Aesthetic reconstruction of retroauricular keloid: Creating a keystone flap from the mastoid-helix area

Abstract

Advances in aesthetic rhinoplasty using conchal cartilage grafts have led to a high occurrence of retroauricular keloids. The purpose of this study is to introduce our surgical experiences using a keystone flap in retroauricular keloids following conchal cartilage grafts. The present study is a retrospective review of patients with pathologically confirmed retroauricular keloids following conchal cartilage grafts. These cases were surgically excised and we covered the defect with a keystone flap followed by one-time steroid injection at postoperative day 14 and silicone gel sheeting application for 3 months. Treatment outcome was recorded as recurrence or non-recurrence. In all patients, a follow-up period of minimum 12 months was required. Of these patients, 90.0% had successful treatment of their auricular keloids, whereas 10.0% had recurrences. The postoperative course was uneventful. In conclusion, our aesthetic reconstruction using a keystone flap created from the mastoid-helix area is a useful treatment strategy in terms of retroauricular keloids following conchal cartilage grafts.

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Computerbasierte Testung neurokognitiver Aspekte im Rahmen der audiologischen Diagnostik

Laryngo-Rhino-Otol
DOI: 10.1055/s-0043-124972

Hintergrund Im Hinblick auf den demographischen Wandel der Gesellschaft gewinnen in der Hörrehabilitation neurokognitive Fähigkeiten immer mehr an Bedeutung. Fragestellung Ziel der Studie war es zu untersuchen, inwiefern eine neurokognitive Testung mittels PC-gestützter Aufgaben zur Evaluation der unterschiedlichen Bereiche der Kognition auch für ältere Patienten mit und ohne Hörstörung geeignet ist und wie sich diese in den klinischen Alltag des HNO-Arztes integrieren lässt. Patientenbeschreibung 171 Patienten ≥ 50 Jahren mit und ohne eine beidseitige Hörbeeinträchtigung wurden eingeschlossen: n = 90 im Alter zwischen 50 und 64 Jahren (57,0 ± 4,5) und 81 Ältere ab 65 (72,5 ± 5,4). Methode Eine computerbasierte Testung mit rein visuellen Instruktionen beinhaltete neben der Aufmerksamkeit, der Verarbeitungsgeschwindigkeit, dem Kurz- und Langzeitgedächtnis auch exekutive Funktionen. Zuvor erfolgte ein Probedurchgang unter Anleitung einer geschulten Mitarbeiterin. Ergebnisse Auch wenn die Testung unabhängig von Alter oder Hörstatus in allen Fällen eigenständig möglich war, benötigten Hörgeschädigte 15 Minuten länger zur Durchführung und beurteilten diese als anstrengender als Hörgesunde (71 % versus 63 %). Patienten mittleren Alters sahen die Durchführbarkeit für Menschen des höheren Lebensalters mit 30 % signifikant (p = 0,02) kritischer als die betroffene Altersgruppe selbst (10 %). Schlussfolgerung Eine umfassende kognitive Testung älterer Schwerhöriger mit computerbasierten Aufgaben lässt sich problemlos in den klinischen HNO Alltag integrieren und könnte eine wertvolle Ergänzung der audiologischen Diagnostik im Hinblick auf eine bestmögliche Hörrehabilitation darstellen.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Inherited thrombotic thrombocytopenic purpura mimicking immune thrombocytopenic purpura during pregnancy: a case report

Thrombotic thrombocytopenic purpura is a very rare hereditary blood deficiency disorder of ADAMTS13 (von Willebrand factor-cleaving protease) and a life-threatening thrombotic microangiopathy characterized by ...

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Reassessment of Differentiated Thyroid Cancer Patients Using the Eighth TNM/AJCC Classification System: A Comparative Study

Thyroid , Vol. 0, No. 0.


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Effect of Diabetes Sleep Education for T2DM Who Sleep After Midnight: A Pilot Study from China

Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.


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The Association Between Sleeping Time and Metabolic Syndrome Features, Among Older Adults Living in Mediterranean Region: The MEDIS Study

Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.


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Clinical study to evaluate the performance of a noninvasive focused ultrasound device for thigh fat and circumference reduction compared to control

Summary

Background and objectives

An FDA-cleared focused ultrasound device (UltraShape, Syneron Candela^®, Yokneam, Israel) for noninvasive abdominal fat reduction produces localized mechanical cellular membrane disruption in adipocytes. This study seeks to determine the safety and efficacy of this device for use on the thighs.

Study designs/Materials and methods

Fourteen women aged 33-60 were selected to receive 3 biweekly treatments to one thigh with the other thigh serving as an internal control. The subjects had a BMI range of 18-30 kg/m² and a weight range of 54-83 kg. After the third treatment, patients were followed at 4, 8, and 16 weeks. Fat thickness was measured by both caliper and ultrasound. In addition, thigh circumference and the patient's weight were measured. Pain, edema, erythema, and adverse events as well as investigator and patient overall satisfaction were recorded at all visits.

Results

In comparison with the control, there was a statistically significant average reduction in fat thickness measured by calipers at all time points with a 22.20% (P = .0165) improvement in 16 weeks. By ultrasound, there was a 19.23% (4.03 mm P = .0051) reduction in fat thickness at 16 weeks with statistically significant improvement at the other follow-up visits. At 16 weeks, thigh circumference improved, on average, 2.8 cm (P = .0059) at the midline. 90.0% of the subjects were satisfied with the results at 16 weeks, and the investigator was 100% satisfied. No adverse events were reported; no edema was observed in any subject. All subjects experienced mild erythema. All reported zero pain on a 0-10 scale.

Conclusion

Focused ultrasound is safe, effective, and well tolerated to improve the circumference and fat thickness of the thighs without significant side effects. There were no significant adverse events. Investigators and subjects were highly satisfied with the results.

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Antibody Immunodominance: The Key to Understanding Influenza Virus Antigenic Drift

Viral Immunology , Vol. 0, No. 0.


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Preventing Peanut Allergy

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


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Shaping substrate selectivity in a broad spectrum metallo-{beta}-lactamase [PublishAheadOfPrint]

Metallo-β-lactamases (MBLs) are the major group of carbapenemases produced by bacterial pathogens. The design of MBL inhibitors has been limited, among other issues, by the incomplete knowledge about how these enzymes modulate substrate recognition. While most MBLs are broad-spectrum enzymes, B2 MBLs are exclusive carbapenemases. This narrower substrate profile has been attributed to a sequence insertion present in B2 enzymes that limits the accessibility to the active site. In this work, we evaluate the role of sequence insertions naturally occurring in the B2 enzyme Sfh-I and in the broad-spectrum B1 enzyme SPM-1. We engineered a chimeric protein in which the sequence insertion of SPM-1 was replaced by the one present in Sfh-I. The chimeric variant is a selective cephalosporinase, revealing that the substrate profile of MBLs can be further tuned depending on the protein context. These results also show that the stable scaffold of MBLs allows a modular engineering much richer than the one observed in nature.

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Unravelling the metabolic routes of retapamulin: insights into drug development of pleuromutilins [PublishAheadOfPrint]

Retapamulin, a semi-synthetic pleuromutilin derivative, is exclusively used for the topical short-term medication of impetigo and staphylococcal infections. In the present study, we report that retapamulin is adequately and rapidly metabolized in vitro via various metabolic pathways such as hydroxylation, including mono-, di- and tri-hydroxylation and demethylation. Like tiamulin and valnemulin, the major metabolic routes of retapamulin were hydroxylation at the 2β and 8α positions of the mutilin moiety. Moreover, in vivo metabolism concurred with the results of the in vitro assays. Additionally, we observed the significant inter-species metabolic differences of retapamulin. Until now, modifying the side chain was the mainstream for new drug discovery of the pleuromutilins. This approach, however, could not resolve the low bioavailability and short efficacy of the drugs. Considering the rapid metabolism of the pleuromutilins mediated by cytochrome P450 enzymes, we propose that blocking the active metabolic site (C-2 and C-8 motif) or administering the drug in combination with cytochrome P450 enzymes inhibitor to be promising pathways in the development of novel pleuromutilins drugs with slow metabolism and long efficacy.

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Cellular pharmacokinetics and intracellular activity of gepotidacin against Staphylococcus aureus with different resistance phenotypes in models of cultured phagocytic cells. [PublishAheadOfPrint]

Gepotidacin (GSK2140944), a novel triazaacenaphthylene bacterial topoisomerase inhibitor, is currently in clinical development for the treatment of bacterial infections. This study examines in vitro its activity against intracellular Staphylococcus aureus (involved in the persistent character of skin and skin structure infections) using a pharmacodynamic model and in relation to cellular pharmacokinetics in phagocytic cells. Compared to oxacillin, vancomycin, linezolid, daptomycin, azithromycin, and moxifloxacin, gepotidacin was (i) more potent intracellularly (C_s [apparent bacteriostatic effect] reached at an extracellular concentration of about 0.7 x its MIC and not affected by resistance mechanisms to the comparators) and (ii) caused a maximal reduction of the intracellular burden (E_max) of about -1.6 log₁₀ CFU (better than linezolid, macrolides, and daptomycin; similar to moxifloxacin). After 24 h of incubation of infected cells with antibiotics at 100 X their MIC, the intracellular persisting fraction was < 0.1 % with moxifloxacin, 0.5 % with gepotidacin and > 1 % with other drugs. Accumulation and efflux of gepotidacin in phagocytes was very fast (k_in and k_out ~0.3 min^-1; plateau reached within 15 minutes) but modest (intracellular to extracellular concentration ratio ~1.6). In cell fractionation studies, about 40-60 % of the drug was recovered in the soluble fraction and ~40% associated with lysosomes in uninfected cells. In infected cells, about 20% of cell-associated gepotidacin was recovered in a sedimentable fraction that also contained bacteria. This study highlights the potential for further study of gepotidacin to fight infections where intracellular niches may play a determining role in bacterial persistence and relapses.

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Population Pharmacokinetic Model for Cefuroxime Used in Coronary Artery Bypass Graft Surgery with Cardiopulmonary Bypass: Model-Based Evaluation of Standard Dosing Regimens [PublishAheadOfPrint]

The purpose of this study was to investigate the population PK of cefuroxime in patients undergoing coronary artery bypass graft (CABG) surgery. In this observational pharmacokinetic study, multiple blood samples were collected over a 48-h interval of intravenous cefuroxime administration. The samples were analyzed by using a validated high-performance liquid chromatography (HPLC) method. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. A total of 468 blood samples were analyzed from 78 patients. The PK for cefuroxime was best described by a two-compartment model with between-subject variability on clearance, volume of the central compartment, and volume of the peripheral compartment. Clearance of cefuroxime was related to creatinine clearance (CL_CR). Dosing simulations showed that standard dosing regimens of 1.5 g could achieve the PK-PD target of 65% fT_>MIC for an MIC of 8 mg/L in patients with CL_CR of 30, 60, 90 ml/min, whereas this dosing regimens failed to achieve the PK-PD target in patients with CL_CR of ≥125 ml/min. In conclusion, administration of standard doses of 1.5 g three times daily provided adequate antibiotic prophylaxis in patients undergoing CABG surgery. Lower doses failed to achieve the PK-PD target. Patients with high CL_CR values are required either higher doses or shorter intervals of cefuroxime dosing. On the other hand, lower doses (1 g three times daily) produced adequate target attainment for patients with low CLCR (≤30 ml/min).

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Population pharmacokinetics of high-dose tigecycline in patients with sepsis or septic shock [PublishAheadOfPrint]

Background and objective: Tigecycline is a glycylcycline often used in critically ill patients as antibiotic of last resort. The pharmacokinetics (PK) of tigecycline in Intensive Care Unit (ICU) patients can be affected by severe pathophysiological changes so that standard dosing might not be adequate. The aim of this study was to describe population PK of high dose tigecycline in patients with sepsis or septic shock and evaluate relationship between individual PK parameters and patient's covariates.

Materials and Methods: The study population consisted of 37 adult ICU patients receiving 200 mg loading dose of tigecycline followed by multiple doses of 100 mg every 12 h. Blood samples were collected at 0.5, 2, 4, 8 and 12 h after dose administration. Two-compartment model with inter-individual (IIV) and inter-occasion (IOV) variability in PK parameters was used to describe the concentration-time course of tigecycline.

Results: The estimated values of mean population PK parameters were 22.1 L/h and 69.4 L/h for elimination and inter-compartmental clearance, 162 L and 87.9 L for volume of central and peripheral compartment. The IIV and IOV in clearance was lower than 20%. The estimated values of distribution volumes were different than previously published values, which might be due to pathophysiological changes in ICU patients. No systematic relationship between individual PK parameters and patient's covariates was found.

Conclusions: The developed model does not show evidence that individual tigecycline dosing adjustment based on patient's covariates is necessary to obtain the same target concentration in patients with sepsis or septic shock. Dosing adjustments should be based on the pathogens, their susceptibility and PK targets.

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Amikacin Pharmacokinetic-Pharmacodynamic (PK-PD) Analysis in Pediatric Cancer Patients [PublishAheadOfPrint]

We performed PK-PD and simulation analyses to evaluate standard 15 mg/kg/day amikacin in children with cancer and to determine an optimal dosing strategy. A population pharmacokinetic model was developed from clinical data collected in 34 pediatric patients and used in a simulation study to predict the population probability of various dosing regimens to achieve accepted safety- (fC_min < 10 mg/L) and efficacy-linked (fC_max/MIC ≥ 8) targets. In addition, an adaptive resistance PD (ARPD) model of Pseudomonas aeruginosa was built based on literature time-kill curve data and linked to the PK model to perform PK-ARPD simulations and compare results with the probability approach. Using the probability approach, an amikacin dose of 60 mg/kg administered once daily is expected to achieve the target fC_max/MIC in 80% of pediatric patients weighing 8-70 kg with a 97.5% probability and almost all patients were predicted to have fC_min < 10 mg/L. However, PK-ARPD simulation predicted that 60 mg/kg/day is unlikely to suppress bacterial resistance with repeated dosing. Furthermore, PK-ARPD simulation suggested that amikacin 90 mg/kg given in two divided doses (45 mg/kg BID) are expected to hit safety and efficacy targets, and associated with a lower rate of bacterial resistance. The disagreement between the two methods is due to the inability of probability approach in predicting development of drug resistance with repeated dosing. This originates from the use of PK-PD indices based on the MIC that neglects measurement errors, ignores the time-course dynamic nature of bacterial growth and killing, and incorrectly assumes the MIC to be constant during treatment.

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Evaluating the Relationship between Vancomycin Trough Concentration and 24-Hour Area under the Concentration-Time Curve in Neonates [PublishAheadOfPrint]

Bacterial sepsis is a major cause of morbidity and mortality in neonates, especially those involving methicillin-resistant Staphylococcus aureus (MRSA). Guidelines by the Infectious Diseases Society of America recommend vancomycin 24-hour area under the concentration-time curve to MIC ratio (AUC₂₄/MIC, hr) > 400 as the best predictor of successful treatment against MRSA infections when MIC (mg/L) is ≤ 1. The relationship between steady state vancomycin trough concentrations and AUC₂₄ (mg ⋅ hr/L) has not been studied in an Asian neonatal population. We conducted a retrospective chart review in Singapore hospitals, and collected patient characteristics and therapeutic drug monitoring data from neonates on vancomycin therapy over a 5-year period. A one-compartment population pharmacokinetic model was built from the collected data, internally validated, and then used to assess the relationship between steady state trough concentrations and AUC₂₄. A Monte Carlo simulation sensitivity analysis was also conducted. A total of 76 neonates with 429 vancomycin concentrations were included for analysis. Median (interquartile range) was 30 weeks (28-36 weeks) for postmenstrual age (PMA) and 1043 g (811-1919 g) for weight at initiation of treatment. Vancomycin clearance was predicted by weight, PMA, and serum creatinine. For MRSA isolates with MIC ≤ 1, our major finding was that the minimum steady state trough concentration range predictive of achieving AUC₂₄/MIC > 400 was 8 to 8.9 mg/L. Steady state troughs within 15 to 20 mg/L are unlikely to be necessary to achieve AUC₂₄/MIC > 400, while troughs within 10 to 14.9 mg/L may be more appropriate.

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Tn6450, a novel multidrug resistance transposon characterized in a Proteus mirabilis isolate from chicken in China [PublishAheadOfPrint]

A novel 65.8-kb multidrug resistance transposon, designated as Tn6450, was characterized in a Proteus mirabilis isolate from chicken in China. Tn6450 contains 18 different antimicrobial resistance genes, including cephalosporinase gene bla_DHA-1 and fluoroquinolones resistance genes qnrA1 and aac(6' )-Ib-cr. It carries a class 1/2 hybrid integron composed of intI2 and 3' conserved segment of class 1 integron. Tn6450 is derived from Tn7 via acquisition of new mobile elements and resistance genes.

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Single Intravenous Dose of Oritavancin for the Treatment of Gram-positive Acute Bacterial Skin and Skin Structure Infections: Summary of Safety from the Phase 3 SOLO studies [PublishAheadOfPrint]

Oritavancin is a lipoglycopeptide with bactericidal activity against gram-positive organisms. Its rapid concentration-dependent bactericidal activity and long elimination half-life allow for single dose treatment of acute bacterial skin and skin structure infections (ABSSSI). SOLO I and SOLO II were randomized, double-blind studies evaluating efficacy and safety of a single 1200 mg IV dose of oritavancin versus twice-daily IV vancomycin for 7 to 10 days in ABSSSI patients. Safety data were pooled across both studies for safety analysis. The pooled safety database comprised 976 oritavancin patients and 983 vancomycin patients. The incidence of adverse events, serious adverse events, and discontinuations due to adverse events were similar for oritavancin (55.3, 5.8 and 3.7%, respectively) and vancomycin (56.9, 5.9 and 4.2%, respectively). The median time to onset (3.8 days vs. 3.1 days, respectively) and duration (3.0 days for both groups) of adverse events were also similar between the two groups. The most frequently reported events were nausea, headache, and vomiting. Greater than 90% of all events were mild or moderate in severity. There were slightly more infections and infestation, abscesses or cellulitis, hepatic and cardiac adverse events in the oritavancin group; however, more than 80% of these events were mild or moderate. Subgroup analyses did not identify clinically meaningful differences in the incidence of adverse events attributed to oritavancin. A single 1200 mg dose of oritavancin was well tolerated and had a similar safety profile to twice-daily vancomycin. The long elimination half-life of oritavancin compared to vancomycin did not result in clinically meaningful delay to onset or prolongation of adverse events.

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FKS2 and FKS3 genes of opportunistic human pathogen Candida albicans influence echinocandin susceptibility [PublishAheadOfPrint]

Candida albicans, a prevailing opportunistic fungal pathogen of humans, has a diploid genome containing three homologous FKS genes that are evolutionary conserved. One of these, the essential gene FKS1, encodes the catalytic subunit of glucan synthase (GS) that is the target of echinocandin drugs and also serves as site of drug resistance. The two other GS-encoding genes, FKS2 and FKS3, are also expressed but their role in resistance is considered unimportant. However, we report here that expression of FKS1 is upregulated in strains lacking either FKS2 or FKS3. Furthermore, in contrast to what is observed in heterozygous FKS1 deletion strains, cells lacking FKS2 or FKS3 contain increased amounts of cell wall glucan, are more resistant to echinocandin drugs and, consistently, are tolerant to cell wall damaging agents. Our data indicate that C. albicans FKS2 and FKS3 can act as negative regulators of FKS1, thereby influencing echinocandin susceptibility.

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Orientia tsutsugamushi is highly susceptible to the RNA polymerase switch region inhibitor Corallopyronin A in vitro and in vivo [PublishAheadOfPrint]

Scrub typhus is a potentially lethal infection caused by the obligate intracellular bacterium Orientia (O.) tsutsugamushi. Reports on the emergence of doxycycline-resistant strains highlight the urgent need to develop novel anti-infectives against scrub typhus.

Corallopyronin A (CorA) is a novel α-pyrone compound synthesized by the myxobacterium Corallococcus coralloides and was characterized as a non-competitive inhibitor of the "switch region" of bacterial RNA polymerase (RNAP). We investigated the antimicrobial action of CorA against the human-pathogenic Karp strain of O. tsutsugamushi in vitro and in vivo. The minimal inhibitory concentration of CorA against O. tsutsugamushi was remarkably low (0.0078 μg/ml), 16-fold lower compared to Rickettsia (R.) typhi. In the lethal intraperitoneal O. tsutsugamushi mouse infection model, a minimum daily dose of 100 μg CorA protected 100% of infected mice. Two days of treatment were sufficient to confer protection. In contrast to BALB/c mice, SCID mice succumbed to the infection despite CorA or tetracycline treatment, suggesting that antimicrobial treatment required synergistic action of the adaptive immune response. Similar to tetracycline, CorA did not prevent latent infection of O. tsutsugamushi in vivo. However, latency was not caused by acquisition of antimicrobial resistance, since O. tsutsugamushi reisolated from latently infected BALB/c mice remained fully susceptible to CorA. No mutations were found in the CorA binding regions of the beta and beta' RNAP subunit genes rpoB and rpoC.

Inhibition of the RNAP switch region of O. tsutsugamushi by CorA is therefore a novel and highly potent target for antimicrobial therapy of scrub typhus.

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Using yeast synthetic lethality to inform drug combination for malaria [PublishAheadOfPrint]

Combinatorial chemotherapy is imperative for the treatment of malaria. However, finding a suitable partner drug for a new candidate is challenging. Here we develop an algorithm that identifies all the gene pairs of Plasmodium falciparum which possess orthologues in yeast that have a synthetic lethal interaction, but are absent in humans. This suggests new options for drug combinations, in particular for inhibitors of targets like P. falciparum calcineurin, cation ATPase 4, or phosphatidylinositol 4-kinase.

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Quantitative analysis of gentamicin exposure in neonates and infants calls into question its current dosing recommendations [PublishAheadOfPrint]

Optimal dosing of gentamicin in neonates is still a matter of debate despite its common use. We identified gentamicin dosing regimens from 8 international guidelines and 7 Swiss Neonatal Intensive Care Units. Dose per administration, dosing interval, total daily dose and demographic characteristics between guidelines were compared. There was considerable variability with respect to dose (4 to 6 mg/kg), dosing interval (24 h to 48 h), total daily dose (2.5 to 6 mg/kg/day) and patient demographic characteristics which were used to calculate individualized dosing regimens. A model-based simulation study in 1071 neonates was performed to determine achievement of efficacious peak gentamicin concentrations according to predefined minimum inhibitory concentrations (MICs) (C_max/MIC ≥ 10) and safe trough concentrations (C_min ≤ 2 mg/L) with recommended dosing regimens. MIC targets of 0.5 and 1 mg/L were used. Dosing optimization was performed giving priority to the first day of treatment and with the goal of simplifying dosing. Current gentamicin neonatal guidelines, achieve effective peak concentrations if MIC is 0.5 mg/L but not for MICs ≥ 1 mg/L. Model-based simulations indicate that to attain peak gentamicin concentrations ≥ 10 mg/L, a dose of 7.5 mg/kg should be administered using an extended dosing interval regimen. Trough concentrations ≤ 2 mg/L can be maintained with a dosing interval of 36 to 48 hours in neonates according to gestational and postnatal age. For treatment beyond 3 days, therapeutic drug monitoring is advised to maintain adequate serum concentrations.

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The p38-MK2/3 Module Is Critical for IL-33-Induced Signaling and Cytokine Production in Dendritic Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

IL-33 is an IL-1 cytokine superfamily member. Binding of IL-33 to the IL-33R induces activation of the canonical NF-B signaling and activation of MAPKs. In bone marrow–derived dendritic cells, IL-33 induces the production of IL-6, IL-13, and TNF-α. However, the signaling pathways resulting in IL-33–induced effector functions of dendritic cells are unknown. In this article, we show that the IL-33–induced cytokine production is only partly dependent on p65. Thereby, p65 mediates the production of IL-6, but not of IL-13, whereas the p38–Mapk-activated protein kinases 2/3 (MK2/3) signaling module mediates the IL-13, but not the IL-6, production. In addition, GM-CSF, which is critical for the differentiation and proliferation of bone marrow–derived dendritic cells, potentiates the p65-dependent IL-6 and the p38-MK2/3–dependent IL-13 production. Furthermore, we found that effective TNF-α production is only induced in the presence of GM-CSF and IL-33 via the p38-MK2/3 signaling module. Taken together, we found that the p38-MK2/3 signaling module is essential to mediate IL-33–induced cytokine production in dendritic cells.

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Intestinal Inflammation-Mediated Clearance of Amebic Parasites Is Dependent on IFN-{gamma} [INFECTIOUS DISEASE AND HOST RESPONSE]

Intestinal amebiasis is a major cause of diarrhea. However, research on host–amebae interactions has been hampered owing to a lack of appropriate animal models. Recently, a mouse model of intestinal amebiasis was established, and using it, we reported that Entamoeba moshkovskii colonized the intestine in a manner similar to that of the pathogenic Entamoeba histolytica. In this study, we evaluated the protective mechanisms present against amebae using this model. CBA/J mice infected with E. histolytica had a persistent infection without apparent symptoms. In contrast, E. moshkovskii–infected mice rapidly expelled the ameba, which was associated with weight loss, diarrhea, and intestinal damage characterized by apoptosis of intestinal epithelial cells (IECs). Expression of NKG2D on intestinal intraepithelial lymphocytes (IELs) and IFN-–producing cells in Peyer's patches were significantly induced after infection with E. moshkovskii but not with E. histolytica. IFN-–deficient mice infected with E. moshkovskii showed no obvious symptoms. Notably, none of these mice expelled E. moshkovskii, indicating that IFN- is responsible not only for intestinal symptoms but also for the expulsion of amebae. Furthermore, apoptosis of IECs and expression of NKG2D on IELs observed in E. moshkovskii–infected mice did not occur in the absence of IFN-. In vivo blocking of NKG2D in mice infected with E. moshkovskii enabled ameba to survive longer and remarkably reduced apoptotic IECs. Our results clearly demonstrate a novel protective mechanism exerted by IFN- against intestinal amebae, including induction of cytotoxicity of IELs toward IECs.

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Human NK Cells Downregulate Zap70 and Syk in Response to Prolonged Activation or DNA Damage [INNATE IMMUNITY AND INFLAMMATION]

The extent of NK cell activity during the innate immune response affects downstream immune functions and, ultimately, the outcome of infectious or malignant disease. However, the mechanisms that terminate human NK cell responses have yet to be defined. When activation receptors expressed on NK cell surfaces bind to ligands on diseased cells, they initiate a signal that is propagated by a number of intracellular kinases, including Zap70 and Syk, eventually leading to NK cell activation. We assayed Zap70 and Syk content in NK cells from healthy human donors and identified a subset of NK cells with unusually low levels of these two kinases. We found that this Zap70^lowSyk^low subset consisted of NK cells expressing a range of surface markers, including CD56^hi and CD56^low NK cells. Upon in vitro stimulation with target cells, Zap70^lowSyk^low NK cells failed to produce IFN- and lysed target cells at one third the capacity of Zap70^hiSyk^hi NK cells. We determined two independent in vitro conditions that induce the Zap70^lowSyk^low phenotype in NK cells: continuous stimulation with activation beads and DNA damage. The expression of inhibitory receptors, including NKG2A and inhibitory killer Ig-like receptors (KIRs), was negatively correlated with the Zap70^lowSyk^low phenotype. Moreover, expression of multiple KIRs reduced the likelihood of Zap70 downregulation during continuous activation, regardless of whether NK cells had been educated through KIR–HLA interactions in vivo. Our findings show that human NK cells are able to terminate their functional activity without the aid of other immune cells through the downregulation of activation kinases.

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Identification of a Multipotent Progenitor Population in the Spleen That Is Regulated by NR4A1 [IMMUNE SYSTEM DEVELOPMENT]

The developmental fate of hematopoietic stem and progenitor cells is influenced by their physiological context. Although most hematopoietic stem and progenitor cells are found in the bone marrow of the adult, some are found in other tissues, including the spleen. The extent to which the fate of stem cells is determined by the tissue in which they reside is not clear. In this study, we identify a new progenitor population, which is enriched in the mouse spleen, defined by cKit⁺CD71^lowCD24^high expression. This previously uncharacterized population generates exclusively myeloid lineage cells, including erythrocytes, platelets, monocytes, and neutrophils. These multipotent progenitors of the spleen (MPPS) develop from MPP2, a myeloid-biased subset of hematopoietic progenitors. We find that NR4A1, a transcription factor expressed by myeloid-biased long term-hematopoietic stem cells, guides the lineage specification of MPPS. In vitro, NR4A1 expression regulates the potential of MPPS to differentiate into erythroid cells. MPPS that express NR4A1 differentiate into a variety of myeloid lineages, whereas those that do not express NR4A1 primarily develop into erythroid cells. Similarly, in vivo, after adoptive transfer, Nr4a1-deficient MPPS contribute more to erythrocyte and platelet populations than do wild-type MPPS. Finally, unmanipulated Nr4a1^–/– mice harbor significantly higher numbers of erythroid progenitors in the spleen compared with wild-type mice. Together, our data show that NR4A1 expression by MPPS limits erythropoiesis and megakaryopoeisis, permitting development to other myeloid lineages. This effect is specific to the spleen, revealing a unique molecular pathway that regulates myeloid bias in an extramedullary niche.

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Memory T Cell Proliferation before Hepatitis C Virus Therapy Predicts Antiviral Immune Responses and Treatment Success [INFECTIOUS DISEASE AND HOST RESPONSE]

The contribution of the host immune system to the efficacy of new anti-hepatitis C virus (HCV) drugs is unclear. We undertook a longitudinal prospective study of 33 individuals with chronic HCV treated with combination pegylated IFN-α, ribavirin, and telaprevir/boceprevir. We characterized innate and adaptive immune cells to determine whether kinetics of the host response could predict sustained virologic response (SVR). We show that characteristics of the host immune system present before treatment were correlated with successful therapy. Augmentation of adaptive immune responses during therapy was more impressive among those achieving SVR. Most importantly, active memory T cell proliferation before therapy predicted SVR and was associated with the magnitude of the HCV-specific responses at week 12 after treatment start. After therapy initiation, the most important correlate of success was minimal monocyte activation, as predicted by previous in vitro work. In addition, subjects achieving SVR had increasing expression of the transcription factor T-bet, a driver of Th1 differentiation and cytotoxic effector cell maturation. These results show that host immune features present before treatment initiation predict SVR and eventual development of a higher frequency of functional virus-specific cells in blood. Such host characteristics may also be required for successful vaccine-mediated protection.

http://ift.tt/2DytJgf

The STAT3-IL-10-IL-6 Pathway Is a Novel Regulator of Macrophage Efferocytosis and Phenotypic Conversion in Sterile Liver Injury [INNATE IMMUNITY AND INFLAMMATION]

The disposal of apoptotic bodies by professional phagocytes is crucial to effective inflammation resolution. Our ability to improve the disposal of apoptotic bodies by professional phagocytes is impaired by a limited understanding of the molecular mechanisms that regulate the engulfment and digestion of the efferocytic cargo. Macrophages are professional phagocytes necessary for liver inflammation, fibrosis, and resolution, switching their phenotype from proinflammatory to restorative. Using sterile liver injury models, we show that the STAT3–IL-10–IL-6 axis is a positive regulator of macrophage efferocytosis, survival, and phenotypic conversion, directly linking debris engulfment to tissue repair.

http://ift.tt/2DvQFwy

Extracellular Lactate: A Novel Measure of T Cell Proliferation [NOVEL IMMUNOLOGICAL METHODS]

Following activation, T cells rapidly divide and acquire effector functions. This energetically demanding process depends upon the ability of T cells to undergo metabolic remodeling from oxidative phosphorylation to aerobic glycolysis, during which glucose is converted into lactate and released extracellularly. In this article, we demonstrate that extracellular lactate can be used to dynamically assess human T cell responses in vitro. Extracellular lactate levels strongly correlated with T cell proliferation, and measuring lactate compared favorably with traditional methods for determining T cell responses (i.e., [³H]thymidine incorporation and the use of cell proliferation dyes). Furthermore, we demonstrate the usefulness of measuring lactate as a read-out in conventional suppression assays and high-throughput peptide-screening assays. Extracellular lactate was stably produced over 7 d, and results were reproducibly performed over several freeze–thaw cycles. We conclude that the use of extracellular lactate measurements can be a sensitive, safe, stable, and easy-to-implement research tool for measuring T cell responses and cellular metabolic changes in vitro.

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In This Issue [IN THIS ISSUE]

http://ift.tt/2DvK7xT

Dendritic Cells on the Way to Glory [PILLARS OF IMMUNOLOGY]

http://ift.tt/2n2luha

Pillars Article: Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor {alpha}. J. Exp. Med. 1994. 179:1109-1118 [PILLARS OF IMMUNOLOGY]

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The Hypoxia-Adenosine Link during Intestinal Inflammation [BRIEF REVIEWS]

Intestinal inflammation is a key element in inflammatory bowel disease and is related to a combination of factors, including genetics, mucosal barrier dysfunction, bacteria translocation, deleterious host–microbe interactions, and dysregulated immune responses. Over the past decade, it has been appreciated that these inflammatory lesions are associated with profound tissue hypoxia. Interestingly, an endogenous adaptive response under the control of hypoxia signaling is enhancement in adenosine signaling, which impacts these different endpoints, including promoting barrier function and encouraging anti-inflammatory activity. In this review, we discuss the hypoxia–adenosine link in inflammatory bowel disease, intestinal ischemia/reperfusion injury, and colon cancer. In addition, we provide a summary of clinical implications of hypoxia and adenosine signaling in intestinal inflammation and disease.

http://ift.tt/2n1B9NW

Cutting Edge: Low-Affinity TCRs Support Regulatory T Cell Function in Autoimmunity [CUTTING EDGE]

Regulatory T cells (Tregs) use a distinct TCR repertoire and are more self-reactive compared with conventional T cells. However, the extent to which TCR affinity regulates the function of self-reactive Tregs is largely unknown. In this study, we used a two-TCR model to assess the role of TCR affinity in Treg function during autoimmunity. We observed that high- and low-affinity Tregs were recruited to the pancreas and contributed to protection from autoimmune diabetes. Interestingly, high-affinity cells preferentially upregulated the TCR-dependent Treg functional mediators IL-10, TIGIT, GITR, and CTLA4, whereas low-affinity cells displayed increased transcripts for Areg and Ebi3, suggesting distinct functional profiles. The results of this study suggest mechanistically distinct and potentially nonredundant roles for high- and low-affinity Tregs in controlling autoimmunity.

http://ift.tt/2DArY24

Type 2 Cysteinyl Leukotriene Receptors Drive IL-33-Dependent Type 2 Immunopathology and Aspirin Sensitivity [ALLERGY AND OTHER HYPERSENSITIVITIES]

Cysteinyl leukotrienes (cysLTs) facilitate mucosal type 2 immunopathology by incompletely understood mechanisms. Aspirin-exacerbated respiratory disease, a severe asthma subtype, is characterized by exaggerated eosinophilic respiratory inflammation and reactions to aspirin, each involving the marked overproduction of cysLTs. Here we demonstrate that the type 2 cysLT receptor (CysLT₂R), which is not targeted by available drugs, is required in two different models to amplify eosinophilic airway inflammation via induced expression of IL-33 by lung epithelial cells. Endogenously generated cysLTs induced eosinophilia and expanded group 2 innate lymphoid cells (ILC2s) in aspirin-exacerbated respiratory disease–like Ptges^–/– mice. These responses were mitigated by deletions of either Cysltr2 or leukotriene C₄ synthase (Ltc4s). Administrations of either LTC₄ (the parent cysLT) or the selective CysLT₂R agonist N-methyl LTC₄ to allergen sensitized wild-type mice markedly boosted ILC2 expansion and IL-5/IL-13 generation in a CysLT₂R-dependent manner. Expansion of ILC2s and IL-5/IL-13 generation reflected CysLT₂R-dependent production of IL-33 by alveolar type 2 cells, which engaged in a bilateral feed-forward loop with ILC2s. Deletion of Cysltr1 blunted LTC₄-induced ILC2 expansion and eosinophilia but did not alter IL-33 induction. Pharmacological blockade of CysLT₂R prior to inhalation challenge of Ptges^–/– mice with aspirin blocked IL-33–dependent mast cell activation, mediator release, and changes in lung function. Thus, CysLT₂R signaling, IL-33–dependent ILC2 expansion, and IL-33–driven mast cell activation are necessary for induction of type 2 immunopathology and aspirin sensitivity. CysLT₂R-targeted drugs may interrupt these processes.

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Inhibition of the Deubiquitinase Usp14 Diminishes Direct MHC Class I Antigen Presentation [ANTIGEN RECOGNITION AND RESPONSES]

Infected or transformed cells must present peptides derived from endogenous proteins on MHC class I molecules to be recognized and targeted for elimination by Ag-specific cytotoxic T cells. In the first step of peptide generation, proteins are degraded by the proteasome. In this study, we investigated the role of the ubiquitin-specific protease 14 (Usp14), a proteasome-associated deubiquitinase, in direct Ag presentation using a ligand-stabilized model protein expressed as a self-antigen. Chemical inhibition of Usp14 diminished direct presentation of the model antigenic peptide, and the effect was especially pronounced when presentation was restricted to the defective ribosomal product (DRiP) form of the protein. Additionally, presentation specifically from DRiP Ags was diminished by expression of a catalytically inactive form of Usp14. Usp14 inhibition did not appreciably alter protein synthesis and only partially delayed protein degradation as measured by a slight increase in the half-life of the model protein when its degradation was induced. Taken together, these data indicate that functional Usp14 enhances direct Ag presentation, preferentially of DRiP-derived peptides, suggesting that the processing of DRiPs is in some ways different from other forms of Ag.

http://ift.tt/2DxEVcV

B Cell-Intrinsic MyD88 Signaling Promotes Initial Cell Proliferation and Differentiation To Enhance the Germinal Center Response to a Virus-like Particle [ANTIGEN RECOGNITION AND RESPONSES]

Although TLR signaling in B cells has been implicated in the germinal center (GC) responses during viral infections and autoimmune diseases, the underlying mechanism is unclear. Bacterial phage Qβ-derived virus-like particle (Qβ-VLP) contains TLR ligands, which can enhance Qβ-VLP-induced Ab response, including GC response, through TLR/MyD88 signaling in B cells. In this study, by examining Ag-specific B cell response to Qβ-VLP, we found that lack of B cell MyD88 from the beginning of the immune response led to a more severe defect in the GC scale than abolishing MyD88 at later time points of the immune response. Consistently, B cell–intrinsic MyD88 signaling significantly enhanced the initial proliferation of Ag-specific B cells, which was accompanied with a dramatic increase of plasma cell generation and induction of Bcl-6⁺ GC B cell precursors. In addition, B cell–intrinsic MyD88 signaling promoted strong T-bet expression independent of IFN- and led to the preferential isotype switching to IgG2a/c. Thus, by promoting the initial Ag-specific B cell proliferation and differentiation, B cell–intrinsic MyD88 signaling enhanced both T-independent and T-dependent Ab responses elicited by Qβ-VLP. This finding will provide additional insight into the role of TLR signaling in antiviral immunity, autoimmune diseases, and vaccine design.

http://ift.tt/2n2DRTj

Murine Red Blood Cells Lack Ligands for B Cell Siglecs, Allowing Strong Activation by Erythrocyte Surface Antigens [ANTIGEN RECOGNITION AND RESPONSES]

CD22 and sialic acid–binding Ig-like lectin (Siglec)-G are members of the Siglec family of inhibitory coreceptors expressed on B cells that participate in enforcement of peripheral B cell tolerance. We have shown previously that when a BCR engages its cognate Ag on a cell surface that also expresses Siglec ligands, B cell Siglecs are recruited to the immunological synapse, resulting in suppression of BCR signaling and B cell apoptosis. Because all cells display sialic acids, and CD22 and Siglec-G have distinct, yet overlapping, specificities for sialic acid–containing glycan ligands, any cell could, in principle, invoke this tolerogenic mechanism for cell surface Ags. However, we show in this article that C57BL/6J mouse RBCs are essentially devoid of CD22 and Siglec-G ligands. As a consequence, RBCs that display a cell surface Ag, membrane-bound hen egg lysozyme, strongly activate Ag-specific B cells. We reasoned that de novo introduction of CD22 ligands in RBCs should abolish B cell activation toward its cognate Ag on the surface of RBCs. Accordingly, we used a glyco-engineering approach wherein synthetic CD22 ligands linked to lipids are inserted into the membrane of RBCs. Indeed, insertion of CD22 ligands into the RBC cell surface strongly inhibited B cell activation, cytokine secretion, and proliferation. These results demonstrate that the lack of Siglec ligands on the surface of murine RBCs permits B cell responses to erythrocyte Ags and show that Siglec-mediated B cell tolerance is restricted to cell types that express glycan ligands for the B cell Siglecs.

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Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models [AUTOIMMUNITY]

Genetic absence of the urokinase-type plasminogen activator (uPA) reduces arthritis progression in the collagen-induced arthritis (CIA) mouse model to an extent just shy of disease abrogation, but this remarkable observation has not been translated into therapeutic intervention. Our aim was to test the potential in mice of an Ab that blocks the proteolytic capacity of uPA in the CIA model and the delayed-type hypersensitivity arthritis model. A second aim was to determine the cellular origins of uPA and the uPA receptor (uPAR) in joint tissue from patients with rheumatoid arthritis. A mAb that neutralizes mouse uPA significantly reduced arthritis progression in the CIA and delayed-type hypersensitivity arthritis models. In the CIA model, the impact of anti-uPA treatment was on par with the effect of blocking TNF-α by etanercept. A pharmacokinetics evaluation of the therapeutic Ab revealed target-mediated drug disposition consistent with a high turnover of endogenous uPA. The cellular expression patterns of uPA and uPAR were characterized by double immunofluorescence in the inflamed synovium from patients with rheumatoid arthritis and compared with synovium from healthy donors. The arthritic synovium showed expression of uPA and uPAR in neutrophils, macrophages, and a fraction of endothelial cells, whereas there was little or no expression in synovium from healthy donors. The data from animal models and human material provide preclinical proof-of-principle that validates uPA as a novel therapeutic target in rheumatic diseases.

http://ift.tt/2n0t100

GM-CSF Promotes Chronic Disability in Experimental Autoimmune Encephalomyelitis by Altering the Composition of Central Nervous System-Infiltrating Cells, but Is Dispensable for Disease Induction [AUTOIMMUNITY]

GM-CSF has been portrayed as a critical cytokine in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and, ostensibly, in multiple sclerosis. C57BL/6 mice deficient in GM-CSF are resistant to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG)_35–55. The mechanism of action of GM-CSF in EAE is poorly understood. In this study, we show that GM-CSF augments the accumulation of MOG_35–55-specific T cells in the skin draining lymph nodes of primed mice, but it is not required for the development of encephalitogenic T cells. Abrogation of GM-CSF receptor signaling in adoptive transfer recipients of MOG_35–55-specific T cells did not alter the incidence of EAE or the trajectory of its initial clinical course, but it limited the extent of chronic CNS tissue damage and neurologic disability. The attenuated clinical course was associated with a relative dearth of MOG_35–55-specific T cells, myeloid dendritic cells, and neutrophils, as well as an abundance of B cells, within CNS infiltrates. Our data indicate that GM-CSF drives chronic tissue damage and disability in EAE via pleiotropic pathways, but it is dispensable during early lesion formation and the onset of neurologic deficits.

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Production of IL-17 by MAIT Cells Is Increased in Multiple Sclerosis and Is Associated with IL-7 Receptor Expression [AUTOIMMUNITY]

Multiple sclerosis (MS) is a T cell–driven inflammatory disease of the CNS. Research on T cell subsets involved in MS pathogenesis has mainly focused on classical CD4⁺ T cells, especially Th17 cells, as they produce the proinflammatory, MS-associated cytokine IL-17. However, the abundant unconventional mucosal-associated invariant T (MAIT) cells are also able to produce IL-17. MAIT cells are characterized by high CD161 expression and a semi-invariant Vα7.2 TCR, with which they recognize bacterial and yeast Ags derived from the riboflavin (vitamin B2) metabolism. In this study, we characterized MAIT cells from the peripheral blood of MS patients in comparison with healthy individuals with respect to their type-17 differentiation. We found a specific increase of IL-17⁺ MAIT cells as well as an increased expression of retinoic acid–related orphan receptor (ROR)t and CCR6 in MAIT cells from MS patients, whereas the expression of T cell activation markers HLA-DR and CD38 was not different. IL-17 production by MAIT cells furthermore correlated with the surface expression level of the IL-7 receptor α-chain (CD127), which was significantly increased on MAIT cells from MS patients in comparison with healthy individuals. In summary, our findings indicate an augmented type-17 differentiation of MAIT cells in MS patients associated with their IL-7 receptor surface expression, implicating a proinflammatory role of these unconventional T cells in MS immunopathology.

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Select Clr-g Expression on Activated Dendritic Cells Facilitates Cognate Interaction with a Minor Subset of Splenic NK Cells Expressing the Inhibitory Nkrp1g Receptor [IMMUNE REGULATION]

Natural killer gene complex–encoded immunomodulatory C-type lectin-like receptors include members of the NKRP1 and C-type lectin-like 2 (CLEC2) gene families, which constitute genetically linked receptor-ligand pairs and are thought to allow for NK cell–mediated immunosurveillance of stressed or infected tissues. The mouse C-type lectin-like receptor Nkrp1g was previously shown to form several receptor-ligand pairs with the CLEC2 proteins Clr-d, Clr-f, and Clr-g, respectively. However, the physiological expression of Nkrp1g and its CLEC2 ligands as well as their functional relevance remained poorly understood. Recently, we demonstrated a gut-restricted expression of Clr-f on intestinal epithelial cells that is spatially matched by Nkrp1g on subsets of intraepithelial lymphocytes. In this study, we investigated expression and ligand interaction of Nkrp1g in the splenic compartment, and found an exclusive expression on a small subset of NK cells that upregulates Nkrp1g after cytokine exposure. Whereas transcripts of Clr-d and Clr-f are virtually absent from the spleen, Clr-g transcripts were abundantly detected throughout different leukocyte populations and hematopoietic cell lines. However, a newly generated anti–Clr-g mAb detected only residual Clr-g surface expression on splenic monocytes, whereas many hematopoietic cell lines brightly display Clr-g. Clr-g surface expression was strongly upregulated on splenic CD8α⁺ conventional dendritic cells (DCs) and plasmacytoid DCs upon TLR-mediated activation and detectable by Nkrp1g, which dampens NK cell effector functions upon Clr-g engagement. Hence, different to the intestinal tract, in the spleen, Nkrp1g is selectively expressed by a subset of NK cells, thereby potentially allowing for an inhibitory engagement with Clr-g-expressing activated DCs during immune responses.

http://ift.tt/2Dp1vQR

Novel TCR-Mediated Mechanisms of Notch Activation and Signaling [IMMUNE REGULATION]

The Notch receptor is an evolutionarily highly conserved transmembrane protein that is essential to a wide spectrum of cellular systems. Notch signaling is especially important to T cell development, and its deregulation leads to leukemia. Although not well characterized, it continues to play an integral role in peripheral T cells, in which a unique mode of Notch activation can occur. In contrast to canonical Notch activation initiated by adjacent ligand-expressing cells, TCR stimulation is sufficient to induce Notch signaling. However, the interactions between these two pathways have not been defined. In this article, we show that Notch activation occurs in peripheral T cells within a few hours post–TCR stimulation and is required for optimal T cell activation. Using a panel of inhibitors against components of the TCR signaling cascade, we demonstrate that Notch activation is facilitated through initiation of protein kinase C–induced ADAM activity. Moreover, our data suggest that internalization of Notch via endocytosis plays a role in this process. Although ligand-mediated Notch stimulation relies on mechanical pulling forces that disrupt the autoinhibitory domain of Notch, we hypothesized that, in T cells in the absence of ligands, these conformational changes are induced through chemical adjustments in the endosome, causing alleviation of autoinhibition and receptor activation. Thus, T cells may have evolved a unique method of Notch receptor activation, which is described for the first time, to our knowledge, in this article.

http://ift.tt/2DwN5lH

Human M2 Macrophages Limit NK Cell Effector Functions through Secretion of TGF-{beta} and Engagement of CD85j [IMMUNE REGULATION]

NK cells play important roles during immunosurveillance against tumors and viruses as they trigger cytotoxicity against susceptible cells and secrete proinflammatory cytokines such as IFN-. In addition, upon activation, macrophages can become proinflammatory (M1) or anti-inflammatory (M2) cells. Although the consequences of the cross-talk between M1 and NK cells are known, the outcome of the cross-talk between M2 and NK cells remains ill-defined. Therefore, in the current work, we investigated the outcome and the underlying mechanisms of the interaction between resting or stimulated human NK cells with M1 or M2. We observed a lower percentage of activated NK cells that produced less IFN- upon coculture with M2. Also, CD56^dim NK cells cocultured with M2 displayed lower degranulation and cytotoxic activity than NK cells cocultured with M1. Soluble TGF-β and M2-driven upregulation of CD85j (ILT-2) on NK cells accounted for the diminished IFN- production by CD56^bright NK cells, whereas M2-driven upregulation of CD85j on NK cells accounted for the generation of hyporesponsive CD56^dim NK cells with limited degranulation and cytotoxic capacity. Accordingly, M2 expressed higher amounts of HLA-G, the main ligand for CD85j, than M1. Hyporesponsiveness to degranulation in NK cells was not restored at least for several hours upon removal of M2. Therefore, alternatively activated macrophages restrain NK cell activation and effector functions through different mechanisms, leading to NK cells that display diminished IFN- production and at least a transiently impaired degranulation ability. These results unravel an inhibitory circuit of possible relevance in pathological situations.

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Deficiency of the AIM2-ASC Signal Uncovers the STING-Driven Overreactive Response of Type I IFN and Reciprocal Depression of Protective IFN-{gamma} Immunity in Mycobacterial Infection [IMMUNE REGULATION]

The nucleic acids of Mycobacterium tuberculosis can be detected by intracellular DNA sensors, such as cyclic GMP-AMP synthase and absent in melanoma 2 (AIM2), which results in the release of type I IFN and the proinflammatory cytokine IL-1β. However, whether cross-talk occurs between AIM2–IL-1β and cyclic GMP-AMP synthase–type I IFN signaling upon M. tuberculosis infection in vivo is unclear. In this article, we demonstrate that mycobacterial infection of AIM2^–/– mice reciprocally induces overreactive IFN-β and depressive IFN- responses, leading to higher infection burdens and more severe pathology. We also describe the underlying mechanism whereby activated apoptosis-associated speck-like protein interacts with a key adaptor, known as stimulator of IFN genes (STING), and inhibits the interaction between STING and downstream TANK-binding kinase 1 in bone marrow–derived macrophages and bone marrow–derived dendritic cells, consequently reducing the induction of type I IFN. Of note, apoptosis-associated speck-like protein expression is inversely correlated with IFN-β levels in PBMCs from tuberculosis patients. These data demonstrate that the AIM2–IL-1β signaling pathway negatively regulates the STING–type I IFN signaling pathway by impeding the association between STING and TANK-binding kinase 1, which protects the host from M. tuberculosis infection. This finding has potential clinical significance.

http://ift.tt/2Dyv2Mg

IL-4-Induced Gene 1: A Negative Immune Checkpoint Controlling B Cell Differentiation and Activation [IMMUNE REGULATION]

Emerging data highlight the crucial role of enzymes involved in amino acid metabolism in immune cell biology. IL-4–induced gene-1 (IL4I1), a secreted l-phenylalanine oxidase expressed by APCs, has been detected in B cells, yet its immunoregulatory role has only been explored on T cells. In this study, we show that IL4I1 regulates multiple steps in B cell physiology. Indeed, IL4I1 knockout mice exhibit an accelerated B cell egress from the bone marrow, resulting in the accumulation of peripheral follicular B cells. They also present a higher serum level of natural Igs and self-reactive Abs. We also demonstrate that IL4I1 produced by B cells themselves controls the germinal center reaction, plasma cell differentiation, and specific Ab production in response to T dependent Ags, SRBC, and NP-KLH. In vitro, IL4I1-deficient B cells proliferate more efficiently than their wild-type counterparts in response to BCR cross-linking. Moreover, the absence of IL4I1 increases activation of the Syk-Akt-S6kinase signaling pathway and calcium mobilization, and inhibits SHP-1 activity upon BCR engagement, thus supporting that IL4I1 negatively controls BCR-dependent activation. Overall, our study reveals a new perspective on IL4I1 as a key regulator of B cell biology.

http://ift.tt/2n0OZQp

EZH2 Represses the B Cell Transcriptional Program and Regulates Antibody-Secreting Cell Metabolism and Antibody Production [IMMUNE REGULATION]

Epigenetic remodeling is required during B cell differentiation. However, little is known about the direct functions of epigenetic enzymes in Ab-secreting cells (ASC) in vivo. In this study, we examined ASC differentiation independent of T cell help and germinal center reactions using mice with inducible or B cell–specific deletions of Ezh2. Following stimulation with influenza virus or LPS, Ezh2-deficient ASC poorly proliferated and inappropriately maintained expression of inflammatory pathways, B cell–lineage transcription factors, and Blimp-1–repressed genes, leading to fewer and less functional ASC. In the absence of EZH2, genes that normally gained histone H3 lysine 27 trimethylation were dysregulated and exhibited increased chromatin accessibility. Furthermore, EZH2 was also required for maximal Ab secretion by ASC, in part due to reduced mitochondrial respiration, impaired glucose metabolism, and poor expression of the unfolded-protein response pathway. Together, these data demonstrate that EZH2 is essential in facilitating epigenetic changes that regulate ASC fate, function, and metabolism.

http://ift.tt/2Dw0Zo7

A Cellular MicroRNA Facilitates Regulatory T Lymphocyte Development by Targeting the FOXP3 Promoter TATA-Box Motif [IMMUNE SYSTEM DEVELOPMENT]

The CD4⁺CD25⁺FOXP3⁺ regulatory T cells (Tregs) mediate immunological self-tolerance and suppress various immune responses. FOXP3 is a key transcriptional factor for the generation and development of Tregs. Its expression is regulated by various cytokines including TGF-β, IL-2, and IL-10. It is important to further identify the regulatory factors for Tregs. Given that many microRNAs (miRNAs) could specifically interact with the core promoter region and specifically enhance the transcription of many target genes, we searched for any possible miRNA(s) targeting the core promoter region of the FOXP3 gene. We found that miR-4281, an miRNA specifically expressed in hominids, can potently and specifically upregulate FOXP3 expression by directly interacting with the TATA-box motif in the human FOXP3 promoter. Consequently, miR-4281 significantly accelerated the differentiation of human naive cells to induced Tregs (iTregs) that possess immune suppressor functions and weaken the development of graft-versus-host disease in a humanized mouse model. Interestingly, iTregs induced by the combination of TGF-β, IL-2, and chemically synthesized miR-4281 were more stable and functional than those induced by TGF-β and IL-2 alone. Moreover, we found that the IL-2/STAT5 signal transduction upregulates FOXP3 expression not only through the classical pathway, but also by enhancing the expression of the miR-4281 precursor gene (SNCB) and, correspondingly, miR-4281. This study reveals a novel mechanism regulating FOXP3 expression and human iTreg development and, therefore, offers a new therapeutic target to manipulate immunosuppressive system.

http://ift.tt/2n2LQj4

Newly Generated CD4+ T Cells Acquire Metabolic Quiescence after Thymic Egress [IMMUNE SYSTEM DEVELOPMENT]

Mature naive T cells circulate through the secondary lymphoid organs in an actively enforced quiescent state. Impaired cell survival and cell functions could be found when T cells have defects in quiescence. One of the key features of T cell quiescence is low basal metabolic activity. It remains unclear at which developmental stage T cells acquire this metabolic quiescence. We compared mitochondria among CD4 single-positive (SP) T cells in the thymus, CD4⁺ recent thymic emigrants (RTEs), and mature naive T cells in the periphery. The results demonstrate that RTEs and naive T cells had reduced mitochondrial content and mitochondrial reactive oxygen species when compared with SP thymocytes. This downregulation of mitochondria requires T cell egress from the thymus and occurs early after young T cells enter the circulation. Autophagic clearance of mitochondria, but not mitochondria biogenesis or fission/fusion, contributes to mitochondrial downregulation in RTEs. The enhanced apoptosis signal-regulating kinase 1/MAPKs and reduced mechanistic target of rapamycin activities in RTEs relative to SP thymocytes may be involved in this mitochondrial reduction. These results indicate that the gain of metabolic quiescence is one of the important maturation processes during SP–RTE transition. Together with functional maturation, it promotes the survival and full responsiveness to activating stimuli in young T cells.

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Stevens–Johnson syndrome/toxic epidermal necrolysis and erythema multiforme drug-related hospitalisations in a national administrative database

Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and erythema multiforme (EM) are immunologically-mediated dermatological disorders commonly triggered by drug exposure and/or other external agents...

http://ift.tt/2BkpmiN

Does hyperthyroidism worsen prognosis of thyroid carcinoma? A retrospective analysis on 2820 consecutive thyroidectomies

Hyperthyroidism is associated with high incidence of thyroid carcinoma; furthermore, tumors arisen in hyperthyroid tissue show an aggressive behavior. Thyroid Stimulating Hormone (TSH) and Thyroid-stimulating ...

http://ift.tt/2n52lwb

An automated A-value measurement tool for accurate cochlear duct length estimation

There has been renewed interest in the cochlear duct length (CDL) for preoperative cochlear implant electrode selection and postoperative generation of patient-specific frequency maps. The CDL can be estimated...

http://ift.tt/2BlazEl

Seltene Ursache einer supraklavikulären Schwellung

http://ift.tt/2rqGO5G

In response to socioeconomic disparities and comorbidities, not race, affect salivary gland malignancy survival outcomes

http://ift.tt/2DpGTYS

Early-injection laryngoplasty may lower risk of thyroplasty: A systematic review and meta-analysis

Objective

To determine whether injection laryngoplasty within 6 months following the onset of unilateral vocal fold paralysis (UVFP) decreases the rate of permanent thyroplasty in adults.

Data Sources

Search strategies created by a medical librarian were implemented in multiple online research databases.

Review Methods

Inclusion and exclusion criteria were designed to capture randomized clinical trials and cohort studies examining adults with UVFP who received injection laryngoplasty early in the course of treatment, within 6 months of onset, or who were observed. The primary outcome was the rate of thyroplasty. The Newcastle-Ottawa scale was used to assess quality of included cohort studies. Random effects meta-analysis was used to calculate an overall relative risk (RR). Heterogeneity was evaluated with the I² statistic.

Results

The search strategy resulted in 1,177 studies, of which four cohort studies remained for meta-analysis after applying inclusion and exclusion criteria. All studies were rated as 9 of 9 on the Newcastle-Ottawa scale. Meta-analysis of 275 patients with UVFP revealed that the overall pooled RR of undergoing thyroplasty in those receiving an early injection was 0.25 (95% confidence interval 0.14–0.45) compared to conservative management (late or no injection). The I² overall was 62.4%.

Conclusion

Otolaryngologists should offer injection laryngoplasty to patients with a diagnosis of UVFP within 6 months of diagnosis (recommendation based on grade C evidence with a preponderance of benefit over harm). Laryngoscope, 2018

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Innervation status in chronic vocal fold paralysis and implications for laryngeal reinnervation

Objective

Treatment options for symptomatic unilateral vocal fold paralysis (VFP) include vocal fold augmentation, laryngeal framework surgery, and laryngeal reinnervation. Laryngeal reinnervation (LR) has been suggested to provide "tone" to the paralyzed VF. This implies a loss of tone as a result of denervation without reinnervation. We performed laryngeal electromyography (LEMG) in patients with chronic VFP to understand the innervation status associated with a chronically paralyzed vocal fold.

Study Design

Retrospective review of LEMG data in adult patients with chronic VFP from January 2009 to December 2014.

Methods

LEMG was performed at least 6 months after-onset of VFP. Qualitative LEMG, quantitative LEMG, and adductory synkinesis testing were performed, and the parameters were collected.

Results

Twenty-seven vocal folds were studied (23 unilateral VFP and 2 bilateral VFP). Average age was 59 ± 17 years. The median duration from recurrent laryngeal nerve injury to LEMG was 8.5 months (range 6–90 months). The majority of patients, 24 of 27 (89%), had motor unit potentials during phonation tasks on LEMG, and only 3 of 27 (11%) patients were electrically silent. Quantitative LEMG showed 287.8 mean turns per second (normal ≥ 400). Motor unit configuration was normal in 12 of 27 (44%), polyphasic in 12 of 27 (44%), and absent in the electrically silent patients. Adductory synkinesis was found in 6 of 20 (30%) patients.

Conclusion

Chronic vocal fold paralysis is infrequently associated with absent motor-unit recruitment, indicating some degree of preserved innervation and/or reinnervation in these patients. LEMG should be part of the routine workup for chronic VFP prior to consideration of LR.

Level of Evidence

4. Laryngoscope, 2018

http://ift.tt/2DpGKEO

Perception and duration of pain after office-based vocal fold injection augmentation

Objectives/Hypothesis

In-office laryngology procedures are important in the treatment of voice and swallowing disorders. Patient tolerance determines which procedures can be performed without sedation or formal anesthesia. This study examines pain perception during and after in-office vocal fold injection augmentation.

Study Design

Prospective cohort study.

Methods

Patients scheduled for office-based vocal fold injection augmentation were prospectively enrolled at an academic voice center. The short-form McGill Pain Questionnaire was administered before, during, and after the procedure and on postprocedure days 1, 3, and 7. Pre- and postprocedure vital signs were recorded and heart rate was continuously monitored. Telephone questionnaires were completed on postprocedure days 1 and 3.

Results

Forty-five patients consented to participate in our study (24 males, mean age 61 years). Most patients experienced mild to moderate pain with increasing heart rate during the procedure. Pain remained or increased 20 minutes after the procedure and improved but persisted for 1 day. Sensory and affective discomfort was endorsed by the majority. A minority of patients experienced bruising and changes in swallowing with diet modification for 3 days after the procedure. Sixteen percent had discomfort after 1 week.

Conclusions

This is the first prospective study examining patient perception of pain during and after in-office injection augmentation using a validated scale and pain descriptors with extended follow-up. The results may offer guidance for patient counseling, consent, and treatment to improve tolerance and success.

Level of Evidence

4. Laryngoscope, 2018

http://ift.tt/2DX4z7Q

Programmed death ligand-1 expression as immunotherapeutic target in sinonasal cancer

Abstract

Background

Sinonasal cancer carries a poor prognosis, especially in recurrent stages, and it is a disease with very limited treatment options.

Methods

The expression of programmed death ligand-1 (PD-L1) as a marker for immunotherapy was evaluated in 53 sinonasal squamous cell carcinoma (SCC) and 126 intestinal-type adenocarcinoma (ITAC) samples. Results were correlated to clinicopathological characteristics and follow-up data.

Results

Membranous PD-L1 staining of tumor cells was observed in 34% (18/53) of the sinonasal SCC samples and in 17% (22/126) of the ITAC samples. The PD-L1 positivity on infiltrating immune cells occurred in 45% (24/53) of the sinonasal SCC samples and in 33% (41/126) of the ITAC samples. Expression of PD-L1 showed no correlation to clinicopathological parameters and was not an independent risk factor for survival.

Conclusion

The PD-L1 positivity does not seem to have prognostic value. However, a proportion of patients with sinonasal SCC and ITAC may benefit from therapy with immune checkpoint inhibitors that recently have been approved for clinical application in head and neck cancer.

http://ift.tt/2Dr40ly

Targeting of miR-31/96/182 to the Numb gene during head and neck oncogenesis

Abstract

Background

MicroRNAs (miRNAs) play crucial roles in head and neck squamous cell carcinoma (HNSCC). This study investigates whether miR-31, miR-96, and miR-182 are involved in targeting Numb during HNSCC.

Methods

The expression of miR-31/96/182 in tumor tissues was analyzed. Reporter assay, knockdown, expression, and oncogenic analysis were carried out in cell lines.

Results

Upregulation of miR-31/96/182 was detected in tumor tissues. In addition, advanced tumors showed higher expression levels of these miRNAs. The expression of these miRNAs was upregulated after treatment with areca ingredients (P < .01 or P < .001). These miRNAs directly targeted the 3′ untranslated region (UTR) sequence of the Numb gene. An increased migration and invasion of HNSCC cells was associated with the exogenous expression of miR-31/96/182 (P < .01 or P < .001), and this was reverted by expression of Numb.

Conclusion

This study provides new evidence demonstrating that there is frequent and concordant upregulation of miR-31, miR-96, and miR-182 during HNSCC and these miRNAs co-target Numb.

http://ift.tt/2E0KyNS

Multicenter assessment of exclusive endoscopic endonasal approach for the treatment of 53 olfactory neuroblastomas

Abstract

Background

Given the particularities of olfactory neuroblastoma (ONB) and the lack of studies on the subject, a multicenter collaborative study was conducted to assess treatment strategy.

Methods

Fifty-three patients with ONB were included from the French Rare Head and Neck Cancer Expert Network (REFCOR) database: 16T1, 8T2, 19T3, and 10T4. All cases were treated endoscopically with skull base removal and repair in 26 cases (49%) and without external craniotomy.

Results

The overall survival (OS) and disease-free survival (DFS) rates at 5 years were 87% and 71%, respectively, with mean follow-up of 45.4 ± 26.5 months. The complication rate was 18.8% with 4 cases of meningitis. Pathological analysis showed positive margins in 26.8%, notably on the dura-mater and periorbita, without impairment of OS or DFS. Forty-eight patients received adjuvant radiotherapy on T ± N. Ten patients had a recurrence (18.9%). Six patients died of their disease. Prophylactic neck irradiation seemed to reduce the recurrence rate.

Conclusion

Exclusively endoscopic treatment proved efficient and reliable in a large controlled series.

http://ift.tt/2Dr3YtW

Neutrophil-to-lymphocyte ratio in head and neck cancer prognosis: A systematic review and meta-analysis

Abstract

Background

Hematologic markers, such as the neutrophil-to-lymphocyte ratio (NLR), characterize the inflammatory response to cancer and are associated with poorer survival in various malignancies. We evaluate the effect of pretreatment NLR on overall survival (OS) in patients with head and neck squamous cell carcinoma (HNSCC).

Methods

Using multiple databases, a systematic search for articles evaluating the effect of NLR on OS in patients with HNSCC was performed. An inverse variation, random-effects model was used to analyze the data.

Results

A total of 24 of 241 articles, including 6479 patients, were analyzed. The combined hazard ratio for OS in patients with an elevated NLR (range 2.04-5) was 1.78 (confidence interval [CI] 1.53-2.07; P < .0001). The hazard ratios for site-specific cancer: oral cavity 1.56 CI 1.23-1.98 (P < .001), nasopharynx 1.66 CI 1.35-2.04 (P < .001), larynx 1.55 CI 1.26-1.92 (P < .001), and hypopharynx 2.36 CI 1.54-3.61 (P < .001).

Conclusion

An elevated NLR is predictive of poorer OS in patients with HNSCC.

http://ift.tt/2DZj5Mj

Effect of time to simulation and treatment for patients with oropharyngeal cancer receiving definitive radiotherapy in the era of risk stratification using smoking and human papillomavirus status

Abstract

Background

The effect of increasing time to definitive radiotherapy (RT) for patients with oropharyngeal squamous cell carcinoma (SCC) is unknown.

Methods

Nodal tumor volumes at staging and simulation were compared for patients with oropharyngeal SCC. Time from staging to initiation of RT was tabulated. The primary endpoint of interest was nodal progression at simulation.

Results

Increasing time to simulation was associated with nodal progression in 144 patients (r = 0.474; P < .001). Patients with human papillomavirus (HPV)-associated oropharyngeal SCC were more likely to have nodal progression (50% vs 26%; P = .008). A threshold of 32 days was associated (sensitivity 77.9% and specificity 60.2%) with nodal progression (P < .001). Increasing time from staging to treatment initiation was associated with a greater risk of distant failure (hazard ratio [HR] 4.157; 95% confidence interval [CI] 1.170-14.764) but not progression-free survival (PFS; P = .179) or overall survival (OS; P = .474).

Conclusion

Increasing time before RT for patients with oropharyngeal SCC is associated with nodal progression and increased hazard of distant failure, although not PFS or OS in our population.

http://ift.tt/2Dr3ST6

Role of dental hardware in oral cavity squamous cell carcinoma in the low-risk nonsmoker nondrinker population

Abstract

Background

Oral cavity squamous cell carcinoma (SCC) arising in nonsmokers and nondrinkers remains poorly characterized. We hypothesized that these patients had prior exposure to metallic dental hardware.

Methods

We utilized a questionnaire querying the lifetime oral health status of 54 patients. Demographics and extensive oral health history were collected.

Results

The majority of patients (74%) had prior exposure to metallic dental hardware. The younger population with almost exclusively oral tongue cancer had a high prevalence of metallic orthodontic braces (40%) within 15 years before diagnosis. In the 51+ year age group, 82% had crowns, dental implants, and/or dentures with metallic elements.

Conclusion

Exposure to metallic dental hardware has increased in the past few decades given the rise of orthodontic braces and older adults retaining more teeth. Although this study does not prove a causal relationship between oral cavity SCC and dental hardware, this is a step toward identifying and investigating their role.

http://ift.tt/2DZAwN0

Robotic surgery for submandibular gland resection through a trans-hairline approach: The first human series and comparison with applicable approaches

Abstract

Background

Many submandibular gland diseases are treated by surgical intervention. Transcervical surgery results in an obvious cervical scar, whereas the retroauricular approach leaves a scar in the postauricular area. Therefore, robotic submandibular gland resection through a trans-hairline approach is developed to improve postoperative aesthetic outcomes.

Methods

From 2012 to 2017, 24 consecutive patients who met the inclusion criteria and had received submandibular gland resection through the trans-hairline robotic surgery were analyzed.

Results

All surgical procedures were successfully performed without conversion and appreciable complications. The incision was completely concealed within the hairs. Treatments of submandibular gland benign or malignant tumors were completed without any positive margins or disease recurrence.

Conclusion

This study demonstrated the feasibility and safety of the trans-hairline approach for robotic submandibular gland resection in the first human series. The procedure is applicable to many submandibular gland diseases with complete disease control, and has aesthetic advantages over other robotic surgical approaches.

http://ift.tt/2Dr3MLe

Novel method to save the parathyroid gland during thyroidectomy: Subcapsular saline injection

Abstract

Background

Saving the parathyroid gland during thyroidectomy remains challenging. Subcapsular saline injection (SCASI) was developed in February 2015. Its ability to spare the parathyroid gland was assessed.

Methods

All consecutive patients who underwent total thyroidectomy with or without neck lymph node dissection in 2013-2015 were included in this retrospective cohort study. Patients were divided into the SCASI and non-SCASI groups. Serum parathyroid hormone (PTH) levels were measured on day 1 and 6 months after surgery. Transient and permanent hypoparathyroidism were defined as day 1 and 6 month PTH < 10.0 and <15.0 pg/mL, respectively.

Results

The groups (both had 98 patients each) did not differ in demographics, tumor size, operation extent, pathology, thyroiditis rate, and incidental parathyroid gland excision rate. Compared with non-SCASI patients, patients who underwent the SCASI method exhibited transient hypoparathyroidism (35.7% vs 19.4%, P < .001) and permanent hypoparathyroidism (4.1% vs 0%, P = .043) significantly less frequently.

Conclusion

The procedure of SCASI effectively spared the parathyroid gland during thyroidectomy.

http://ift.tt/2E1s1RD

Evaluation of margins in head and neck squamous cell carcinoma from the surgeon's perspective

Abstract

Background

The surgeon's evaluation of resection status based on frozen section analysis during operation and pathological examination of resected specimens often differ. For this study, we recapitulated the surgeon's perspective during an operation, accordingly classified the evaluation of margins by the surgeon, and analyzed its impact on the outcome compared with the pathological results.

Methods

This was a retrospective analysis. As data sources, paper-based and digital patient files, as well as the Munich Cancer Registry database were used.

Results

Three hundred ninety-six cases were included in this analysis. Only the evaluation of margins by the surgeon influenced local control, and the pathological results influenced disease-free survival (DFS). Surprisingly, margins of >5 mm of normal tissue to cancer growth led to local control and overall survival (OS) significantly worse than 1 to 5-mm resections.

Conclusion

The evaluation of margins by the surgeon is of significant importance for local control and OS. It is largely based on frozen section analysis, which, therefore, should be used whenever possible.

http://ift.tt/2DrMjSZ

Generic quality of life in persons with hearing loss: a systematic literature review

Abstract

Background

To the best of our knowledge, no empirically based consensus has been reached as to if, and to what extent, persons with hearing loss (HL) have reduced generic Quality of life (QoL). There seems to be limited knowledge regarding to what extent a hearing aid (HA) would improve QoL. The main aim of the present study was to review studies about the relationship between HL and QoL. A supporting aim was to study the association between distress and HL.

Methods

Literature databases (Cinahl, Pub Med and Web of Science) were searched to identify relevant journal articles published in the period from January 2000 to March 17, 2016. We performed a primary search pertaining to the relationship between HL, HA and QoL (search number one) followed by a supporting search pertaining to the relationship between distress/mood/anxiety and HL (search number two). After checking for duplications and screening the titles of the papers, we read the abstracts of the remaining papers. The most relevant papers were read thoroughly, leaving us with the journal articles that met the inclusion criteria.

Results

Twenty journal articles were included in the present review: 13 were found in the primary search (HL and QoL), and seven in the supporting search (HL and distress). The literature yields equivocal findings regarding the association between generic QoL and HL. A strong association between distress and HL was shown, where distressed persons tend to have a lowered generic QoL. It is suggested that QoL is lowered among HL patients. Some studies suggest an increased generic QoL following the use of HA, especially during the first few months after initiation of treatment. Other studies suggest that HA use is one of several possible factors that contribute to improve generic QoL.

Conclusions

The majority of the studies suggest that HL is associated with reduced generic QoL. Using hearing aids seem to improve general QoL at follow-up within the first year. HL is a risk factor for distress. Further research is needed to explore the relationship between HL and generic QoL, in addition to the importance of influencing variables on this relationship.

http://ift.tt/2mXRGTW

An automated A-value measurement tool for accurate cochlear duct length estimation

Abstract

Background

There has been renewed interest in the cochlear duct length (CDL) for preoperative cochlear implant electrode selection and postoperative generation of patient-specific frequency maps. The CDL can be estimated by measuring the A-value, which is defined as the length between the round window and the furthest point on the basal turn. Unfortunately, there is significant intra- and inter-observer variability when these measurements are made clinically. The objective of this study was to develop an automated A-value measurement algorithm to improve accuracy and eliminate observer variability.

Method

Clinical and micro-CT images of 20 cadaveric cochleae specimens were acquired. The micro-CT of one sample was chosen as the atlas, and A-value fiducials were placed onto that image. Image registration (rigid affine and non-rigid B-spline) was applied between the atlas and the 19 remaining clinical CT images. The registration transform was applied to the A-value fiducials, and the A-value was then automatically calculated for each specimen. High resolution micro-CT images of the same 19 specimens were used to measure the gold standard A-values for comparison against the manual and automated methods.

Results

The registration algorithm had excellent qualitative overlap between the atlas and target images. The automated method eliminated the observer variability and the systematic underestimation by experts. Manual measurement of the A-value on clinical CT had a mean error of 9.5 ± 4.3% compared to micro-CT, and this improved to an error of 2.7 ± 2.1% using the automated algorithm. Both the automated and manual methods correlated significantly with the gold standard micro-CT A-values (r = 0.70, p < 0.01 and r = 0.69, p < 0.01, respectively).

Conclusion

An automated A-value measurement tool using atlas-based registration methods was successfully developed and validated. The automated method eliminated the observer variability and improved accuracy as compared to manual measurements by experts. This open-source tool has the potential to benefit cochlear implant recipients in the future.

http://ift.tt/2F1O6hY

Does hyperthyroidism worsen prognosis of thyroid carcinoma? A retrospective analysis on 2820 consecutive thyroidectomies

Abstract

Background

Hyperthyroidism is associated with high incidence of thyroid carcinoma; furthermore, tumors arisen in hyperthyroid tissue show an aggressive behavior. Thyroid Stimulating Hormone (TSH) and Thyroid-stimulating antibodies, present in Graves's disease, seem to play a key role in carcinogenesis and tumoral growth.

Methods

We retrospectively reviewed our series of patients who underwent thyroidectomy for thyroid carcinoma. We compared pathological features and surgical outcomes of hyperthyroid versus euthyroid patients.

Results

From 2007 to 2015, 909 thyroidectomies were performed at our institution for thyroid cancer: 87 patients were hyperthyroid and 822 euthyroid. We observed, in hyperthyroid patients, a higher rate of transient hypoparathyroidism (28.1% vs 13.2%; p < 0.01) and of node metastases (12.6% vs 6.1%; p = 0.03); also local recurrence rate was higher (5.7% vs 2.5%) even if not statistically significant (p = 0.17). Five-year disease free survival rate was significant lower in the same group (89.1% vs 96.6%; p = 0.03).

Conclusion

Thyroid cancers in hyperthyroid patients have an aggressive behavior, with high incidence of local invasion and a worse prognosis than euthyroid patients. All hyperthyroid patients should undergo a careful evaluation with ultrasound and scintigraphy; in case of suspicious nodules, an aggressive approach, including thyroidectomy and lymphectomy, is justified. In patients with toxic adenoma, thyroid cancer is uncommon, thus a loboisthmectomy can be safely performed.

Trial registration number

Research registry n. 2670 registered 19 June 2017 (retrospectively registered).

http://ift.tt/2DzSiIB

Identification of T-cell epitopes from benzylpenicillin conjugated to human serum albumin and implication in penicillin allergy

Abstract

Background

There is in vitro evidence that T-cells from allergic patients react to benzylpenicillin-human serum albumin (BP-HSA) bioconjugates. Our group has recently shown the existence of naïve CD4⁺ T lymphocytes recognizing BP-HSA in healthy donors. However, BP-haptenated peptides from HSA participating in the immunization of allergic patients have never been identified. The purpose of the present study is to identify immunodominant BP-haptenated peptides from HSA involved in immunization of patients to BP and to refine the frequency calculation of naïve CD4⁺ T-cells recognizing BP.

Methods

Co-cultures were established with CD4⁺ T-cell from non-allergic donors and mature autologous dendritic cells (DCs) loaded with BP-HSA or BP-haptenated peptides from HSA. The CD4⁺ T-cell response specific for BP-HSA or for individual BP-haptenated peptides was measured using an interferon-γ (IFN-γ) ELISpot assay. Frequency of BP-specific CD4⁺ T-cell was then calculated using the Poisson distribution. BP-HSA and BP-haptenated peptides recognition by allergic patients was evaluated on peripheral blood mononuclear cells (PBMCs) using a lymphocyte transformation test (LTT).

Results

Results showed that BP-HSA and BP-haptenated peptides were recognized by naïve T-cells from 15/16 and 13/14 tested healthy donors respectively. Most donors responded to 3 peptides with BP covalently bound on lysines 159, 212 and 525. Two of these benzylpenicilloylated peptides (lysines 159 and 525) were also found to induce PBMCs proliferation in patients with allergic reaction to penicillins.

Conclusion

This study identifies and characterizes for the first time the BP-haptenated peptides from HSA involved in the immunization of patients to penicillins.

This article is protected by copyright. All rights reserved.

http://ift.tt/2G3Jmd3

A Method to Measure Diagnostic Errors from Big Data Could be Key to Preventing Disability and Death from Misdiagnosis

In an effort to reduce patient misdiagnoses and associated poor patient outcomes from lack of prompt treatment, a Johns Hopkins Armstrong Institute for Patient Safety and Quality researcher is helping to lead the way in providing hospitals a new approach to quantify and monitor diagnostic errors in their quality improvement efforts. The approach, called Symptom-Disease Pair Analysis of Diagnostic Error, or SPADE, is featured in a paper published today in BMJ Quality & Safety.

http://ift.tt/2F41rGF

Clostridium perfringens Septicemia and a Bleeding Ulcer of a Jejunal Interposition: A Case Report and Short Review of the Literature

Introduction. We report a case of Clostridium perfringens septicemia in a patient presenting with a bleeding ulcer of a jejunal interposition. Case Presentation. An 81-year-old female patient was acutely admitted to our hospital due to hematemesis and melena. She had a history of metastatic gastrointestinal stromal tumor, for which she was receiving second line treatment with sunitinib. She had also undergone a Merendino procedure 4 years prior to presentation. The patient underwent emergency gastroscopy, which revealed a bleeding ulcer in the jejunal interposition. Despite initial endoscopic control of the bleeding and transfusion of blood products, the hemoglobin level continued to drop, and the patient was treated for an assumed hemolytic transfusion reaction. The patient died 3 days following admission, and the results of blood cultures later confirmed a Clostridium perfringens septicemia. The postmortem examination revealed a diffuse spread of Clostridium perfringens to multiple organs. Conclusion. This case is a reminder of the importance of considering septicemia, particularly in association with Clostridium perfringens, as a potential cause of hemolysis. It also demonstrates the extent of organ involvement in a case of diffuse clostridial myonecrosis.

http://ift.tt/2BjWEyv

‘Depression Education’ Effective For Some Teens

In an assessment of their "depression literacy" program, which has already been taught to tens of thousands, Johns Hopkins researchers say the Adolescent Depression Awareness Program (ADAP) achieved its intended effect of encouraging many teenagers to speak up and seek adult help for themselves or a peer. 

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Assessment of the efficacy of a new complex antisensitive skin cream

Summary

Background

Sensitive skin is frequently complaint in dermatology consultation with cutaneous manifestations such as stinging, redness, dryness, and burning sensation that affect the quality of life. Its pathogenesis is mainly related to dysfunction of neurosensory, skin barrier, and also immune activity. The treatment is generally based on continuous and topical therapy by nonirritating complex.

Objective

To evaluate the antisensitive function of a new complex cream composed by Yunnan Portulaca oleracea extract, Prinsepia utilis oil, beta-glucan, and sodium hyaluronate extracted from mushroom.

Methods

A randomized double-blind and self-control study was conducted on 20 selected volunteers with sensitive skin. Subjects applied the test cream to 1 side of the face, and the control cream (tolerance-extreme cream) to the other side of the face, twice daily over 28 days. Evaluations were performed at baseline and at 28 days. Expert clinical grading of facial skin including dryness, roughness, desquamation, and erythema was assessed. Subject self-assessment questionnaires, digital photography and noninvasive bioinstrumentation of hydration, transepidermal water loss, lipid index, skin texture, and wettability were also included in the study.

Results

Products were well tolerated. For all parameters studied, no significant difference was observed between test and control creams. Results showed that test cream provided a statistically significant improvement in clinical grading scores for dryness, roughness, and erythema at 28 days compared to baseline. In addition, statistically significant improvement of skin hydration and texture parameters (eg, smoothness and roughness) was demonstrated. Volunteers' questionnaire revealed self-perceived benefits consistent with expert visual grading.

Conclusion

This study confirmed the effectiveness and tolerance of the new complex cream in subjects with sensitive skin. The test cream could serve as a daily care moisturizer for face.

http://ift.tt/2n05Yn1

Analysis of images for detection of oral epithelial dysplasia: A review

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Reetoja Nag, Raunak Kumar Das
This paper provides a review of various image analysis approaches that have been previously used for recognition of dysplasia in images of the epithelium of the oral cavity. This domain has become especially admissible with the uncovering of the importance of image analysis which can probably be an aid to subjective diagnosis by histopathologists. Oral malignancy is a rampant form of cancer found among people of the Indian subcontinent due to various deleterious habits like consumption of tobacco, areca nut, betel leaf etc. Oral Submucous Fibrosis, a precancer, whose pathological category falls between normal epithelium and epithelial dysplasia, is caused because of these habits and can ultimately lead to oral cancer. Hence early detection of this condition is necessary. Image analysis methods for this purpose have an enormous potential which can also reduce the heavy workload of pathologists and to refine the criterion of interpretation. This paper starts with a critique of statistics of oral carcinoma in India and distribution of cancer in intra-oral sites and moves on to its causes and diagnostic approaches including causative agents, problems in curative approach and importance of image analysis in cancer detection. The various image analysis methods to appraise the cytological and architectural changes accompanied by Oral Epithelial Dysplasia in the images of the oral epithelial region have been described in relation to 2005 WHO Classification System and it was found that in future, analysis of images based on the mentioned methods has the potential in better interpretation and diagnosis of oral carcinoma.



http://ift.tt/2mXv45V

Does volumetric measurement serve as an imaging biomarker for tumor aggressiveness of ameloblastomas?

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Ali-Farid Safi, Martin Kauke, Marco Timmer, Andrea Grandoch, Hans-Joachim Nickenig, Elif Gültekin, Reinhard Büttner, Matthias Kreppel, Joachim Zöller




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Influence of anemia and BMI on prognosis of laryngeal squamous cell carcinoma: Development of an updated prognostic model

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): R.J.L.M. te Riele, E.A.C. Dronkers, M.H. van den Brink, M.J. De Herdt, A. Sewnaik, J.A. Hardillo, R.J. Baatenburg de Jong
Objectiveevaluating the impact of anemia and body mass index (BMI) on survival, and development of a prognostic model for overall survival for patients with laryngeal squamous cell carcinoma (LSCC).Materials and methodsA retrospective cohort study was performed including all consecutive patients with LSCC diagnosed and treated at the Erasmus Medical Center between January 2006 and December 2013. Patient- and tumor-specific data were collected using data from the Netherlands Comprehensive Cancer Organization and supplemented with data from patient records available in the Erasmus MC. All comorbidities were scored at the time of diagnosis.Resultsin total 788 patients were included. Mean follow-up time was 50 months (SD: ±30), during which 298 patients (37.8%) died. In both univariate and multivariate analysis BMI and anemia were significant predictors for overall survival. Multivariate analysis was performed using known predictors such as age, TNM-stage and comorbidity (ACE-27). The hazard ratio of anemia was 1.41 (95% CI: 1.05–1.90) and of BMI was 0.97 (95% CI: 0.94–0.99). BMI had an inverse association with overall survival in both univariate and multivariate survival analysis. Updating and validating an existing prognostic model with addition of anemia and BMI enhanced the performance of the prognostic model (C-statistic) from 0.77 (95% CI: 0.74–0.79) to 0.79 (95% CI: 0.77–0.82).Conclusionanemia and BMI are predictors of overall survival for LSCC, independent of other known predictors of overall survival. Adding anemia and BMI to an existing prognostic model provides better prediction of overall survival.



http://ift.tt/2n0qVOF

Three-dimensional printing of patient-specific surgical plates in head and neck reconstruction: A prospective pilot study

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Wei-fa Yang, Wing Shan Choi, Yiu Yan Leung, Justin Paul Curtin, Ruxu Du, Chun-yu Zhang, Xian-shuai Chen, Yu-xiong Su
BackgroundSurgical plates have been extensively used in head and neck reconstruction and conventional plates are mass-produced with universal configurations. To overcome disadvantages of conventional surgical plates, we have been exploring patient-specific surgical plates using the three-dimensional (3D) printing technology. We hypothesized that the application of 3D-printed patient-specific surgical plates in head and neck reconstruction is feasible, safe and precise.MethodsWe are conducting a prospective clinical trial to assess the feasibility, safety and accuracy of applying 3D-printed patient-specific surgical plates in head and neck reconstruction. The primary endpoint was the intraoperative success rate. Secondary endpoints included the incidence and severity of postoperative adverse events within six months postoperatively. The accuracy of surgical outcomes was also explored by comparing the planned and final positions of the maxilla, mandible and grafted bone segments.ResultsFrom December 2016 to October 2017, ten patients were enrolled and underwent head and neck reconstruction using 3D-printed patient-specific surgical plates. The patient-specific surgical plates adapted to bone surface precisely and no plate-bending was performed. The intraoperative success rate was 100%. The average follow-up period was 6.5 months. No major adverse events were observed. The mean absolute distance deviation of integral mandible or maxilla was 1.40 ± 0.63 mm, which showed a high accuracy of reconstruction.ConclusionsThe 3D printing of patient-specific surgical plates could be effective in head and neck reconstruction. Surgical procedures were simplified. The precise jaw reconstruction was achieved with high accuracy. Long-term results with a larger sample size are warranted to support a final conclusion.The study protocol has been registered in ClinicalTrials.gov with a No. of NCT03057223.



http://ift.tt/2Bj2hx2