaling, and glucose metabolism. Thus, we identified ICOS as a key costimulatory pathway that controls induction and maintenance of CIA and provide evidence that T cell glycolytic pathways can be potential therapeutic targets for rheumatoid arthritis.

https://ift.tt/2Fb9hOl

Lysosome-Mediated Plasma Membrane Repair Is Dependent on the Small GTPase Arl8b and Determines Cell Death Type in Mycobacterium tuberculosis Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Mycobacterium tuberculosis is an extremely successful pathogen, and its success is widely attributed to its ability to manipulate the intracellular environment of macrophages. A central phenomenon of tuberculosis pathology enabling immune evasion is the capacity of virulent M. tuberculosis (H37Rv) to induce macrophage necrosis, which facilitates the escape of the mycobacteria from the macrophage and spread of infection. In contrast, avirulent M. tuberculosis (H37Ra) induces macrophage apoptosis, which permits Ag presentation and activation of adaptive immunity. Previously, we found that H37Rv induces plasma membrane microdisruptions, leading to necrosis in the absence of plasma membrane repair. In contrast, H37Ra permits plasma membrane repair, which changes the host cell death modality to apoptosis, suggesting that membrane repair is critical for sequestering the pathogen in apoptotic vesicles. However, mechanisms of plasma membrane repair induced in response to M. tuberculosis infection remain unknown. Plasma membrane repair is known to induce a Ca²⁺-mediated signaling, which recruits lysosomes to the area of damaged plasma membrane sites for its resealing. In this study, we found that the small GTPase Arl8b is required for plasma membrane repair by controlling the exocytosis of lysosomes in cell lines and in human primary macrophages. Importantly, we found that the Arl8b secretion pathway is crucial to control the type of cell death of the M. tuberculosis–infected macrophages. Indeed, Arl8b-depleted macrophages infected with avirulent H37Ra undergo necrotic instead of apoptotic cell death. These findings suggest that membrane repair mediated by Arl8b may be an important mechanism distinguishing avirulent from virulent M. tuberculosis–induced necrotic cell death.

https://ift.tt/2Kbnui8

Downregulation of CD3{zeta} in NK Cells from Systemic Lupus Erythematosus Patients Confers a Proinflammatory Phenotype [AUTOIMMUNITY]

Cytotoxic function and cytokine profile of NK cells are compromised in patients with systemic lupus erythematosus (SLE). CD3, an important molecule for NK cell activation, is downregulated in SLE T cells and contributes to their altered function. However, little is known about the role of CD3 in SLE NK cells. We studied CD3 levels and its contribution to cytotoxic, degranulation, and cytokine production capacity of NK cells from patients with SLE. Furthermore, we studied the human NK cell line, NKL, in which manipulation of CD3 levels was achieved using small interfering RNA and NK cells from Rag2 mice deficient in CD3. We found reduced CD3 expression in NK cells from SLE patients independent of disease activity. Downregulation of CD3 expression in NK cells is mediated, at least in part, by Caspase 3, the activity of which is higher in NK cells from patients with SLE compared with NK cells from healthy donors. CD3 levels correlated inversely with natural cytotoxicity and the percentage of cells capable of producing the proinflammatory cytokines IFN- and TNF. In contrast, CD3 levels showed a direct correlation with levels of Ab-dependent cellular cytotoxicity. Experiments performed in CD3-silenced NKL and CD3-deficient NK cells from Rag2 mice confirmed the dependence of NK cell function on CD3 levels. Our results demonstrate a differential role for CD3 in natural cytotoxicity and Ab-dependent cellular cytotoxicity. We conclude that downregulated CD3 confers a proinflammatory phenotype to SLE NK cells and contributes to their altered function in patients with SLE.

https://ift.tt/2KaDtwM

Altered Ratio of T Follicular Helper Cells to T Follicular Regulatory Cells Correlates with Autoreactive Antibody Response in Simian Immunodeficiency Virus-Infected Rhesus Macaques [INFECTIOUS DISEASE AND HOST RESPONSE]

Individuals with chronic HIV-1 infection have an increased prevalence of autoreactive Abs. Many of the isolated HIV broadly neutralizing Abs from these individuals are also autoreactive. However, the underlying mechanism(s) that produce these autoreactive broadly neutralizing Abs remains largely unknown. The highly regulated coordination among B cells, T follicular helper (T_FH) cells, and T follicular regulatory (T_FR) cells in germinal centers (GCs) of peripheral lymphatic tissues (LTs) is essential for defense against pathogens while also restricting autoreactive responses. We hypothesized that an altered ratio of T_FH/T_FR cells in the GC contributes to the increased prevalence of autoreactive Abs in chronic HIV infection. We tested this hypothesis using a rhesus macaque (RM) SIV model. We measured the frequency of T_FH cells, T_FR cells, and GC B cells in LTs and anti-dsDNA and anti-phospholipid Abs from Indian RMs, with and without SIV infection. We found that the frequency of anti-dsDNA and anti-phospholipid Abs was much higher in chronically infected RMs (83.3% [5/6] and 66.7% [4/6]) than in acutely infected RMs (33.3% [2/6] and 18.6% [1/6]) and uninfected RMs (0% [0/6] and 18.6% [1/6]). The increased ratio of T_FH/T_FR cells in SIV infection correlated with anti-dsDNA and anti-phospholipid autoreactive Ab levels, whereas the frequency of T_FR cells alone did not correlate with the levels of autoreactive Abs. Our results provide direct evidence that the ratio of T_FH/T_FR cells in LTs is critical for regulating autoreactive Ab production in chronic SIV infection and possibly, by extension, in chronic HIV-1 infection.

https://ift.tt/2KaDa56

The Effects of Reflux on the Elderly

Reflux-related complaints are a frequent cause for otolaryngology consultation, and with the aging population the concerns specific to the elderly reflux patient are critical. The elderly patient is less likely to present with typical laryngopharyngeal reflux (LPR) or gastroesophageal reflux disease (GERD) symptoms. Importantly, elderly patients typically have objective findings more severe than the level of the symptoms. Therefore, upfront invasive esophageal testing as opposed to an initial medical therapy trial is the recommended management strategy. For all patients irrespective of age, lifestyle and diet modifications continue to represent the cornerstone of medical management for LPR and GERD.

https://ift.tt/2qUTGxo

Endocrine Surgery in the Geriatric Population

Age must be a factor when considering endocrine surgery. Age itself is a risk factor for complications after thyroidectomy, specifically pulmonary, infectious, and cardiac complications. For this reason, in patients with nodular thyroid disease or thyroid microcarcinoma, length of observation must be measured against age and surgical risk. Outcomes of thyroid surgery in geriatric patients can be improved with several measures, including careful preoperative risk stratification based on comorbidities and frailty. In this population subset, it is imperative to have an earnest discussion with patients, their families, and any surrogate decision maker regarding potential outcomes of treatment versus observation.

https://ift.tt/2qVVLsT

Mechanism Underlying the Effects of Estrogen Deficiency on Otoconia

Abstract

Otoconia-related vertigo and balance deficits, particularly benign paroxysmal positional vertigo (BPPV), are common. Our recent studies in humans show that, while BPPV prevalence greatly increases with age in both genders, peri-menopausal women are especially susceptible. In the present study, we show that bilateral ovariectomized (OVX) mice have significant balance behavioral deficits, and that estrogen deficiency compromises otoconia maintenance and anchoring by reducing the expression of otoconial component and anchoring proteins. There is ectopic debris formation in the ampulla under estrogen deficiency due to aberrant matrix protein expression. Furthermore, phytoestrogen is effective in rescuing the otoconia abnormalities. By comparing the expression levels of known estrogen receptor (Esr) subtypes, and by examining the otoconia phenotypes of null mice for selected receptors, we postulate that Esr2 may be critical in mediating the effects of estrogen in otoconia maintenance.

https://ift.tt/2qUon6s

Increased Circulating Follicular Regulatory T-Like Cells May Play a Critical Role in Chronic Hepatitis B Virus Infection and Disease Progression

Viral Immunology, Ahead of Print.


https://ift.tt/2K8IRAl

Pembrolizumab combined with stereotactic body radiotherapy in a patient with human immunodeficiency virus and advanced non-small cell lung cancer: a case report

Pembrolizumab has significantly improved outcomes in patients with advanced non-small cell lung cancer. Combining programmed death-1 inhibitor with stereotactic body radiotherapy showed a slight toxicity and g...

https://ift.tt/2HMdqOg

Location and Causation of Residual Lymph Node Metastasis After Surgical Treatment of Regionally Advanced Differentiated Thyroid Cancer

Thyroid, Ahead of Print.


https://ift.tt/2K6o2Wm

Diagnostic Accuracy of Preoperative Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios in Detecting Occult Papillary Thyroid Microcarcinomas in Benign Multinodular Goitres

Objective. To investigate the diagnostic accuracy of neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte (PLR) ratios in detecting occult papillary thyroid microcarcinomas in benign, multinodular goitres. Methods. 397 total thyroidectomy patients were identified from the institutional thyroid surgery database between 2007 and 2016 (94 males, 303 females, mean age 53 ± 14.5 years). NLR and PLR were calculated as the absolute neutrophil and absolute platelet counts divided by the absolute lymphocyte count, respectively, based on the preoperative complete blood cell count. Results. NLR was significantly higher in carcinomas and microcarcinomas compared to benign pathology (), whereas a direct association could not be established for PLR. Both NLR and PLR scored low in all parameters of diagnostic accuracy, with overall accuracy ranging between 45 and 50%. Conclusions. As surrogate indices of the systemic inflammatory response, NLR and PLR are inexpensive and universally available from routine blood tests. Although we found higher NLR values in cases of malignancy, NLR and PLR cannot effectively predict the presence of occult papillary microcarcinomas in otherwise benign, multinodular goitres.

https://ift.tt/2vJbBwK

An Autopsy Report of an Adenoid Cystic Carcinoma Arising in the Trachea

Abstract

While adenoid cystic carcinoma is a common malignancy to arise within the salivary glands (21.9%) (Kokemueller et al. in Int J Oral Maxillofac Surg 33:25–31, 2004), it is seldom encountered as a tracheal mass and represents < 1% of all lung cancers. Tracheal tumors are an uncommon cause of dyspnoea due to their relatively rare occurrence (Baydur and Gottlieb in JAMA 234:829–831, 1975). They pose considerable diagnostic challenge clinically as their symptoms mimics more commoner ailments like asthma and chronic bronchitis. As they carry good prognosis, a timely diagnosis is highly warranted for appropriate therapeutic intervention. We describe a rare autopsy case of an adenoid cystic carcinoma in a middle-aged gentleman who presented with severe breathlessness and dyspnoea and succumbed to his illness after a brief hospital stay. Because the symptoms were non-specific, he was treated on lines of asthma and bronchitis.

https://ift.tt/2HKUQpq

An Autopsy Report of an Adenoid Cystic Carcinoma Arising in the Trachea

Abstract

While adenoid cystic carcinoma is a common malignancy to arise within the salivary glands (21.9%) (Kokemueller et al. in Int J Oral Maxillofac Surg 33:25–31, 2004), it is seldom encountered as a tracheal mass and represents < 1% of all lung cancers. Tracheal tumors are an uncommon cause of dyspnoea due to their relatively rare occurrence (Baydur and Gottlieb in JAMA 234:829–831, 1975). They pose considerable diagnostic challenge clinically as their symptoms mimics more commoner ailments like asthma and chronic bronchitis. As they carry good prognosis, a timely diagnosis is highly warranted for appropriate therapeutic intervention. We describe a rare autopsy case of an adenoid cystic carcinoma in a middle-aged gentleman who presented with severe breathlessness and dyspnoea and succumbed to his illness after a brief hospital stay. Because the symptoms were non-specific, he was treated on lines of asthma and bronchitis.

https://ift.tt/2HKUQpq

Lenvatinib and Iodine Therapy in Treating Patients With Radioactive Iodine-Sensitive Differentiated Thyroid Cancer

Conditions:   Differentiated Thyroid Gland Carcinoma;   Thyroid Gland Follicular Carcinoma;   Thyroid Gland Papillary Carcinoma
Intervention:   Drug: Lenvatinib
Sponsors:   Emory University;   Eisai Inc.
Not yet recruiting

https://ift.tt/2HVUFFK

An Autopsy Report of an Adenoid Cystic Carcinoma Arising in the Trachea

Abstract

While adenoid cystic carcinoma is a common malignancy to arise within the salivary glands (21.9%) (Kokemueller et al. in Int J Oral Maxillofac Surg 33:25–31, 2004), it is seldom encountered as a tracheal mass and represents < 1% of all lung cancers. Tracheal tumors are an uncommon cause of dyspnoea due to their relatively rare occurrence (Baydur and Gottlieb in JAMA 234:829–831, 1975). They pose considerable diagnostic challenge clinically as their symptoms mimics more commoner ailments like asthma and chronic bronchitis. As they carry good prognosis, a timely diagnosis is highly warranted for appropriate therapeutic intervention. We describe a rare autopsy case of an adenoid cystic carcinoma in a middle-aged gentleman who presented with severe breathlessness and dyspnoea and succumbed to his illness after a brief hospital stay. Because the symptoms were non-specific, he was treated on lines of asthma and bronchitis.

https://ift.tt/2HKUQpq

Cholangiocarcinoma in a Child with Progressive Abdominal Distension and Secondary Hypercalcemia

Cholangiocarcinoma is extremely rare in childhood and has been reported in association with other underlying diseases. The survival and prognosis are dismal especially in patients with unresectable or advanced stage cholangiocarcinoma. Overall survival in patients with metastatic cholangiocarcinoma could be increased by using combination chemotherapy with cisplatin and gemcitabine. A case of childhood cholangiocarcinoma was hereby reported.

https://ift.tt/2K78ilO

Diagnostik und Therapie des M. Osler

Zusammenfassung

Der M. Osler stellt eine autosomal-dominante seltene Erberkrankung dar. Die Betroffenen leiden v. a. unter der Epistaxis. Die Diagnosestellung beruht auf den Curaçao-Kriterien und der Gendiagnostik. Organmanifestationen finden sich als arteriovenöse Shunts im Bereich von Lunge, Leber, Gastrointestinaltrakt, seltener im Zentralnervensystem (ZNS) und anderen Körperregionen. Viele Patienten mit gastrointestinalen und anderen Organmanifestationen sind häufig klinisch asymptomatisch. Das Organscreening ist von elementarer Bedeutung zur Vermeidung von Komplikationen und sollte an Zentren mit besonderer Expertise durchgeführt werden. Derzeit existiert keine kausale Therapieoption. Von HNO-ärztlicher Seite stellt die nasale Schleimhautpflege sowie die endonasale Lasertherapie eine wichtige Säule in der Behandlung der Epistaxis dar. Medikamentöse Therapieansätze zielen auf die Kompensation der Haploinsuffizienz sowie Antiangiogenese ab und sind z. T. mit schwerwiegenden Nebenwirkungen assoziiert.

https://ift.tt/2qTSwC5

Radiological differences between HIV-positive and HIV-negative children with cholesteatoma

Publication date: July 2018
Source:International Journal of Pediatric Otorhinolaryngology, Volume 110
Author(s): J.K. McGuire, J.J. Fagan, M. Wojno, K. Manning, T. Harris
IntroductionHIV-positive children are possibly more prone to developing cholesteatoma. Chronic inflammation of the middle ear cleft may be more common in patients with HIV and this may predispose HIV-positive children to developing cholesteatoma. There are no studies that describe the radiological morphology of the middle ear cleft in HIV-positive compared to HIV-negative children with cholesteatoma.ObjectivesCompare the radiological differences of the middle ear cleft in HIV-positive and HIV-negative children with cholesteatoma.MethodsA retrospective, cross-sectional, observational analytical review of patients with cholesteatoma at our institute over a 6 year period.ResultsForty patients were included in the study, 11 of whom had bilateral cholesteatoma and therefore 51 ears were eligible for our evaluation. HIV-positive patients had smaller (p=0.02) mastoid air cell systems (MACS). Forty percent of HIV-positive patients had sclerotic mastoids, whereas the rate was 3% in HIV-negative ears (p<0.02). Eighty-two percent of the HIV-positive patients had bilateral cholesteatoma compared to 7% of the control group (p<0.02). There was no difference between the 2 groups with regards to opacification of the middle ear cleft, bony erosion of middle ear structures, Eustachian tube obstruction or soft tissue occlusion of the post-nasal space.ConclusionHIV-positive paediatric patients with cholesteatoma are more likely to have smaller, sclerotic mastoids compared to HIV-negative patients. They are significantly more likely to have bilateral cholesteatoma. This may have implications in terms of surveillance of HIV-positive children, as well as, an approach to management, recurrence and follow-up. HIV infection should be flagged as a risk factor for developing cholesteatoma.



https://ift.tt/2Hmckt5

Trends in management of obstructive sleep apnea in pediatric patients with Down syndrome

Publication date: July 2018
Source:International Journal of Pediatric Otorhinolaryngology, Volume 110
Author(s): Jennifer Best, Sean Mutchnick, Jonathan Ida, Kathleen R. Billings
IntroductionResidual obstructive sleep apnea (OSA) after adenotonsillectomy (T&A) is a common problem in children with Down Syndrome (DS). Our objective was to describe trends in surgical and medical management of OSA in pediatric patients with DS, and to present an algorithmic approach to managing these children.MethodsRetrospective case series of children with DS seen at a tertiary care medical center between 1/2008-6/2016 who underwent polysomnography (PSG) after having a T&A performed for sleep disordered breathing (SDB).ResultsSixty-five patients met inclusion criteria. The mean age at T&A was 4.8 years and 52.0% were male. The mean apnea-hypopnea index (AHI) was 23.2 events/hour for patients who had pre-T&A PSGs. The mean AHI was 10.7 events/hour after T&A. Twenty-three patients (35.4%) underwent at least one additional surgical procedure after T&A; 5 (7.7%) patients had ≥ two additional procedures. The most common additional surgical procedures were revision adenoidectomies (n = 8) and lingual tonsillectomies (n = 13). Fifteen (23.1%) patients underwent at least one drug-induced sleep endoscopy (DISE) to help direct selection of surgical site/s.ConclusionsResidual OSA is common after T&A in children with Down syndrome and can be managed by additional surgical interventions in many instances with successful reduction of the AHI. DISE has become part of a standard algorithm for managing persistent OSA in children with Down syndrome after T&A.



https://ift.tt/2qUGKrj

The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions

Abstract

Antibodies targeting PD-1 have been demonstrated durable anti-cancer activity in certain cancer types. However, the anti-PD-1 antibodies are less or not efficacious in many situations, which might be attributed to co-expression of multiple inhibitory receptors or presence of immunosuppressive cells in the tumor microenvironment. Most of the anti-PD-1 antibodies used in clinical studies are of IgG4 isotype with the S228P mutation (IgG4_S228P). The functional impact by the interaction of anti-PD-1 IgG4_S228P antibody with Fc gamma receptors (FcγRs) is poorly understood. To assess the effects, we generated a pair of anti-PD-1 antibodies: BGB-A317/IgG4_S228P and BGB-A317/IgG4-variant (abbreviated as BGB-A317), with the same variable regions but two different IgG4 Fc-hinge sequences. There was no significant difference between these two antibodies in binding to PD-1. However, BGB-A317/IgG4_S228P binds to human FcγRI with high affinity and mediates crosslinking between PD-1 and FcγRI. In contrast, BGB-A317 does neither. Further cell-based assays showed that such crosslinking could reverse the function of an anti-PD-1 antibody from blocking to activating. More importantly, the crosslinking induces FcγRI⁺ macrophages to phagocytose PD-1⁺ T cells. In a mouse model transplanted with allogeneic human cancer cells and PBMCs, BGB-A317 showed significant tumor growth inhibition, whereas BGB-A317/IgG4_S228P had no such inhibition. Immunohistochemistry study revealed an inverse correlation between FcγRI⁺ murine macrophage infiltration and the density of CD8⁺PD-1⁺ human T cells within tumors in the BGB-A317/IgG4_S228P-treated group. These evidences suggested that FcγRI⁺ binding and crosslinking had negative impact on the anti-PD-1 antibody-mediated anti-cancer activity.

https://ift.tt/2qPLT4C

Chronische myeloische Leukämie

Zusammenfassung

Die Einführung des Tyrosinkinaseinhibitors (TKI) Imatinib verbesserte die Prognose bei chronischer myeloischer Leukämie (CML) erheblich. Mit den Zweitgenerationsinhibitoren Nilotinib, Dasatinib und Bosutinib werden im Vergleich zu Imatinib raschere und tiefere molekulare Remissionen mit verändertem Nebenwirkungsprofil erzielt. Lang andauernde, behandlungsfreie Remissionen bei einer steigenden Zahl von Patienten verstärken die Hoffnung auf eine Heilbarkeit der CML. Entscheidend ist ein konsequentes zytogenetisches und molekulares Follow-up der CML-Patienten mit standardisierten Methoden, um den Remissionsstatus regelmäßig zu überprüfen. Der Einsatz von Interferon-α parallel zu oder nach einer TKI-Therapie geht mit der Induktion einer Immunantwort gegen den leukämischen Klon einher, was die Remissionsrate weiter erhöht. Ein neuer allosterischer Kinaseinhibitor (Asciminib) könnte die CML-Therapie künftig weiter verbessern.

https://ift.tt/2HnuJS8