Hypothesizing the potential implications of exposing known carcinogens on normal stem cells

Publication date: Available online 5 March 2018
Source:Oral Oncology
Author(s): A. Thirumal Raj, Supriya Kheur




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An enlarging nodule on the shin

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Otoemisiones en los niños tratados con gentamicina de un hospital comarcal

Publication date: Available online 5 March 2018
Source:Acta Otorrinolaringológica Española
Author(s): Jose Miguel Sequi Canet, Carlos Miguel Angelats Romero, Jose Miguel Sequi Sabater, Ana Miralles Torres, Miguel Boronat Garcia, Marta Gomez Delgado
IntroducciónLas recomendaciones de la Comisión Nacional para la Detección Precoz de la Hipoacusia (CODEPEH) aconsejan re-valorar la audición de aquellos niños que hayan sufrido algún evento potencialmente dañino para la audición como es la utilización de antibióticos ototóxicos como la gentamicina. Las otoemisiones evocadas son un buen método de evaluación de la integridad de la función coclear.Material y métodoSe presenta un estudio prospectivo que incluye a 92 niños, sin otros factores de riesgo auditivo, en los que se pautó tratamiento con gentamicina intravenosa por riesgo séptico/sepsis o infección urinaria y en los que se realizaron otoemisiones seriadas: al ingreso, al finalizar el tratamiento y al mes del alta (si estaban alteradas).ResultadosNingún sujeto presentó otoemisiones alteradas al final del seguimiento.ConclusiónLa gentamicina parece un antibiótico seguro en tratamientos con una duración <10días y a las dosis descritas. Las otoemisiones son un método barato, rápido, incruento y fiable para comprobar la posible ototoxicidad por gentamicina. Su realización podría ahorrar la determinación de niveles del fármaco.IntroductionThe National Commission for the Early Detection of Hearing Loss (CODEPEH) recommends the re-evaluation of hearing in children who have suffered any potentially harmful event, such as the prescription of ototoxic antibiotics such as gentamicin. The evoked otoacoustic emissions (EOAE) are a good method for assessing the integrity of cochlear functionality.Material and methodA prospective study is presented, including 92 children who were treated with intravenous gentamicin for septic risk/sepsis or urinary tract infection. The children underwent serial EOAE: on admission, at the end of treatment and one month later (if altered on discharge).ResultsIn the end, none of the subjects were affected by the treatment.ConclusionGentamicin appears to be a safe antibiotic in treatments lasting <10days and at the doses described. EOAE are an inexpensive, fast, non-invasive and reliable method to check for gentamicin ototoxicity. This could save in the determination of drug levels.



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Model-based Dosage Individualization of Ganciclovir in Neonates and Young Infants with Congenital Cytomegalovirus Infection: A Pilot Study [PublishAheadOfPrint]

Background: Newborns with congenital cytomegalovirus (CMV) infection are at high risk for developing permanent sequelae. Intravenous ganciclovir therapy is frequently used for the treatment of congenital CMV infection. Target area under the concentration versus time curve (AUC_0–24) of 40-50 μg·h/mL is recommended. The standard dose resulted in a large variability in ganciclovir exposure in newborns, indicating the unmet need of dosage individualization in this vulnerable population, but the implementation of this strategy remains challenging in clinical practice. We aim to evaluate the clinical utility of model-based dosage individualization of ganciclovir in newborns using an opportunistic sampling approach.

Methods: The predictive performance of a published ganciclovir population pharmacokinetic model was evaluated using an independent patient cohort. The individual dose was adjusted based on the target AUC_0-24 to ensure the efficacy.

Results: A total of 26 newborns with congenital CMV infection were included in the present study. Only 11 (42.3%) patients achieved the target AUC_0-24 after giving the standard dose. For all the subtherapeutic (below 80% target AUC) patients (n=5), model-based dosage adjustment was performed using Bayesian estimation method combined with the opportunistic sampling strategy. The adjusted doses were increased 28.6% - 60.0% in these five patients and all adapted AUC_0–24 achieved the target (range: 48.6-66.1 μg·h/mL).

Conclusion: The clinical utility of model-based dosing individualization of ganciclovir was demonstrated in newborns with congenital CMV infection. Population pharmacokinetic model combined with the opportunistic sampling strategy provides a clinical feasible method to adapt ganciclovir dose in neonatal clinical practice.

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The effect of antimicrobial agents on inflammatory cytokines in acute leptospirosis [PublishAheadOfPrint]

The aim of this study was to assess the inflammatory cytokine response and possible association with antimicrobial treatment with penicillin, ceftriaxone and doxycycline in acute leptospirosis. In the early acute stage, IL-10 was higher in mild cases compared to severe cases (p=0.01). IL-6 and IL-8 levels were low in patients who received >5 antimicrobial doses (p<0.01). IL-8 was negatively correlated with number of ceftriaxone doses administered (r=-0.315; p=0.031). Further studies are needed to evaluate the possible down-regulation of pro-inflammatory cytokines by ceftriaxone in leptospirosis.

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Topical treatment for cutaneous leishmaniasis - dermato-pharmacokinetic led optimisation of benzoxaboroles [PublishAheadOfPrint]

Cutaneous leishmaniasis (CL) is caused by several species of the protozoan parasite Leishmania – affecting an estimated 10 million people worldwide. Previously reported strategies for the development of topical CL treatments have focussed primarily on drug permeation and formulation optimisation as the means to increase treatment efficacy.

Our approach aims to identify compounds with anti-leishmanial activity and properties consistent with topical administration. Of the test compounds, five benzoxaboroles showed potent activity (EC₅₀< 5 μM) against intracellular amastigotes of at least one Leishmania species and acceptable activity (20 μM< EC₅₀ <30 μM) against two more species. Benzoxaborole compounds were further prioritised based upon the in vitro evaluation of progression criteria related to skin permeation such as the partition coefficient and solubility. An MDCK-MDR1 assay showed overall good permeability and no significant interaction with the P-glycoprotein transporter for all substrates except LSH002 and LSH031. The benzoxaboroles were degraded, to some extent, by skin enzymes but have superior stability than para-hydroxybenzoate compounds that are known skin esterase substrates. Permeation evaluation through reconstructed human epidermis showed LSH002 to be most permeable followed by LSH003 and LSH001. Skin disposition studies following finite drug formulation application to mouse skin demonstrated the highest permeation for LSH001 followed by LSH003 and LSH002 with a significantly higher amount of LSH001 retained in skin compared to other compounds.

Finally, the efficacy of the leads (LSH001, LSH002 and LSH003) was tested in vivo against Leishmania major. LSH001 suppressed lesion growth upon topical application and LSH003 reduced the lesion size following oral administration.

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Relebactam (MK-7655) in combination with imipenem: Exploring the pharmacokinetic/pharmacodynamic relationship with a hollow fiber infection model [PublishAheadOfPrint]

Resistance to antibiotics among bacterial pathogens is rapidly spreading and therapeutic options against multidrug-resistant bacteria are limited. There is an urgent need for new drugs, especially those that can circumvent the broad array of resistance pathways that bacteria have evolved. In this study, we assessed the pharmacokinetic/pharmacodynamic relationship of the novel β-lactamase inhibitor relebactam (MK-7655; REL) in a hollow fiber infection model. REL is intended for use with the carbapenem β-lactam antibiotic imipenem for the treatment of Gram-negative bacterial infections. In this study, we used an in vitro hollow fiber infection model to confirm the efficacy of human exposures associated with the Phase 2 doses (imipenem 500 mg + REL 125 or 250 mg administered intravenously every 6 hours as a 30-minute infusion) against imipenem-resistant strains of Pseudomonas aeruginosa and Klebsiella pneumoniae. Dose fractionation experiments confirmed that the pharmacokinetic parameter best correlated with REL activity is the area under the concentration-time curve, consistent with findings in a murine pharmacokinetic/pharmacodynamic model. Determination of the pharmacokinetic/pharmacodynamic relationship between β-lactam antibiotics and β-lactamase inhibitors is complex as there is an interdependence between their respective exposure-response relationships. Here, we show that this interdependence could be captured by treating the minimum inhibitory concentration (MIC) of imipenem as dynamic: it changes with time and this change is directly related to REL levels. For the strains tested, the percentage of time above dynamic MIC for imipenem was maintained at the carbapenem target of 30-40%, required for maximum efficacy, for imipenem 500 mg plus REL 250 mg.

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Native human monoclonal antibodies with potent cross-lineage neutralization of influenza B viruses [PublishAheadOfPrint]

Although antibodies that effectively neutralize a broad set of influenza viruses exist in the human antibody repertoire, they are rare. We used a single cell screening technology to identify rare monoclonal antibodies (mAbs) that recognized a broad set of influenza B viruses (IBV). The screen yielded 23 mAbs with diverse germ line origins that recognized hemagglutinins (HAs) derived from influenza strains of both the Yamagata and Victoria lineages of IBV. Of the 23 mAbs, three exhibited low expression in a transient transfection system, four were neutralizers that bound to the HA head region, eleven were stalk-binding non-neutralizers, and five were stalk-binding neutralizers with four of these five representing unique antibody sequences. Of these four unique stalk-binding neutralizing mAbs, all were broadly reactive and neutralizing against a panel of multiple strains spanning both IBV lineages as well as highly effective in treating lethal IBV infections in mice at both 24 and 72 hours post-infection. The mAbs in this group were thermostable and bound different epitopes in the highly conserved HA stalk region. These characteristics suggest these mAbs are suitable for consideration as candidates for clinical studies to address effectiveness in treating of IBV infected patients.

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P174E substitution in GES-1 and GES-5 {beta}-lactamases improves catalytic efficiency towards carbapenems [PublishAheadOfPrint]

GES-type β-lactamases are a group of enzymes that have evolved their hydrolytic activity towards carbapenems. In this study the role of residue 174 inside the -loop of GES-1 and GES-5 was investigated. GES-1^P174E and GES-5^P174Emutants, selected by site-saturation mutagenesis, were purified and kinetically characterized. Comparing with GES-1 and GES-5 wild-type enzymes, GES-1^P174E and GES-5^P174E mutants exhibited lower k_cat and k_cat/K_m values for cephalosporins and penicillins. Concerning carbapenems, the two mutants shared higher k_cat values but lower K_m values respect to those calculated for GES-1 and GES-5. The GES-1^P174E and GES-5^P174E showed high hydrolytic efficiency for imipenem with k_cat/K_m values 100- and 660-fold higher than GES-1. Clavulanic acid and tazobactam are good inhibitors for both GES-1^P174E and GES-5^P174E. Molecular dynamic simulations (MDs) carried out for GES-1, GES-5, GES-1^P174E and GES-5^P174E complexed with imipenem and meropenem have shown that mutation at position 174 induces a drastic increase of enzymes flexibility, in particular in the -loop. The CD spectroscopy spectra of the four enzymes indicates that substitution P174E in GES-1 and GES-5 does not affect the secondary structural content of the enzymes.

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Elevated MIC values to imidazole drugs among Aspergillus fumigatus isolates with TR34/L98H/S297T/F495I mutation [PublishAheadOfPrint]

Use of azole fungicides in agriculture is believed to be one of the main reasons for the emergence of azole resistance in Aspergillus fumigatus. Although widely used in agriculture, imidazole fungicides have not been linked to resistance in A. fumigatus. This study showed that elevated MIC values to imidazole drugs were observed among A. fumigatus isolates with TR₃₄/L98H/S297T/F495I mutation, but not among isolates with TR₃₄/L98H mutation. The STR typing analysis of 580 A. fumigatus isolates from 20 countries suggested that the majority of TR₃₄/L98H/S297T/F495I strains from China were genetically different from the predominated major clade consisted of most of the azole resistant strains and the strains with the same mutation from the Netherlands and Denmark. Alignments of sterol 14α-demethylase sequences implicated that F495I in A. fumigatus was orthologous to F506I in Penicillium digitatum and F489L in Pyrenophora teres, which have been reported to be associated with imidazole resistance. The in vitro antifungal susceptibility testing of different recombinants of cyp51A mutations further confirms the association of F495I mutation with imidazole resistance. In conclusion, this study suggested that environmental use of imidazole fungicides might confer selection pressure for the emergence of azole resistance in A. fumigatus.

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Heavy metal resistance genes are associated with blaNDM-1 and blaCTX-M-15-Enterobacteriaceae [PublishAheadOfPrint]

The occurrence of heavy metal resistance genes in multi-resistant Enterobacteriaceae possessing bla_NDM-1 or bla_CTX-M-15 genes were examined by PCR and S1-PFGE. When compared with clinical susceptible isolates (10.0-30.0%), the pcoA, merA, silC and arsA genes occurred with higher frequencies in bla_NDM-1 (48.8-71.8%) and bla_CTX-M-15 (19.4-52.8%) positive isolates, and they are mostly located on plasmids. Given the high association of metal resistance genes with multidrug resistant Enterobacteriaceae, the use of heavy metals in hospitals and the environment needs increased vigilance.

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Acylhydrazones as antifungal agents targeting the synthesis of fungal sphingolipids [PublishAheadOfPrint]

The incidence of invasive fungal infections has risen dramatically in the past decades. Current antifungal drugs are either toxic, likely to interact with other drugs, have a narrow spectrum of activity or induce fungal resistance. Hence, there is a great need for new antifungals, possibly with novel mechanisms of action. Previously our group reported an acylhydrazone called BHBM that targeted the sphingolipid pathway, and showed strong antifungal activity against several fungi. In this study, we screened 19 derivatives of BHBM. Three out of nineteen derivatives were highly active against Cryptococcus neoformans in vitro and had low toxicity on mammalian cells. In particular, one of them, called D13, had a high selectivity index and showed better activity in an animal model of cryptococcosis, candidiasis and pulmonary aspergillosis. D13 also displayed suitable pharmacokinetic properties and was able to pass through the blood brain barrier. These results suggest that acylhydrazones are promising molecules for the research and development of new antifungal agents.

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Population pharmacokinetics of piperacillin in septic patients - should alternative dosing strategies be considered? [PublishAheadOfPrint]

Sufficient antibiotic dosing in septic patients is essential for reducing mortality. Piperacillin/tazobactam is often used for empiric treatment but due to the pharmacokinetic (PK) variability seen in septic patients, optimal dosing may be a challenge. We determined the PK profile for piperacillin 4g every 8h in 22 septic patients admitted to a medical ward. Piperacillin concentrations were compared to clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/L) and the following PK/PD targets were evaluated: 50% f T>MIC and 100% f T>MIC. A two-compartment population PK model described the data well, with clearance divided into renal and non-renal components. The renal component was proportional to the estimated creatinine clearance (eCL_Cr), and constituted 74% of the total clearance in a typical individual (eCL_Cr of 83.9 mL/min). Patients with high eCL_Cr (>130 mL/min) were at risk of sub-therapeutic concentrations for the current regimen, with 90% PTA reached at MICs of 2.0 (50% f T>MIC) and 0.125 mg/L (100% f T>MIC). Simulations of alternative dosing regimens and modes of administration showed that dose increment and prolonged infusion increased the chance of achieving pre-defined PK/PD targets. Alternative dosing strategies may therefore be needed to optimize piperacillin exposure in septic patients.

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Metabolism, Excretion and Mass Balance of Solithromycin in Humans [PublishAheadOfPrint]

Solithromycin, a novel macrolide and the first fluoroketolide, is being developed as a therapy for community-acquired bacterial pneumonia, with a distinct mechanism that provides activity against macrolide-resistant bacteria. The pharmacokinetics, metabolism, and excretion of solithromycin, were studied in healthy male subjects after oral administration of a single 800 mg (~100 μCi) dose of [¹⁴C]solithromycin. Solithromycin was well tolerated and absorption from the solution occurred with a median time to peak concentration of 4.0 hours. Solithromycin and the total radioactivity had similar profiles with no long-lived metabolites. The whole blood total radioactivity was approximately 75% of plasma total radioactivity. Recovery was essentially complete (mean 90.6%), with 76.5% and 14.1% of the dose recovered in feces and urine, respectively. Unchanged solithromycin (CEM-101) was the predominant circulating radioactive component in plasma (77% of the total radioactivity AUC) with two minor plasma metabolites, CEM-214 and CEM-122 (N-acetyl CEM-101), each accounting for approximately 5% of the total radioactivity. Urinary excretion was predominantly as parent. Solithromycin was primarily eliminated in the feces after extensive metabolism via a complex metabolic pathway with CEM-262 as the major constituent (27.36% of administered dose). Overall oxidative pathways, presumably carried out mostly by CYP3A4, represented the majority of the metabolism with N-acetylation present to a lesser extent. No disproportionate human metabolites were observed.

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Spread of Plasmid-Encoded NDM-1 and GES-5 Carbapenemases among Extensively Drug-Resistant and Pandrug-Resistant Clinical Enterobacteriaceae in Durban, South Africa [PublishAheadOfPrint]

Whole-genome sequence analyses revealed the presence of bla_NDM-1 (n=31), bla_GES-5 (n=8), bla_OXA-232 (n=1), or bla_NDM-5 (n=1) in extensively drug-resistant and pandrug-resistant Enterobacteriaceae isolated from in-patients in 10 private hospitals (2012-2013) in Durban, South Africa. Two novel NDM-1 encoding plasmids from Klebsiella pneumoniae were closed by PacBio sequencing. In p19-10_01 (IncFIB(K), 223.434 bp) bla_NDM-1 was part of a Tn1548-like structure (16.276 bp) delineated by IS26. The multireplicon plasmid p18-43_01 (IncR_1/IncFIB(pB171)/IncFII(Yp); 212.326 bp) shared an 80-kb region with p19-10_01, not including the bla_NDM-1 containing region. The two plasmids were used as references for tracing NDM-1 encoding plasmids in the other genome assemblies. The p19-10_01 sequence was detected in K. pneumonia (n=7) only. Whereas p18-43_01 was tracked to K. pneumoniae (n=4), Klebsiella michiganensis (n=1), Serratia marcescens (n=11), Enterobacter spp. (n=7), and Citrobacter freundii (n=1), revealing horizontal spread of this bla_NDM-1-bearing plasmid structure. Global phylogeny showed clustering of the K. pneumoniae (18/20) isolates together with closely related carbapenemase-negative ST101 isolates from other geographical origin. The South African isolates divided into three phylogenetic sub-branches, where each group had distinct resistance and replicon profile, and Fig. carrying either p19-10_01, p18-10_01 or pCHE-A1 (8201 bp). The latter carrying bla_GES-5 and aacA4 within an integron mobilization unit. Our findings imply independent plasmid acquisition followed by local dissemination. Additionally, we detected bla_OXA-232 carried by pPKPN4 in K. pneumoniae (ST14) and bla_NDM-5 contained by a pNDM-MGR194-like genetic structure in Escherichia coli (ST167), adding even more complexity to the multilayer molecular mechanisms behind nosocomial spread of CRE in Durban, South Africa.

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Pneumonia and renal replacement therapy are risk factors for ceftazidime-avibactam treatment failures and resistance among patients with carbapenem-resistant Enterobacteriaceae infections [PublishAheadOfPrint]

Ceftazidime-avibactam was used to treat 77 patients with carbapenem-resistant Enterobacteriaceae (CRE) infections at our center. Thirty- and 90-day survival rates were 81% and 69%, respectively; rates were higher than predicted by SAPS II and SOFA scores at the onset of infection. Clinical success was achieved in 55% of patients, but varied by site of infection. Success rates were lowest for pneumonia (36%) and higher for bacteremia (75%) and urinary tract infections (88%). By multivariate analysis, pneumonia (P=0.045) and receipt of renal replacement therapy (RRT; P=0.046) were associated with clinical failure. Microbiologic failures occurred in 32% of patients, and occurred more commonly among patients infected with KPC-3-producing than KPC-2-producing CRE (P=0.002). Pneumonia was an independent predictor of microbiologic failures (P=0.007). Ceftazidime-avibactam resistance emerged in 10% of patients, including 14% infected with Klebsiella pneumoniae and 32% with microbiologic failures. RRT was an independent predictor for the development of resistance (P=0.009). Resistance was identified exclusively among K. pneumoniae harboring variant KPC-3 enzymes. Upon phylogenetic analysis of whole genome sequences, resistant isolates from 87.5% (7/8) of patients clustered within a previously defined sequence type (ST)258, clade II sub-lineage; resistant isolates from one patient clustered independently from other ST258, clade II isolates. In conclusion, our report offers new insights into the utility and limitations of ceftazidime-avibactam across CRE infection types. Immediate priorities are to identify ceftazidime-avibactam dosing and therapeutic regimens that improve upon the poor outcomes among patients with pneumonia, and in those receiving RRT.

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Combination immune checkpoint inhibitor therapy nivolumab and ipilimumab associated with multiple endocrinopathies

Summary

Immune checkpoint inhibitors are the mainstay of treatment for advanced melanoma, and their use is being increasingly implicated in the development of autoimmune endocrinopathies. We present a case of a 52-year-old man with metastatic melanoma on combination nivolumab and ipilumimab therapy who developed concurrent hypophysitis, type 1 diabetes mellitus (T1DM) and diabetes insipidus. He presented prior to third cycle of combination treatment with a headache, myalgias and fatigue. Biochemistry and MRI pituitary confirmed anterior pituitary dysfunction with a TSH: 0.02 mU/L (0.5–5.5 mU/L), fT4: 5.2 pmol/L (11–22 pmol/L), fT3: 4.0 pmol/L (3.2–6.4 pmol/L), cortisol (12:00 h): <9 nmol/L (74–286 nmol/L), FSH: 0.7 IU/L (1.5–9.7 IU/L), LH: <0.1 IU/L (1.8–9.2 IU/L), PRL: 1 mIU/L (90–400 mIU/L), SHBG: 34 nmol/L (19–764 nmol/L) and total testosterone: <0.4 nmol/L (9.9–27.8 nmol/L). High-dose dexamethasone (8 mg) was administered followed by hydrocortisone, thyroxine and topical testosterone replacement. Two weeks post administration of the third cycle, he became unwell with lethargy, weight loss and nocturia. Central diabetes insipidus was diagnosed on the basis of symptoms and sodium of 149 mmol/L (135–145 mmol/L). Desmopressin nasal spray was instituted with symptom resolution and normalization of serum sodium. Three weeks later, he presented again polyuric and polydipsic. His capillary glucose was 20.8 mmol/L (ketones of 2.4 mmol), low C-peptide 0.05 nmol/L (0.4–1.5 nmol/L) and HbA1c of 7.7%. T1DM was suspected, and he was commenced on an insulin infusion with rapid symptom resolution. Insulin antibodies glutamic acid decarboxylase (GAD), insulin antibody-2 (IA-2) and zinc transporter-8 (ZnT8) were negative. A follow-up MRI pituitary revealed findings consistent with recovering autoimmune hypophysitis. Immunotherapy was discontinued based on the extent of these autoimmune endocrinopathies.

Learning points:

The most effective regime for treatment of metastatic melanoma is combination immunotherapy with nivolumab and ipilumimab, and this therapy is associated with a high incidence of autoimmune endocrinopathies.

Given the high prevalence of immune-related adverse events, the threshold for functional testing should be low.

Traditional antibody testing may not be reliable to identify early-onset endocrinopathy.

Routine screening pathways have yet to be adequately validated through clinical trials.

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One Year Posttransplant, Recipients of Hepatitis C Kidneys Disease-Free

In a small study, doctors at Johns Hopkins have successfully transplanted 10 hepatitis C-infected kidneys into patients without hepatitis C and prevented the patients from becoming infected by hepatitis C. The success of these transplants could mean more organs being available for the nearly 100,000 people in the U.S. currently waiting for a kidney transplant.

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Bioglass reconstruction of posterior meatal wall after canal wall down mastoidectomy

Canal wall down (CWD) mastoidectomy has many drawbacks including chronic otorrhea, granulations, dizziness on exposure to cold or hot water and tendency of debris accumulation in the mastoid cavity demanding periodic cleaning. Many of these problems can be solved by reconstruction of the posterior meatal wall (PMW).

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Audiological profiling in postmenopausal women with osteoporosis

To compare the audiological profiles in postmenopausal women with and without osteoporosis and to study the pattern of hearing loss in osteoporotic patients.

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Corrigendum to “Retropharyngeal abscess as a result of hyaluronic acid injection pharyngoplasy: A first of its kind” [Am J Otolaryngol 38(6) (Nov–Dec 2017) 718–719]

The authors regret that we accidentally did not include Dr. Sivakumar Cinnadurai as an author for our manuscript submission. He has an integral role in the case report, and thus, we are requesting that he is added as an author.

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The clinical value of the RGB value of an image of the interarytenoid area for diagnosis of laryngopharyngeal reflux

I read with great interest the excellent article entitled "Image analysis of interarytenoid area to detect cases of laryngopharyngeal reflux: An objective method" by Nayak et al. [1] This is a meaningful work. The authors attempted to objectively diagnose laryngopharyngeal reflux (LPR) by analyzing the change in the RGB (red, green, blue) value of an image of the interarytenoid area. The authors found strong correlations between R and G values and both the reflux finding score (RFS) and reflux symptom index (RSI).

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Cortactin expression in nasal polyps of aspirin-exacerbated respiratory disease (aerd) patients

The term aspirin-exacerbated respiratory disease (AERD) refers to a combination of asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), and acute respiratory tract reactions to nonsteroidal anti-inflammatory drugs. AERD has now been included among the CRSwNP endotypes, and is considered one of the most aggressive in terms of disease recurrence.Cortactin is a multi-domain protein with a part in several cellular mechanisms involving actin assembly and cytoskeleton arrangement. Cortactin seems to have a role in inflammatory responses and to be implicated in human airway secretion and contraction mechanisms.

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Effect of allergic rhinitis on nasal obstruction outcomes after functional open Septorhinoplasty

To evaluate whether a diagnosis of allergic rhinitis affects surgical outcomes of open septorhinoplasty (OSR) and to examine whether OSR provides the same level of improvement in quality of life to patients with and without allergic rhinitis.

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Neuromuscular function of the soft palate and uvula in snoring and obstructive sleep apnea: A systematic review

A collapsible upper airway is a common cause of obstructive sleep apnea. The exact pathophysiology leading to a more collapsible airway is not well understood. A progressive neuropathy of the soft palate and pharyngeal dilators may be associated with the progression of snoring to OSA. The purpose of this study is to systematically review the international literature investigating the neurophysiologic changes in the soft palate and uvula that contribute to progression from snoring to OSA.

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Skin cancer prevention messages on Facebook: Likes, shares, and comments

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Assessing the Safety of Superficial Chemical Peels in Darker Skin: A Retrospective Study

There is limited data about the side effects and complications of chemical peels in darker skin types. Side effects are infrequent and include post-inflammatory erythema, crust, and post-inflammatory hyperpigmentation with no permanent sequelae. When performed in an appropriate manner, superficial chemical peels have a relatively low complication rate in darker skin types.

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Somatic and psychiatric comorbidities of hidradenitis suppurativa in children and adolescents.

- Epidemiologic data on hidradenitis suppurativa in childhood and adolescence are sparse; - This study demonstrates the psychiatric and somatic comorbidities of hidradenitis suppurativa in young patients; - Young patients with hidradenitis suppurativa need care for the comorbidities of HS, which may accumulate over time.

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Patient quality of life fluctuates before and after Mohs micrographic surgery: A longitudinal assessment of the patient experience

Patient QOL is initially impaired from restricted social interactions and appearance concerns after Mohs micrographic surgery (MMS), but QOL improves from baseline by three months after MMS. Patients younger than 65, women, and smokers report worse QOL before and after MMS, Characterizing the evolution of and risk factors for impaired QOL may allow targeted management to improve the experience of MMS patients.

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The Prognostic Significance of Tumor-Infiltrating Lymphocytes for Primary Melanoma Varies by Sex

Some studies suggest tumor-infiltrating lymphocytes in primary melanoma are associated with a lower likelihood of sentinel lymph node mestastases. In this institutional cohort study, TILs were found to be predictive of SLN status in men but not among women. TILs status may be more useful for clinical decision-making among men than women

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An Effective Game-Based Learning Intervention for Improving Melanoma Recognition

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Type I pityriasis rubra pilaris treated with tumor necrosis factor inhibitors, ustekinumab, or secukinumab: a systematic review

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Music enjoyment with cochlear implantation

Since the advent of cochlear implant (CI) surgery in the 1960s, there have been remarkable technological and surgical advances enabling excellent speech perception in quiet with many CI users able to use the telephone. However, many CI users struggle with music perception, particularly with the pitch-based and melodic elements of music. Yet remarkably, despite poor music perception, many CI users enjoy listening to music based on self-report questionnaires, and prospective studies have suggested a disassociation between music perception and enjoyment.

http://ift.tt/2Fv5UWy

HPV18 Persistence Impairs Basal and DNA Ligand-Mediated IFN-{beta} and IFN-{lambda}1 Production through Transcriptional Repression of Multiple Downstream Effectors of Pattern Recognition Receptor Signaling [INFECTIOUS DISEASE AND HOST RESPONSE]

Although it is clear that high-risk human papillomaviruses (HPVs) can selectively infect keratinocytes and persist in the host, it still remains to be unequivocally determined whether they can escape antiviral innate immunity by interfering with pattern recognition receptor (PRR) signaling. In this study, we have assessed the innate immune response in monolayer and organotypic raft cultures of NIKS cells harboring multiple copies of episomal HPV18 (NIKSmcHPV18), which fully recapitulates the persistent state of infection. We show for the first time, to our knowledge, that NIKSmcHPV18, as well as HeLa cells (a cervical carcinoma–derived cell line harboring integrated HPV18 DNA), display marked downregulation of several PRRs, as well as other PRR downstream effectors, such as the adaptor protein stimulator of IFN genes and the transcription factors IRF1 and 7. Importantly, we provide evidence that downregulation of stimulator of IFN genes, cyclic GMP-AMP synthase, and retinoic acid–inducible gene I mRNA levels occurs at the transcriptional level through a novel epigenetic silencing mechanism, as documented by the accumulation of repressive heterochromatin markers seen at the promoter region of these genes. Furthermore, stimulation of NIKSmcHPV18 cells with salmon sperm DNA or poly(deoxyadenylic-deoxythymidylic) acid, two potent inducers of PRR signaling, only partially restored PRR protein expression. Accordingly, the production of IFN-β and IFN-₁ was significantly reduced in comparison with the parental NIKS cells, indicating that HPV18 exerts its immunosuppressive activity through downregulation of PRR signaling. Altogether, our findings indicate that high-risk human papillomaviruses have evolved broad-spectrum mechanisms that allow simultaneous depletion of multiple effectors of the innate immunity network, thereby creating an unreactive cellular milieu suitable for viral persistence.

http://ift.tt/2oSSc5z

The Antimicrobial Peptide CRAMP Is Essential for Colon Homeostasis by Maintaining Microbiota Balance [MUCOSAL IMMUNOLOGY]

Commensal bacteria are critical for physiological functions in the gut, and dysbiosis in the gut may cause diseases. In this article, we report that mice deficient in cathelin-related antimicrobial peptide (CRAMP) were defective in the development of colon mucosa and highly sensitive to dextran sulfate sodium (DSS)-elicited colitis, as well as azoxymethane-mediated carcinogenesis. Pretreatment of CRAMP^–/– mice with antibiotics markedly reduced the severity of DSS-induced colitis, suggesting CRAMP as a limiting factor on dysbiosis in the colon. This was supported by observations that wild-type (WT) mice cohoused with CRAMP^–/– mice became highly sensitive to DSS-induced colitis, and the composition of fecal microbiota was skewed by CRAMP deficiency. In particular, several bacterial species that are typically found in oral microbiota, such as Mogibacterium neglectum, Desulfovibrio piger, and Desulfomicrobium orale, were increased in feces of CRAMP^–/– mice and were transferred to WT mice during cohousing. When littermates of CRAMP^+/– parents were examined, the composition of the fecal microbiota of WT pups and heterozygous parents was similar. In contrast, although the difference in fecal microbiota between CRAMP^–/– and WT pups was small early on after weaning and single mouse housing, there was an increasing divergence with prolonged single housing. These results indicate that CRAMP is critical in maintaining colon microbiota balance and supports mucosal homeostasis, anti-inflammatory responses, and protection from carcinogenesis.

http://ift.tt/2oWbgQH

Passive Serum Therapy to Immunomodulation by IVIG: A Fascinating Journey of Antibodies [TRANSLATING IMMUNOLOGY]

The immunoregulatory and anti-infective properties of normal circulating polyclonal Abs have been exploited for the therapeutic purposes in the form of IVIG as well as several hyperimmune globulins. Current knowledge on the therapeutic use of normal Igs is based on the discoveries made by several pioneers of the field. In this paper, we review the evolution of IVIG over the years. More importantly, the process started as an s.c. replacement in globulin–deficient patients, underwent metamorphosis into i.m. Ig, was followed by IVIG, and is now back to s.c. forms. Following successful use of IVIG in immune thrombocytopenic purpura, there has been an explosion in the therapeutic applications of IVIG in diverse autoimmune and inflammatory conditions. In addition to clinically approved pathological conditions, IVIG has been used as an off-label drug in more than 100 different indications. The current worldwide consumption of IVIG is over 100 tons per year.

http://ift.tt/2I2MpDc

TP53 Haploinsufficiency Rescues Emergency Granulopoiesis in FANCC-/- Mice [INNATE IMMUNITY AND INFLAMMATION]

Emergency (stress) granulopoiesis is an episodic process for the production of granulocytes in response to infectious challenge. We previously determined that Fanconi C, a component of the Fanconi DNA-repair pathway, is necessary for successful emergency granulopoiesis. Fanconi anemia results from mutation of any gene in this pathway and is characterized by bone marrow failure (BMF) in childhood and clonal progression in adolescence. Although murine Fanconi anemia models exhibit relatively normal steady-state hematopoiesis, FANCC^–/– mice are unable to mount an emergency granulopoiesis response. Instead, these mice develop BMF and die during repeated unsuccessful emergency granulopoiesis attempts. In FANCC^–/– mice, BMF is associated with extensive apoptosis of hematopoietic stem and progenitor cells through an undefined mechanism. In this study, we find that TP53 haploinsufficiency completely rescues emergency granulopoiesis in FANCC^–/– mice and protects them from BMF during repeated emergency granulopoiesis episodes. Instead, such recurrent challenges accelerated clonal progression in FANCC^–/–TP53^+/– mice. In FANCC^–/– mice, BMF during multiple emergency granulopoiesis attempts was associated with increased ataxia telangiectasia and Rad3-related protein (Atr) and p53 activation with each attempt. In contrast, we found progressive attenuation of expression and activity of Atr, and consequent p53 activation and apoptosis, in the bone marrow of FANCC^–/–TP53^+/– mice during this process. Therefore, activation of Atr—with consequent Fanconi-mediated DNA repair or p53-dependent apoptosis—is an essential component of emergency granulopoiesis and it protects the bone marrow from genotoxic stress during this process.

http://ift.tt/2oWbmb1

Recent Insights into CD4+ Th Cell Differentiation in Malaria [BRIEF REVIEWS]

CD4⁺ Th cell differentiation is crucial for protecting against blood-stage Plasmodium parasites, the causative agents of malaria. It has been known for decades that more than one type of Th cell develops during this infection, with early models proposing a biphasic Th1/Th2 model of differentiation. Over the past decade, a large body of research, in particular, reports over the past 2–3 y, have revealed substantial complexity in the Th differentiation program during Plasmodium infection. In this article, we review how several studies employing mouse models of malaria, and recent human studies, have redefined the process of Th differentiation, with a particular focus on Th1 and T follicular helper (Tfh) cells. We review the molecular mechanisms that have been reported to modulate Th1/Tfh differentiation, and propose a model of Th1/Tfh differentiation that accommodates observations from all recent murine and human studies.

http://ift.tt/2oOrJGm

In This Issue [IN THIS ISSUE]

http://ift.tt/2oSiFAj

Cutting Edge: Divergent Requirement of T-Box Transcription Factors in Effector and Memory NK Cells [CUTTING EDGE]

The T-box transcription factors T-bet and Eomesodermin (Eomes) instruct discrete stages in NK cell development. However, their role in the immune response of mature NK cells against pathogens remains unexplored. We used an inducible deletion system to elucidate the cell-intrinsic role of T-bet and Eomes in mature NK cells during the course of mouse CMV infection. We show both T-bet and Eomes to be necessary for the expansion of virus-specific NK cells, with T-bet upregulation induced by IL-12 signaling and STAT4 binding to a conserved enhancer region upstream of the Tbx21 loci. Interestingly, our data suggest maintenance of virus-specific memory NK cell numbers and phenotype was dependent on T-bet, but not Eomes. These findings uncover a nonredundant and stage-specific influence of T-box transcription factors in the antiviral NK cell response.

http://ift.tt/2I7st2c

Carbon Monoxide Impairs CD11b+Ly-6Chi Monocyte Migration from the Blood to Inflamed Pancreas via Inhibition of the CCL2/CCR2 Axis [INNATE IMMUNITY AND INFLAMMATION]

Acute pancreatitis (AP) is a sterile inflammation, in which inflammatory monocytes (CD11b⁺Ly-6C^hi) are recruited into the inflamed tissue at the onset of disease. Monocyte infiltration and activation at the site of inflammation are critical to the pathogenesis of AP. Our previous studies have shown a protective role for CO in AP, which is partially mediated by inhibition of macrophage activation via TLR4 signaling. In the current study, to gain a better understanding of CO's therapeutic effect, we further investigated whether CO could affect inflammatory monocyte trafficking during AP. In a mouse model of AP, we found that treatment with CO-releasing molecule-2 (CORM-2) impaired recruitment of inflammatory monocytes, but not that of neutrophils, from peripheral blood to inflamed pancreas. During the early stage of AP, a single dose of CORM-2 decreased pancreatic CCL2 and soluble ICAM-1 expression. In addition, using in vivo and in vitro experiments, we found that CORM-2 had the ability to inhibit CD11b⁺Ly-6C^hi monocyte migration via blockade of CCR2 endocytosis. Notably, we showed that CORM-2 inhibited CCR2 endocytosis of inflammatory monocytes (CD14^hiCD16^–) from AP patients. Taken together, our results highlighted CO's effect on inflammatory monocyte trafficking, shedding additional light on its therapeutic potential in AP.

http://ift.tt/2oSiFjN

Cutting Edge: Check Your Mice--A Point Mutation in the Ncr1 Locus Identified in CD45.1 Congenic Mice with Consequences in Mouse Susceptibility to Infection [CUTTING EDGE]

B6.SJL-Ptprc^a Pepc^b/Boy (CD45.1) mice have been used in hundreds of congenic competitive transplants, with the presumption that they differ from C57BL/6 mice only at the CD45 locus. In this study, we describe a point mutation in the natural cytotoxicity receptor 1 (Ncr1) locus fortuitously identified in the CD45.1 strain. This point mutation was mapped at the 40th nucleotide of the Ncr1 locus causing a single amino acid mutation from cysteine to arginine at position 14 from the start codon, resulting in loss of NCR1 expression. We found that these mice were more resistant to CMV due to a hyper innate IFN- response in the absence of NCR1. In contrast, loss of NCR1 increased susceptibility to influenza virus, a result that is consistent with the role of NCR1 in the recognition of influenza Ag, hemagglutinin. This work sheds light on potential confounding experimental interpretation when this congenic strain is used as a tool for tracking lymphocyte development.

http://ift.tt/2oOrFX8

Cell-Specific Requirements for STAT Proteins and Type I IFN Receptor Signaling Discretely Regulate IL-24 and IL-10 Expression in NK Cells and Macrophages [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Il10 forms a cytokine cluster with Il19, Il20, and Il24 in a conserved region of chromosome 1. The latter genes are in the IL-20 subfamily of IL-10–related cytokines and, although they are not as well studied their biologic actions and expression patterns, seem to have little in common with IL-10. IL-24, like IL-10, however, is uniquely expressed in T cells and is a signature gene of the Th2 lineage, which suggests they could be coregulated in certain cell types. Little is known about other cellular sources of IL-24. We investigated IL-24 and IL-10 expression in murine macrophages and NK cells, and found that although they are coexpressed under most stimulation conditions, IL-24 and IL-10 are controlled by distinct, cell type–specific pathways. In bone marrow–derived macrophages, optimal IL-24 expression required LPS+IL-4 costimulation and STAT6 but was independent of type I IFN receptor signaling and STAT4. Conversely, LPS-induced IL-10 was independent of IL-4/STAT6 and STAT4 but, consistent with other reports, required type I IFN receptor signaling for optimal expression. Remarkably, NK-specific IL-24 (but not IL-10) expression was dependent on both type I IFN receptor signaling and STAT4. Induction of IL-24 expression was accompanied by cell-specific recruitment of STAT6 and STAT4 to multiple sites that we identified within Il24, which mediated STAT-dependent histone modifications across the gene. Collectively, our results indicate that despite being coexpressed, IL-10 and IL-24 are independently regulated by different type I IFN receptor signaling pathways in innate immune cells and provide insight into the mechanisms that fine-tune cell type–specific gene expression within the Il10 cluster.

http://ift.tt/2oTWWYD

Cutting Edge: De Novo Glucocorticoid Synthesis by Thymic Epithelial Cells Regulates Antigen-Specific Thymocyte Selection [CUTTING EDGE]

Glucocorticoid (GC) signaling in thymocytes counters negative selection and promotes the generation of a self-tolerant yet Ag-responsive T cell repertoire. Whereas circulating GC are derived from the adrenals, GC are also synthesized de novo in the thymus. The significance of this local production is unknown. In this study we deleted 11β-hydroxylase, the enzyme that catalyzes the last step of GC biosynthesis, in thymic epithelial cells (TEC) or thymocytes. Like GC receptor–deficient T cells, T cells from mice lacking TEC-derived but not thymocyte-derived GC proliferated poorly to alloantigen, had a reduced antiviral response, and exhibited enhanced negative selection. Strikingly, basal expression of GC-responsive genes in thymocytes from mice lacking TEC-derived GC was reduced to the same degree as in GC receptor–deficient thymocytes, indicating that at steady-state the majority of biologically active GC are paracrine in origin. These findings demonstrate the importance of extra-adrenal GC even in the presence of circulating adrenal-derived GC.

http://ift.tt/2I7swLq

High Mutation Frequency of the PIGA Gene in T Cells Results in Reconstitution of GPI Anchor-/CD52- T Cells That Can Give Early Immune Protection after Alemtuzumab-Based T Cell-Depleted Allogeneic Stem Cell Transplantation [TRANSPLANTATION]

Alemtuzumab (ALM) is used for T cell depletion in the context of allogeneic hematopoietic stem cell transplantation (alloSCT) to prevent acute graft-versus-host disease and graft rejection. Following ALM-based T cell–depleted alloSCT, relatively rapid recovery of circulating T cells has been described, including T cells that lack membrane expression of the GPI-anchored ALM target Ag CD52. We show, in a cohort of 89 human recipients of an ALM-based T cell–depleted alloSCT graft, that early lymphocyte reconstitution always coincided with the presence of large populations of T cells lacking CD52 membrane expression. In contrast, loss of CD52 expression was not overt within B cells or NK cells. We show that loss of CD52 expression from the T cell membrane resulted from loss of GPI anchor expression caused by a highly polyclonal mutational landscape in the PIGA gene. This polyclonal mutational landscape in the PIGA gene was also found in CD52^– T cells present at a low frequency in peripheral blood of healthy donors. Finally, we demonstrate that the GPI^–/CD52^– T cell populations that arise after ALM-based T cell–depleted alloSCT contain functional T cells directed against multiple viral targets that can play an important role in immune protection early after ALM-based T cell–depleted transplantation.

http://ift.tt/2oWbfMD

Development of Asthma in Inner-City Children: Possible Roles of MAIT Cells and Variation in the Home Environment [ALLERGY AND OTHER HYPERSENSITIVITIES]

Humans have populations of innate-like T lymphocytes with an invariant TCR α-chain that recognize nonpeptide Ags, including invariant NKT (iNKT) cells and mucosal-associated invariant T (MAIT) cells. iNKT cell involvement in human asthma is controversial, whereas there has been little analysis of MAIT cells. Using peripheral blood cells from 110 participants from the Urban Environment and Childhood Asthma (URECA) birth cohort study, these cells were analyzed for number and function. We determined whether iNKT cell or MAIT cell frequency at 1 y is correlated with the cytokine polarization of mainstream CD4⁺ T cells and/or the development of asthma by age 7 y. Dust samples from 300 houses were tested for iNKT cell antigenic activity. Our results show that a higher MAIT cell frequency at 1 y of age was associated with a decreased risk of asthma by age 7 y. The frequency of MAIT cells was associated with increased production of IFN- by activated CD4⁺ T cells from the URECA cohort. iNKT cell antigenic activity in bedroom dust samples was associated with higher endotoxin concentration and also with reduced risk of asthma. In conclusion, MAIT cell frequency at 1 y may reflect the tendency of the immune system toward Th1 responses and is associated with protection from asthma. Additionally, iNKT cell antigenic activity may be a marker of houses with increased microbial exposures and therefore also with protection from asthma.

http://ift.tt/2oSiGUT

An Antigen-Free, Plasmacytoid Dendritic Cell-Targeting Immunotherapy To Bolster Memory CD8+ T Cells in Nonhuman Primates [IMMUNOTHERAPY AND VACCINES]

The priming, boosting, and restoration of memory cytotoxic CD8⁺ T lymphocytes by vaccination or immunotherapy in vivo is an area of active research. Particularly, nucleic acid–based compounds have attracted attention due to their ability to elicit strong Ag-specific CTL responses as a vaccine adjuvant. Nucleic acid–based compounds have been shown to act as anticancer monotherapeutic agents even without coadministration of cancer Ag(s); however, so far they have lacked efficacy in clinical trials. We recently developed a second-generation TLR9 agonist, a humanized CpG DNA (K3) complexed with schizophyllan (SPG), K3-SPG, a nonagonistic Dectin-1 ligand. K3-SPG was previously shown to act as a potent monoimmunotherapeutic agent against established tumors in mice in vivo. In this study we extend the monoimmunotherapeutic potential of K3-SPG to a nonhuman primate model. K3-SPG activated monkey plasmacytoid dendritic cells to produce both IFN-α and IL-12/23 p40 in vitro and in vivo. A single injection s.c. or i.v. with K3-SPG significantly increased the frequencies of activated memory CD8⁺ T cells in circulation, including Ag-specific memory CTLs, in cynomolgus macaques. This increase did not occur in macaques injected with free CpG K3 or polyinosinic-polycytidylic acid. Injection of 2 mg K3-SPG induced mild systemic inflammation, however, levels of proinflammatory serum cytokines and circulating neutrophil influx were lower than those induced by the same dose of polyinosinic-polycytidylic acid. Therefore, even in the absence of specific Ags, we show that K3-SPG has potent Ag-specific memory CTL response–boosting capabilities, highlighting its potential as a monoimmunotherapeutic agent for chronic infectious diseases and cancer.

http://ift.tt/2I41Ivu

Many Th Cell Subsets Have Fas Ligand-Dependent Cytotoxic Potential [IMMUNE REGULATION]

CD4⁺ Th cells can have cytotoxic activity against cells displaying relevant peptide-MHC class II (p:MHCII) ligands. Cytotoxicity may be a property of Th1 cells and depends on perforin and the Eomes transcription factor. We assessed these assertions for polyclonal p:MHCII-specific CD4⁺ T cells activated in vivo in different contexts. Mice immunized with an immunogenic peptide in adjuvant or infected with lymphocytic choriomeningitis virus or Listeria monocytogenes bacteria induced cytotoxic Th cells that killed B cells displaying relevant p:MHCII complexes. Cytotoxicity was dependent on Fas expression by target cells but was independent of Eomes or perforin expression by T cells. Although the priming regimens induced different proportions of Th1, Th17, regulatory T cells, and T follicular helper cells, the T cells expressed Fas ligand in all cases. Reciprocally, Fas was upregulated on target cells in a p:MHCII-specific manner. These results indicate that many Th subsets have cytotoxic potential that is enhanced by cognate induction of Fas on target cells.

http://ift.tt/2I59423

Th1, Th17, and Th1Th17 Lymphocytes during Tuberculosis: Th1 Lymphocytes Predominate and Appear as Low-Differentiated CXCR3+CCR6+ Cells in the Blood and Highly Differentiated CXCR3+/-CCR6- Cells in the Lungs [INFECTIOUS DISEASE AND HOST RESPONSE]

Th1 lymphocytes are considered the main mediators of protection against tuberculosis (TB); however, their phenotypic characteristics and relationship with Th17 and Th1Th17 populations during TB are poorly understood. We have analyzed Th1, Th17, and Th1Th17 lymphocytes in the blood and pulmonary lesions of TB patients. The populations were identified based on the production of IFN- and/or IL-17 and the coexpression of CXCR3 (X3) and CCR6 (R6). In the blood, IL-17⁺ and IFN-⁺IL-17⁺ lymphocytes were barely detectable (median, <0.01% of CD4⁺ lymphocytes), whereas IFN-⁺ lymphocytes predominated (median, 0.45%). Most IFN-⁺ lymphocytes (52%) were X3⁺R6⁺, suggesting their "nonclassical" (ex-Th17) nature. In the lungs, IL-17⁺ and IFN-⁺IL-17⁺ lymphocytes were more frequent (0.3%, p < 0.005), yet IFN-⁺ cells predominated (11%). Phenotypically, lung CD4⁺ cells were X3^+/loR6^–. The degree of differentiation of blood effector CD4⁺ lymphocytes (evaluated based on CD62L/CD27/CD28 coexpression) increased as follows: X3⁺R6⁺ < X3⁺R6^– < X3^–R6^–, with X3^–R6^– cells being largely terminally differentiated CD62L^–CD27^–CD28^– cells. Lung CD4⁺ lymphocytes were highly differentiated, recalling blood X3^+/–R6^– populations. Following in vitro stimulation with anti-CD3/anti-CD28 Abs, X3⁺R6⁺CD4⁺ lymphocytes converted into X3⁺R6^– and X3^–R6^– cells. The results demonstrate that, during active TB, Th1 lymphocytes predominate in blood and lungs, document differences in X3/R6 expression by blood and lung CD4⁺ cells, and link the pattern of X3/R6 expression with the degree of cell differentiation. These findings add to the understanding of immune mechanisms operating during TB and are relevant for the development of better strategies to control it.

http://ift.tt/2I1GyhH

ILDR2-Fc Is a Novel Regulator of Immune Homeostasis and Inducer of Antigen-Specific Immune Tolerance [IMMUNE REGULATION]

ILDR2 is a member of the Ig superfamily, which is implicated in tricellular tight junctions, and has a putative role in pancreatic islet health and survival. We recently found a novel role for ILDR2 in delivering inhibitory signals to T cells. In this article, we show that short-term treatment with ILDR2-Fc results in long-term durable beneficial effects in the relapsing-remitting experimental autoimmune encephalomyelitis and NOD type 1 diabetes models. ILDR2-Fc also promotes transplant engraftment in a minor mismatch bone marrow transplantation model. ILDR2-Fc displays a unique mode of action, combining immunomodulation, regulation of immune homeostasis, and re-establishment of Ag-specific immune tolerance via regulatory T cell induction. These findings support the potential of ILDR-Fc to provide a promising therapeutic approach for the treatment of autoimmune diseases.

http://ift.tt/2oOrB9Q

TGF-{beta}1 Suppresses the Type I IFN Response and Induces Mitochondrial Dysfunction in Alveolar Macrophages [INNATE IMMUNITY AND INFLAMMATION]

TGF-β1 is a pleiotropic cytokine with an established role in fibrosis; however, the immunosuppressive effects of TGF-β1 are less characterized. Elevated levels of TGF-β1 are found in patients with acute and chronic lung diseases, and the underlying disease processes are exacerbated by respiratory viral infections. The alveolar macrophage is the first line of cellular defense against respiratory viral infections, and its response to infections is dependent on environmental cues. Using the mouse alveolar macrophage line, MH-S, and human CD14⁺ monocyte-derived macrophages, we examined the effects of TGF-β1 on the type I IFN antiviral response, macrophage polarization, and mitochondrial bioenergetics following a challenge with human respiratory syncytial virus (RSV). Our results showed that TGF-β1 treatment of macrophages decreased the antiviral and proinflammatory response, and suppressed basal, maximal, spare mitochondrial respiration, and mitochondrial ATP production. Challenge with RSV following TGF-β1 treatment further exacerbated mitochondrial dysfunction. The TGF-β1 and TGF-β1+RSV–treated macrophages had a higher frequency of apoptosis and diminished phagocytic capacity, potentially through mitochondrial stress. Disruption of TGF-β1 signaling or rescue of mitochondrial respiration may be novel therapeutically targetable pathways to improve macrophage function and prevent secondary bacterial infections that complicate viral respiratory infections.

http://ift.tt/2I1MCqh

ILDR2 Is a Novel B7-like Protein That Negatively Regulates T Cell Responses [IMMUNE REGULATION]

The B7-like protein family members play critical immunomodulatory roles and constitute attractive targets for the development of novel therapies for human diseases. We identified Ig-like domain–containing receptor (ILDR)2 as a novel B7-like protein with robust T cell inhibitory activity, expressed in immune cells and in immune-privileged and inflamed tissues. A fusion protein, consisting of ILDR2 extracellular domain with an Fc fragment, that binds to a putative counterpart on activated T cells showed a beneficial effect in the collagen-induced arthritis model and abrogated the production of proinflammatory cytokines and chemokines in autologous synovial-like cocultures of macrophages and cytokine-stimulated T cells. Collectively, these findings point to ILDR2 as a novel negative regulator for T cells, with potential roles in the development of immune-related diseases, including autoimmunity and cancer.

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Galectin-3 Interacts with the CHI3L1 Axis and Contributes to Hermansky-Pudlak Syndrome Lung Disease [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Hermansky–Pudlak syndrome (HPS) comprises a group of inherited disorders caused by mutations that alter the function of lysosome-related organelles. Pulmonary fibrosis is the major cause of morbidity and mortality in HPS-1 and HPS-4 patients. However, the mechanisms that underlie the exaggerated injury and fibroproliferative repair responses in HPS have not been adequately defined. In particular, although Galectin-3 (Gal-3) is dysregulated in HPS, its roles in the pathogenesis of HPS have not been adequately defined. In addition, although chitinase 3-like 1 (CHI3L1) and its receptors play major roles in the injury and repair responses in HPS, the ability of Gal-3 to interact with or alter the function of these moieties has not been evaluated. In this article, we demonstrate that Gal-3 accumulates in exaggerated quantities in bronchoalveolar lavage fluids, and traffics abnormally and accumulates intracellularly in lung fibroblasts and macrophages from bleomycin-treated pale ear, HPS-1–deficient mice. We also demonstrate that Gal-3 drives epithelial apoptosis when in the extracellular space, and stimulates cell proliferation and myofibroblast differentiation when accumulated in fibroblasts and M2-like differentiation when accumulated in macrophages. Biophysical and signaling evaluations also demonstrated that Gal-3 physically interacts with IL-13Rα2 and CHI3L1, and competes with TMEM219 for IL-13Rα2 binding. By doing so, Gal-3 diminishes the antiapoptotic effects of and the antiapoptotic signaling induced by CHI3L1 in epithelial cells while augmenting macrophage Wnt/β-catenin signaling. Thus, Gal-3 contributes to the exaggerated injury and fibroproliferative repair responses in HPS by altering the antiapoptotic and fibroproliferative effects of CHI3L1 and its receptor complex in a tissue compartment-specific manner.

http://ift.tt/2I1MAi9

Have reducing tonsillectomy rates in England led to increasing incidence of invasive Group A Streptococcus infections in children?

Abstract

Objectives

To determine if there is a correlation between falling tonsillectomy numbers and increasing numbers of tonsillitis admissions and invasive Group A β-haemolytic streptococcus (iGAS) infection in children aged 14 and under in England.

Design

An observational cross-sectional study was performed.

Setting

The data extracted covered the period from 1991 until 2014.

Participants

Hospital admissions for tonsillectomies, tonsillitis/pharyngitis, and and all diagnoses of iGAS in children aged 14 and under who had a tonsillectomy.

Main outcome measures

Correlation between trends in tonsillectomies, tonsillitis/pharyngitis and iGAS.

Results

Across all age groups there was a dramatic reduction in the total number of tonsillectomies performed in England from 28,309 in 1990/1991, down to 6327 in 2013/2014 (77.7% reduction). The numbers of hospital admissions for management of acute tonsillitis and pharyngitis has risen dramatically. iGAS numbers have increased steadily over this time period and more than doubled in children aged 14 and under. There are significant negative correlations between the trend in iGAS infections and numbers of tonsillectomies in all ages. There are also strong positive correlations between the trend in numbers of tonsillitis episodes and the number of iGAS infections in all under14 year groups; the strongest correlation was seen in the 1-4 years age group (+0.92 Pearson correlation coefficient).

Conclusions

There appears to be a correlation between falling tonsillectomy numbers, increasing hospital admissions with tonsillitis and rising iGAS infection in England. Further studies are required to assess the aetiological role of tonsillitis in predisposing to iGAS infection and the potential societal benefit of tonsillectomies.

This article is protected by copyright. All rights reserved.

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Temporal Effects on Monaural Amplitude-Modulation Sensitivity in Ipsilateral, Contralateral and Bilateral Noise

Abstract

The amplitude modulations (AMs) in speech signals are useful cues for speech recognition. Several adaptation mechanisms may make the detection of AM in noisy backgrounds easier when the AM carrier is presented later rather than earlier in the noise. The aim of the present study was to characterize temporal adaptation to noise in AM detection. AM detection thresholds were measured for monaural (50 ms, 1.5 kHz) pure-tone carriers presented at the onset ('early' condition) and 300 ms after the onset ('late' condition) of ipsilateral, contralateral, and bilateral (diotic) broadband noise, as well as in quiet. Thresholds were 2–4 dB better in the late than in the early condition for the three noise lateralities. The temporal effect held for carriers at equal sensation levels, confirming that it was not due to overshoot on carrier audibility. The temporal effect was larger for broadband than for low-band contralateral noises. Many aspects in the results were consistent with the noise activating the medial olivocochlear reflex (MOCR) and enhancing AM depth in the peripheral auditory response. Other aspects, however, indicate that central masking and adaptation unrelated to the MOCR also affect both carrier-tone and AM detection and are involved in the temporal effects.

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Association between (CCTTT)n repeat polymorphism in NOS2 promoter and asthma exacerbations

Publication date: Available online 5 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Keita Hirai, Toshihiro Shirai, Masayuki Suzuki, Tatsuki Shimomura, Kunihiko Itoh

Teaser

NOS2 (CCTTT)n pentanucleotide repeat polymorphisms contributed to varying mRNA expression levels and affected asthma exacerbations.


http://ift.tt/2oRfQ2A

Machine Learning, Natural Language Programming, and Electronic Health Records: the next step in the Artificial Intelligence Journey?

Publication date: Available online 5 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Neil Mehta, Murthy V. Devarakonda




http://ift.tt/2I5HiCv

Glutathione and arginine levels: Predictors for acetaminophen-associated asthma exacerbation?

Publication date: Available online 5 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Claudia R. Morris, David T. Mauger, Jung H. Suh, Wanda Phipatanakul, William J. Sheehan, James N. Moy, Ian M. Paul, Stanley J. Szefler, Daniel J. Jackson, Anne M. Fitzpatrick

Teaser

Retrospective studies have demonstrated associations between acetaminophen and exacerbations in asthma, purportedly due to reductions in the antioxidant, glutathione. In this study of young children with mild asthma treated with acetaminophen, baseline levels of glutathione were not associated with future exacerbations.


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A Special Thank-You to Our Reviewers

Publication date: March 2018
Source:Journal of Allergy and Clinical Immunology, Volume 141, Issue 3





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Egg-specific IgE and basophil activation but not egg-specific T cells correlate with phenotypes of clinical egg allergy

Publication date: Available online 5 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): M. Cecilia Berin, Alexander Grishin, Madhan Masilamani, Donald Y. Leung, Scott H. Sicherer, Stacie M. Jones, A. Wesley Burks, Alice K. Henning, Peter Dawson, Joanna Grabowska, Charuta Agashe, Wendy F. Davidson, Robert A. Wood, Hugh A. Sampson
BackgroundEgg allergy is phenotypically heterogeneous. A subset of egg allergic individuals can tolerate egg in an extensively heated form. Inclusion of baked-egg (BE) into their diet accelerates resolution of egg allergy. Conversely, BE reactivity is associated with persistent disease. The immune basis of this clinical heterogeneity is unknown.ObjectivesTo study egg-specific antibody, basophil, and T cell responses in children with reactivity or tolerance to BE.MethodsAll participants underwent double-blind placebo-controlled challenges to BE, and those who tolerated BE were challenged to unheated egg white protein to confirm clinical egg reactivity. Laboratory studies included serum antibodies, basophil activation tests, and CD154-based detection of egg responsive T cells by flow cytometry.ResultsOf the 129 children studied, BE reactive participants had significantly higher levels of egg, ovalbumin, and ovomucoid-specific IgE, lower ratios of egg-specific IgG4/IgE, and increased basophil activation in response to egg. Among all participants, CD154-based profiling revealed egg-responsive T cells producing IL-4 and IL-13, but little IL-10 or IFN-γ, as well as presence of egg-responsive Foxp3+CD25+CD127low Tregs. Egg-responsive T cells expressed CCR4, CCR6, and CXCR5, indicating capacity for homing to skin, mucosa, and B cell follicles. However, neither the frequency nor phenotype of egg-responsive T cells were different in those with tolerance or reactivity to BE.ConclusionsEgg-specific antibody and basophil responses, but not T cell responses, are higher in those with reactivity versus tolerance to BE. The egg-specific antibody and T cell responses were highly heterogeneous in this cohort. The clinical implications of this immune heterogeneity will need to be studied longitudinally.

Teaser

In a study of 129 children challenged to baked and unheated forms of egg, significantly lower egg-specific IgE and basophil activation, but no differences in egg-specific Th2 cells or Tregs, were associated with tolerance to BE.


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Staphylococcus aureus enhances the tight junction barrier integrity in healthy nasal tissue, but not in nasal polyps

Publication date: Available online 5 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Can Altunbulakli, Rita Costa, Feng Lan, Nan Zhang, Mubeccel Akdis, Claus Bachert, Cezmi A. Akdis

Teaser

Staphylococcus aureus infection increases the expression of the tight junctions (TJs) in healthy nasal tissue; while nasal polyps show decreased TJ expression at baseline and are unable to upregulate TJs to strengthen the epithelial barrier.


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Leukotriene E4 induces airflow obstruction and mast cell activation via the CysLT1 receptor

Publication date: Available online 5 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Nikolaos Lazarinis, Johan Bood, Cristina Gomez, Johan Kolmert, Ann-Sofie Lantz, Pär Gyllfors, Andy Davis, Craig E. Wheelock, Sven-Erik Dahlén, Barbro Dahlén
BackgroundLeukotriene E4 (LTE4) is the final active metabolite among the cysteinyl leukotrienes (CysLTs). Animal studies have identified a distinct LTE4 receptor, suggesting that current CysLT1 receptor antagonists may provide incomplete inhibition of CysLT responses.ObjectiveWe tested this hypothesis by assessing the influence of the CysLT1 antagonist montelukast on responses induced by inhalation of LTE4 in asthmatic subjects.MethodsFourteen subjects with mild intermittent asthma and two subjects with aspirin exacerbated respiratory disease (AERD) received montelukast 20 mg bid and placebo for 5-7 days in a randomized, double blind, crossover study (NCT01841164). The provocative dose of LTE4 causing 20% fall in FEV1 (PD20) was determined at the end of each treatment period by a rising dose challenge. Measurements included lipid mediators in urine and sputum cells 4 hours post LTE4 challenge.ResultsMontelukast completely blocked the LTE4 induced bronchoconstriction. Despite tolerating at least 10 times higher dose of LTE4 after montelukast, there was no difference in the percentage of eosinophils in sputum. The urinary excretion of all major lipid mediators increased after the LTE4 inhalation. Montelukast blocked the release of the mast cell product prostaglandin (PG) D2, as well as the release of PGF2α, and thromboxane, but not the increased excretion of PGE2 and its metabolites nor isoprostanes.ConclusionLeukotriene E4 induces airflow obstruction and mast cell activation via the CysLT1 receptor.CLINICAL IMPLICATIONSClinically available leukotriene antagonists protect against the airway obstruction and the pro-inflammatory effects of the terminal cysteinyl-leukotriene LTE4.

Graphical abstract

Teaser

Animal experiments have found a specific LTE4 receptor. This study demonstrated that LTE4-induced bronchoconstriction in asthmatics was blocked by montelukast, and discovered that LTE4 also mediated activation of mast cells via the CysLT1 receptor.


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Basophil FcεRI expression is linked to time to omalizumab response in chronic spontaneous urticaria

Publication date: Available online 5 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Gustavo Deza, Marta Bertolín-Colilla, Silvia Sánchez, Dulce Soto, Ramon M. Pujol, Ramon Gimeno, Ana M. Giménez-Arnau

Teaser

This study suggests that baseline levels of basophil FcεRI receptor may predict time to response to anti-IgE therapy in chronic spontaneous urticaria.


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Inflammatory health effects of indoor and outdoor particulate matter

Publication date: March 2018
Source:Journal of Allergy and Clinical Immunology, Volume 141, Issue 3





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Allergen induced activation of NK cells represents an early life immune response in development of allergic asthma

Publication date: Available online 5 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Matthew C. Altman, Elizabeth Whalen, Alkis Togias, George T. O'Connor, Leonard B. Bacharier, Gordon R. Bloomberg, Meyer Kattan, Robert A. Wood, Scott Presnell, Petra LeBeau, Katy Jaffee, Cynthia M. Visness, William W. Busse, James E. Gern
BackgroundChildhood asthma in inner city populations is a major public health burden and understanding early life immune mechanisms that promote asthma onset is key to disease prevention. Children who develop asthma demonstrate a high prevalence of aeroallergen sensitization and T helper 2 (Th2)-type inflammation, however the early life immune events that lead to Th2 skewing and disease development are unknown.ObjectiveWe sought to use RNA sequencing of peripheral blood mononuclear cells (PBMCs) collected at age 2 to determine networks of immune responses that occur in children who develop allergy and asthma.MethodsIn a high asthma risk inner city birth cohort, we compared gene expression by RNA sequencing in PBMCs collected at age 2 between children who developed ≥2 aeroallergen sensitizations including dust mite (DM) and/or cockroach (CR) by age 3 and asthma by age 7 (cases) and matched controls who did not develop any aeroallergen sensitization or asthma by age 7.ResultsPBMCs from the cases showed higher levels of expression of natural killer (NK) cell related genes. After CR or DM allergen but not tetanus antigen stimulation, PBMCs from the cases compared to the control group, showed differential expression of 244 genes. This gene set included upregulation of a densely interconnected NK cell-like gene network reflecting a pattern of cell activation and induction of inflammatory signaling molecules including key Th2-type cytokines IL9, IL13, and CCL17 as well as a dendritic cell (DC)-like gene network including upregulation of CD1 lipid antigen presentation molecules. The NK cell-like response was reproducible in an independent group of children with later onset allergic sensitization and asthma, and was found to be specific to only those children that develop both aeroallergen sensitization and asthma.ConclusionThese findings provide important mechanistic insight into an early life immune pathway involved in Th2 polarization leading to development of allergic asthma.

Teaser

Inner city children who have cockroach and/or dust mite allergy as well as asthma at age 7 show exaggerated cytotoxic lymphocyte and lipid antigen presentation gene expression responses to allergen stimulation of PBMCs collected at age 2.


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The Editors' Choice

Publication date: March 2018
Source:Journal of Allergy and Clinical Immunology, Volume 141, Issue 3
Author(s): Zuhair K. Ballas




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Hypersensitivity reactions to therapeutic monoclonal antibodies: phenotypes and endotypes

Publication date: Available online 5 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Ghislaine Annie C Isabwe, Marlene Garcia Neuer, Leticia de las Vecillas Sanchez, Donna-Marie Lynch, Kathleen Marquis, Mariana Castells
BackgroundThe increasing use of monoclonal antibodies (mAbs) has led to a rise in hypersensitivity reactions (HSRs), which prevent their use as first-line therapy. HSRs symptoms, diagnostic tools and directed management approaches have not been standardized.ObjectiveWe propose a novel evidence-based classification of HSRs to mAbs, based on the clinical phenotypes, underlying endotypes and biomarkers; as well as their management with desensitization.MethodsPhenotypes, endotypes and biomarkers of HSRs to 16 mAbs for 104 patients were described and compared to the outcomes of 526 subcutaneous and intravenous desensitizations.ResultsInitial reactions presented with 4 patterns: Type I like reactions (63%), Cytokine-Release reactions (13%), Mixed reactions (21%) and delayed Type IV reactions (3%). In contrast, of the 23% breakthrough HSRs during desensitization, 52% were Cytokine-Release reactions, 32% were Type 1, 12% were Mixed and 4% were Type I with delayed Type IV. Skin testing to 10 mAbs in 58 patients was positive in 41% of patients. Serum tryptase was elevated in one patient and IL-6 was elevated in 8 patients during desensitization and was associated with a Cytokine-Release phenotype.ConclusionHSRs to mAbs can be defined as Type I, Cytokine-Release, Mixed (Type I/Cytokine-Release) and Type IV reactions which are identified by biomarkers such as skin test, tryptase and IL-6. These phenotypes can be used to improve personalized and precision medicine when diagnosing HSRs to mAbs and providing management recommendations with desensitization. Desensitization provides a safe and effective re-treatment option to remain on culprit mAbs as first line therapy.Clinical implicationsWe provide novel evidence-based phenotypes and endotypes of HSRs to 16 monoclonal antibodies and provide tools for diagnosis and management to improve personalized and precision medicine for HSRs to mAbs.

Graphical abstract

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Mast cell activation test in the diagnosis of allergic disease and anaphylaxis

Publication date: Available online 5 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Rajia Bahri, Adnan Custovic, Peter Korosec, Marina Tsoumani, Martin Barron, Jiakai Wu, Rebekah Sayers, Alf Weimann, Monica Ruiz-Garcia, Nandinee Patel, Abigail Robb, Mohamed H. Shamji, Sara Fontanella, Mira Silar, E.N. Clare Mills, Angela Simpson, Paul J. Turner, Silvia Bulfone-Paus
BackgroundFood allergy is an increasing public health issue and the commonest cause of life-threatening anaphylactic reactions. Conventional allergy tests assess for the presence of allergen-specific IgE, significantly overestimating the rate of true clinical allergy resulting in over-diagnosis and adverse impact on health-related quality of life.ObjectiveTo undertake initial validation and assessment of a novel diagnostic tool, the mast cell activation test (MAT).MethodsPrimary human mast cells (hMCs) were generated from peripheral blood precursors, and sensitized using patient sera and then incubated with allergen. Mast cell degranulation was assessed by flow cytometry and mediator release. We compared the diagnostic performance of MAT to existing diagnostic tools to assess in a cohort of peanut-sensitized individuals undergoing double-blind, placebo-controlled challenge.ResultshMCs sensitized with sera from peanut, grass pollen and hymenoptera- (wasp venom) allergic patients demonstrated allergen-specific and dose-dependent degranulation by both expression of surface activation markers (CD63 and CD107a) and functional assays (prostaglandins D2 and β-hexosaminidase release). In this cohort of peanut-sensitized individuals, MAT was found to have superior discrimination performance compared to other testing modalities including component-resolved diagnostics and basophil activation test. Using functional principle component analysis, we identified 5 clusters or patterns of reactivity in the resulting dose-response curves, which at preliminary analysis corresponded to the reaction phenotypes seen at challenge.ConclusionMAT is a robust tool which may confer superior diagnostic performance compared to existing allergy diagnostics, and may be useful to explore differences in effector cell function between basophils and mast cells during allergic reactions.

Graphical abstract

Teaser

We report the development and initial validation of the Mast cell Activation Test (MAT) to diagnose IgE-mediated allergic disease, and found it to be a robust test with favorable diagnostic characteristics.


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Inflammatory health effects of indoor and outdoor particulate matter

Publication date: March 2018
Source:Journal of Allergy and Clinical Immunology, Volume 141, Issue 3
Author(s): Weidong Wu, Yuefei Jin, Chris Carlsten
Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: March 2018. Credit may be obtained for these courses until February 28, 2019.Copyright Statement: Copyright © 2018-2019. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Weidong Wu, PhD, Yuefei Jin, MD, and Chris Carlsten, MD, MPH (authors); Zuhair K. Ballas, MD (editor)Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: The authors declare that they have no relevant conflicts of interest. Z. K. Ballas (editor) disclosed no relevant financial relationships.Activity Objectives:1. To recognize that particulate matter (PM) can have significant pulmonary and cardiovascular effects.2. To identify some of the inflammatory changes and potential health consequences that can occur with exposure to PM.Recognition of Commercial Support: This CME activity has not received external commercial support.List of CME Exam Authors: Evelyn Angulo, MD, Anna Lang, MD, PhD, David Peloza, MD, Cheryl Steiman, MD, and Sameer K. Mathur, MD, PhD.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: The exam authors disclosed no relevant financial relationships.Inflammation is a common and essential event in the pathogenesis of diverse diseases. Decades of research has converged on an understanding that all combustion-derived particulate matter (PM) is inflammatory to some extent in the lungs and also systemically, substantially explaining a significant portion of the massive cardiopulmonary disease burden associated with these exposures. In general, this means that efforts to do the following can all be beneficial: reduce particulates at the source, decrease the inflammatory potential of PM output, and, where PM inhalation is unavoidable, administer anti-inflammatory treatment. A range of research, including basic illumination of inflammatory pathways, assessment of disease burden in large cohorts, tailored treatment trials, and epidemiologic, animal, and in vitro studies, is highlighted in this review. However, meaningful translation of this research to decrease the burden of disease and deliver a clear and cohesive message to guide daily clinical practice remains rudimentary. Ongoing efforts to better understand substantial differences in the concentration and type of PM to which the global community is exposed and then distill how that influences inflammation promises to have real-world benefit. This review addresses this complex topic in 3 sections, including ambient PM (typically associated with ground-level transportation), wildfire-induced PM, and PM from indoor biomass burning. Recognizing the overlap between these domains, we also describe differences and suggest future directions to better inform clinical practice and public health.



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External exposome and allergic respiratory and skin diseases

Publication date: March 2018
Source:Journal of Allergy and Clinical Immunology, Volume 141, Issue 3
Author(s): Lorenzo Cecchi, Gennaro D'Amato, Isabella Annesi-Maesano
Allergies are complex diseases that result from interactions between multiple genetic and environmental factors. However, the increase in allergies observed in the past decades is explained exclusively by environmental changes occurring in the same period. Presently, the exposome, the totality of specific and nonspecific external environmental exposures (external exposome) to which a subject is exposed from preconception onward and their consequences at the organ and cell levels (internal exposome), is being considered to explain the inception, development, and exacerbations of allergic diseases. Among the best-studied environmental factors of the specific external exposome, indoor and outdoor aeroallergens and air pollutants play a key role in the etiopathogenesis of the inflammatory response to allergens and in clinical manifestations of allergic disease. Climate change, urbanization, and loss of biodiversity affect sources, emissions, and concentrations of main aeroallergens and air pollutants and are among the most critical challenges facing the health and quality of life of the still increasing number of allergic patients today and in the coming decades. Thunderstorm-related asthma is a dramatic example of the effects of combined environmental factors and an in vivo model for understanding the mechanisms at work in respiratory allergy. Environment- or lifestyle-driven aberrancies in the gut and skin microbiome composition represent key mediators of allergic diseases. A better knowledge of the effect of the external exposome on allergy development is crucial for urging patients, health professionals, and policymakers to take actions to mitigate the effect of environmental changes and to adapt to them.



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Ectopic lymphoid tissues support local immunoglobulin production in patients with chronic rhinosinusitis with nasal polyps

Publication date: March 2018
Source:Journal of Allergy and Clinical Immunology, Volume 141, Issue 3
Author(s): Jia Song, Hai Wang, Ya-Na Zhang, Ping-Ping Cao, Bo Liao, Zhe-Zheng Wang, Li-Li Shi, Yin Yao, Guan-Ting Zhai, Zhi-Chao Wang, Li-Meng Liu, Ming Zeng, Xiang Lu, Heng Wang, Xiang-Ping Yang, Di Yu, Claus Bachert, Zheng Liu
BackgroundThe contribution of ectopic lymphoid tissues (eLTs) to local immunoglobulin hyperproduction in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) is unclear.ObjectiveWe sought to explore the cellular basis, formation mechanisms, and function of eLTs in patients with CRSwNP.MethodsWe graded lymphoid aggregations in sinonasal mucosa and histologically studied their structures. The expression of lymphorganogenic factors and molecules required for immunoglobulin production was measured by using real-time PCR, and their localization was analyzed by means of immunohistochemistry and immunofluorescence. The phenotype of follicular helper T cells was analyzed by performing flow cytometry. Immunoglobulin levels were quantified by using the Bio-Plex assay or ImmunoCAP system. Nasal tissue explants were challenged ex vivo with Dermatophagoides pteronyssinus group 1 (Der p 1), and the expression of Iε-Cμ and Iε-Cγ circle transcripts was detected by using seminested PCR.ResultsIncreased formation of eLTs with germinal center–like structures was discovered in patients with eosinophilic (20.69%) and noneosinophilic (17.31%) CRSwNP compared with that in patients with chronic rhinosinusitis without nasal polyps (5.66%) and control subjects (3.70%). The presence of eLTs was associated with increased expression of lymphorganogenic and inflammatory chemokines and cytokines, as well as their receptors. The expression of molecules required for immunoglobulin production, generation of follicular helper T cells, and production of IgE in eosinophilic polyps and IgG and IgA in both eosinophilic and noneosinophilic polyps were predominantly upregulated in patients with eLTs. After Der p 1 challenge ex vivo, Iε-Cμ transcript was detected only in eosinophilic polyps with eLTs but not in polyps without eLTs and noneosinophilic polyps.ConclusioneLTs might support local immunoglobulin production and therefore significantly contribute to the development of CRSwNP.



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News Beyond Our Pages

Publication date: March 2018
Source:Journal of Allergy and Clinical Immunology, Volume 141, Issue 3
Author(s): Marc E. Rothenberg, Jean Bousquet




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PD-L1 expression by tumor cell-lines: a predictive marker in melanoma

Abstract

Prognostic biomarkers for melanoma patients after lymph node resection are of clinical relevance and could thus enable the identification of patients who therefore would most benefit from adjuvant treatment. The aim of this work was to determine, using an in vitro model, whether immune-related biomarkers such as MHC-class I and II, melanoma associated antigens, IDO1 and PD-L1, could also be relevant to predict the risk of relapse of stage III melanoma patients after lymph node resection.

We established tumor cell lines from metastatic lymph nodes of 50 melanoma patients. The expression of investigated biomarkers was determined on untreated and IFN-γ treated melanoma cell lines using flow cytometry. Among the selected biomarkers, the IFN-γ induced expression of PD-L1 and IDO1 was associated with an increased risk of relapse (p=0.0001 and p=0.013, respectively) and was also associated with death for IDO1 (p=0.0005). In the future, this immunologic signature could permit the identification of patients at higher risk of relapse, and justifying an adjuvant treatment using immunotherapy.

This article is protected by copyright. All rights reserved.

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The clinical value of the RGB value of an image of the interarytenoid area for diagnosis of laryngopharyngeal reflux

Publication date: Available online 5 March 2018
Source:American Journal of Otolaryngology
Author(s): Zhengcai Lou, Zihan Lou




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Corrigendum to “Retropharyngeal abscess as a result of hyaluronic acid injection pharyngoplasy: A first of its kind” [Am J Otolaryngol 38(6) (Nov–Dec 2017) 718–719]

Publication date: Available online 5 March 2018
Source:American Journal of Otolaryngology
Author(s): Joseph Capo, Samuel Helman, Lianne de Serres, Sivakumar Chinnadurai




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Neuromuscular function of the soft palate and uvula in snoring and obstructive sleep apnea: A systematic review

Publication date: Available online 5 March 2018
Source:American Journal of Otolaryngology
Author(s): Jagatkumar A. Patel, Bryan J. Ray, Camilo Fernandez-Salvador, Christopher Gouveia, Soroush Zaghi, Macario Camacho
ObjectiveA collapsible upper airway is a common cause of obstructive sleep apnea. The exact pathophysiology leading to a more collapsible airway is not well understood. A progressive neuropathy of the soft palate and pharyngeal dilators may be associated with the progression of snoring to OSA. The purpose of this study is to systematically review the international literature investigating the neurophysiologic changes in the soft palate and uvula that contribute to progression from snoring to OSA.MethodsPubMed/MEDLINE and 4 other databases were systematically searched through July 4, 2017. Eligibility: (1) Patients: controls, snoring or OSA patients (2) Intervention: neuromuscular evaluation of the palate and/or uvula (3) Comparison: differences between controls, snoring and OSA patients (4) Outcomes: neuromuscular outcomes (5) Study design: Peer reviewed publications of any design.Results845 studies were screened, 76 were downloaded in full text form and thirty-one studies met criteria. Histological studies of the soft palate demonstrated diffuse inflammatory changes, muscular changes consistent with neuropathy, and neural aberrancies. Sensory testing studies provided heterogeneous outcomes though the majority favored neuronal dysfunction. Studies have consistently demonstrated that increasing severity of snoring and sleep apnea is associated with worsening sensory nerve function of the palate in association with atrophic histological changes to the nerves and muscle fibers of the soft palate and uvula.ConclusionsRecent evidence highlighted in this systematic review implicates the role of neurogenic pathology underlying the loss of soft palate and/or uvular tone in the progression of snoring to sleep apnea.



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Effect of allergic rhinitis on nasal obstruction outcomes after functional open Septorhinoplasty

Publication date: Available online 5 March 2018
Source:American Journal of Otolaryngology
Author(s): Mofiyinfolu Sokoya, Joseph Gonzalez, Andrew A. Winkler
ObjectiveTo evaluate whether a diagnosis of allergic rhinitis affects surgical outcomes of open septorhinoplasty (OSR) and to examine whether OSR provides the same level of improvement in quality of life to patients with and without allergic rhinitis.Study design, setting, subjects and methodsWe performed a retrospective evaluation of 646 patients who underwent open septorhinoplasty in a tertiary otolaryngology practice between 2008 and 2015. Preoperative and postoperative quality of life (QoL) measurement using the validated Nasal Obstruction Symptom Evaluation (NOSE) Scale was performed on 307 patients meeting inclusion criteria. These patients were then divided into two groups based on a diagnosis of allergic rhinitis (non-AR vs AR). Comparisons were then made based on quality of life improvements by the NOSE score.ResultsThere were 213 patients in the non-AR group vs. 94 patients in the AR group. After OSR, patients in both groups experienced significant improvement in nasal airway obstruction. Pre-op NOSE score averages were similar for the non-AR and AR groups (69.9 vs 73.4 p = 0.087). Average improvement in NOSE score for the non-AR and AR groups at 30 days was 48.6 vs 45.9 (p = 0.41); and at 90 day of 48.1 vs 51.5 (p = 0.402).ConclusionPatients with and without allergic rhinitis experience similar OSR outcomes as measured by the NOSE score. Open septorhinoplasty addresses multiple components contributing to nasal airway obstruction, and may offset the effects of allergic rhinitis. When indicated, it should be offered to patients with allergic rhinitis and after complete medical management.



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Macrophage-derived GPNMB accelerates skin healing

Abstract

Healing is a vital response important for the re-establishment of the skin integrity following injury. Delayed or aberrant dermal wound healing leads to morbidity in patients.The development of therapies to improve dermal healing would be useful. Currently, the design of efficient treatments is stalled by the lack of detailed knowledge about the cellular and molecular mechanisms involved in wound healing. Recently, by using state-of-art technologies, it was revealed that macrophages signal via GPNMB to mesenchymal stem cells, accelerating skin healing. Strikingly, transplantation of macrophages expressing GPNMB improves skin healing in GPNMB-mutant mice. Additionally, topical treatment with recombinant GPNMB restored mesenchymal stem cells recruitment and accelerated wound closure in the diabetic skin. From a drug development perspective, this GPNMB is a new candidate for skin healing.

This article is protected by copyright. All rights reserved.

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Malassezia species retrieved from skin with pityriasis versicolor, seborrheic dermatitis and skin free of lesions: a comparison of two sampling methods

Abstract

Malassezia are involved in the pathogenesis of different skin diseases including pityriasis versicolor (PV) and seborrheic dermatitis (SD), but these yeasts are also important inhabitants of the skin microbiome. Culture is not performed routinely, although it may be of value in doubtful cases to support the diagnosis; culture is crucial for identification tools such as matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Culture is also critical to assess the number of organisms and viability and, eventually, to perform antifungal susceptibility tests.

This article is protected by copyright. All rights reserved.

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CD137L dendritic cells induce potent response against cancer-associated viruses and polarize human CD8 + T cells to Tc1 phenotype

Abstract

Therapeutic tumor vaccination based on dendritic cells (DC) is safe; however, its efficacy is low. Among the reasons for only a subset of patients benefitting from DC-based immunotherapy is an insufficient potency of in vitro generated classical DCs (cDCs), made by treating monocytes with GM-CSF + IL-4 + maturation factors. Recent studies demonstrated that CD137L (4-1BBL, TNFSF9) signaling differentiates human monocytes to a highly potent novel type of DC (CD137L-DCs) which have an inflammatory phenotype and are closely related to in vivo DCs. Here, we show that CD137L-DCs induce potent CD8⁺ T-cell responses against Epstein–Barr virus (EBV) and Hepatitis B virus (HBV), and that T cells primed by CD137L-DCs more effectively lyse EBV⁺ and HBV⁺ target cells. The chemokine profile of CD137L-DCs identifies them as inflammatory DCs, and they polarize CD8⁺ T cells to a Tc1 phenotype. Expression of exhaustion markers is reduced on T cells activated by CD137L-DCs. Furthermore, these T cells are metabolically more active and have a higher capacity to utilize glucose. CD137L-induced monocyte to DC differentiation leads to the formation of AIM2 inflammasome, with IL-1beta contributing to CD137L-DCs possessing a stronger T cell activation ability. CD137L-DCs are effective in crosspresentation. PGE2 as a maturation factor is required for enhancing migration of CD137L-DCs but does not significantly reduce their potency. This study shows that CD137L-DCs have a superior ability to activate T cells and to induce potent Tc1 responses against the cancer-causing viruses EBV and HBV which suggest CD137L-DCs as promising candidates for DC-based tumor immunotherapy.

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Former Biomedical Engineering Director at Johns Hopkins, Murray B. Sachs, Ph.D., Dies

Pioneering scientist Murray B. Sachs, Ph.D., who led the biomedical engineering department at Johns Hopkins for 16 years, died March 3 after a long illness. He was 77.

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Professor Emeritus, Dr. Med. Mirko Tos

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Calculation of indirect costs of associated with postoperative caregiver absences after pediatric tonsil surgery

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Cochlear implantation in the elderly: outcomes, long-term evolution, and predictive factors

Abstract

Objective

Our goal in this study is to find out the outcomes of cochlear implantation in elderly (> 60 years) and check if this improvement is similar to that of their younger counterparts in short- and long-term evolution. In addition, we have attempted to ascertain the predictive factors that might affect the verbal comprehension results of older patients.

Study design

Retrospective cohort study.

Methods

Ninety-four patients older than 40 years, divided into two groups. 40–60 years n = 55 and > 60 years n = 39. A pure-tone audiometry, a disyllabic word test, and the test of phonetically balanced sentences of Navarra were made in silence to each patient. These measurements were made pre-implantation and 1, 5, and 10 year post-implantation. Peri- and postoperative complications were registered. The hypothetic predictive factors of post-implanted performance were evaluated in the elderly.

Results

Our study shows no significant difference between young and old adult´s outcomes in short- and long-term evolutions, nor in the complication rate. Furthermore, we proved the significant influence of the side of implantation, use of hearing aids, and duration of hearing loss in the short- and long-term results in the elderly.

Conclusion

This study shows that cochlear implantation in the elderly is as safe, useful, and worthwhile as in young adults. Age has a low influence in cochlear implant outcomes; however, we have found the significant influence of the side of implantation, the use of hearing aids, and the duration of hearing loss in the short- and long-term results.

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Olfactory and gustatory functions after free flap reconstruction and radiotherapy for oral and pharyngeal cancer: a prospective follow-up study

Abstract

Background

The senses of smell and taste can be adversely affected by both tumour- and treatment-related factors amongst head and neck cancer patients. The consequences may negatively impact nutritional status as well as quality of life in this patient population.

Patients and methods

This prospective longitudinal follow-up study is consisted of 44 patients treated for oral cavity, oropharyngeal or hypopharyngeal cancer with tumour resection and microvascular free tissue transfer reconstruction at the Helsinki University Hospital, Helsinki, Finland. Thirty-nine (89%) of them also received radiotherapy. The senses of smell (odour detection, identification and threshold test) and taste (electrogustometry) and quality of life (UW-QOL) were evaluated preoperatively, and at 6 weeks, 3 months, 6 months and 12 months, postoperatively.

Results

There were higher scores in the odour detection values in the 6-week and 3-month tests compared with preoperative values for the tumour side. Other detection scores did not differ statistically from the preoperative values neither in the tumour nor the contralateral side. However, in the odour identification test, all posttreatment values were statistically significantly higher than pretreatment ones. In the olfactory threshold test, no statistically significant differences were found between pre- and posttreatment values. Electrogustometry values for the taste on the tumour side were statistically significantly impaired at 6 weeks (p < 0.05) and at 3 months (p < 0.01) compared with the pretreatment results. They were also impaired at 6 months and at 12 months, although the differences were not statistically significant. The quality of life was impaired after treatment in this patient series. However, the correlation between quality of life and sense of taste was found only at one time point (3 months) and only with contralateral side measurements.

Conclusions

We conclude that in oral and pharyngeal cancer patients the postoperative taste problems are related to the impairment on the taste sensation in the tongue but not with the sense of smell. Moreover, the impairment in the quality of life is not clearly related to the impaired sense of taste.

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