Does the reduction of inferior turbinate size affect lower airway functions?

Publication date: Available online 6 November 2017
Source:Brazilian Journal of Otorhinolaryngology
Author(s): Ozlem Unsal, Mehtap Ozkahraman, Mufide Arzu Ozkarafakili, Meltem Akpinar, Arzu Yasemin Korkut, Senem Kurt Dizdar, Berna Uslu Coskun
IntroductionAlthough the nose and lungs are separate organs, numerous studies have reported that the entire respiratory system can be considered as a single anatomical and functional unit. The upper and lower airways affect each other either directly or through reflex mechanisms.ObjectiveIn this study, we aimed to evaluate the effects of the radiofrequency ablation of persistent inferior turbinate hypertrophy on nasal and pulmonary function.MethodsTwenty-seven patients with bilateral persistent inferior turbinate hypertrophy without septal deviation were included in this study. All of the patients were evaluated using anterior rhinoscopy, nasal endoscopy, acoustic rhinometry, a visual analogue scale, and flow-sensitive spirometry on the day before and 4 months after the radiofrequency ablation procedure.ResultsThe post-ablation measurements revealed that the inferior turbinate ablation caused an increase in the mean cross-sectional area and volume of the nose, as well as in the forced expiratory volume in 1s, forced vital capacity, and peak expiratory flow of the patients. These differences between the pre- and post-ablation results were statistically significant. The post-ablation visual analogue scale scores were lower when compared with the pre-ablation scores, and this difference was also statistically significant.ConclusionThis study demonstrated that the widening of the nasal passage after the reduction of the inferior turbinate size had a favorable effect on the pulmonary function tests.



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A case of segmental stiff skin syndrome treated with systemic losartan

Abstract

Stiff skin syndrome (SSS) is a rare, autosomal dominant cutaneous disorder with progressive, symmetric, sclerotic skin changes of the shoulders, hips, and thighs. In a recent publication, a distinct segmental variant of SSS was proposed. In this report we discuss the case of a boy with segmental SSS and review the current literature.

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Intralabyrinthine sporadic endolymphatic sac tumour

Publication date: Available online 6 November 2017
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): C. Lucas, J.-C. Leclère, E. Mornet, R. Marianowski
IntroductionEndolymphatic sac tumours are benign, slowly growing tumours that invade the temporal bone, and present clinically in the form of unilateral hearing loss. They can be sporadic or occur in the context of Von Hippel-Lindau disease (VHL).Case summaryThe authors report a case of endolymphatic sac tumour arising in the utricle presenting histological and immunohistochemical features corresponding to endolymphatic sac tumour in a patient without VHL.DiscussionEndolymphatic sac tumours invade the posterior part of the petrous temporal bone. According to two studies concerning patients with Von Hippel-Lindau disease, endolymphatic sac tumours arise from the endolymphatic duct. This case of intralabyrinthine sporadic endolymphatic sac tumour supports this hypothesis for sporadic forms, indicating the need for labyrinthectomy associated with tumour resection to avoid recurrence.



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Zika virus (ZIKV) Replication is Substantially Inhibited by Novel Favipiravir and Interferon-alpha Combination Regimens [PublishAheadOfPrint]

Zika virus (ZIKV) is a major public health concern due to its overwhelming spread into the Americas. Currently there are neither licensed vaccines nor antiviral therapies available for the treatment of ZIKV. We aimed to identify and rationally optimize effective therapeutic regimens for ZIKV by evaluating the antiviral potential of approved broad-spectrum antiviral agents favipiravir (FAV), interferon-alpha (IFN), and ribavirin (RBV) as single agent and combinations. For these studies, Vero cells were infected with ZIKV in the presence of increasing concentrations of FAV, IFN, or/and RBV for four days. Supernatants were harvested daily and viral burden was quantified by plaque assay on Vero cells. The time-course of viral burden during treatment in vitro was characterized by a novel translational, mechanism-based model which was subsequently used to rationally optimize combination dosage regimens. The combination regimen of FAV plus IFN provided the greatest extent of viral inhibition without cytotoxicity, reducing viral burden by 4.4-log₁₀ plaque forming units/ml at concentrations of 250 μM FAV with 100 IU/ml IFN. Importantly, these concentrations are achievable in man. The translational, mechanism-based model yielded unbiased and reasonably precise curve fits. Simulations with the model predicted that clinically relevant regimens of FAV plus IFN would markedly reduce viral burden in man, resulting in at least a 10,000-fold reduction in virus during the first four days of treatment. These findings highlight the substantial promise of rationally optimized FAV plus IFN combination dosage regimens which should be further investigated to combat ZIKV.

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Validation of putative apicoplast targeting drugs using a chemical supplementation assay in cultured human malaria parasites [PublishAheadOfPrint]

Malaria parasites contain a relict plastid, the apicoplast, which is considered an excellent drug target due to its bacterial-like ancestry. Numerous parasiticidals have been proposed to target the apicoplast, but few have had their actual targets substantiated. Isopentenyl pyrophosphate (IPP) production is the sole required function of the apicoplast in the blood stage of the parasite life cycle, and IPP supplementation rescues parasites from apicoplast perturbing drugs. Hence, any drug that kills parasites when IPP is supplied in culture must have a non-apicoplast target. Here we use IPP supplementation to discriminate whether 23 purported apicoplast targeting drugs are on or off-target. We demonstrate that a prokaryotic DNA replication inhibitor (ciprofloxacin), several prokaryotic translation inhibitors (chloramphenicol, doxycycline, tetracycline, clindamycin, azithromycin, erythromycin, clarithromycin), a tRNA synthase inhibitor (mupirocine), and two IPP synthesis pathway inhibitors (fosmidomycin or FR900098) have apicoplast targets. Intriguingly, the latter two drugs leave the apicoplast intact, whereas the others eventually result in apicoplast loss. Actinonin, an inhibitor of bacterial post-translation modification does not produce a typical delayed-death response but is rescued with IPP, thereby confirming its apicoplast target. Parasites treated with putative apicoplast fatty acid pathway inhibitors could not be rescued, demonstrating that these drugs have their primary targets outside the apicoplast, which agrees with dispensability of the apicoplast fatty acid synthesis pathways in the blood stage of malaria parasites. IPP supplementation provides a simple test of whether a compound has a target in the apicoplast and can be used to screen novel compounds for mode of action.

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Acinetobacter pittii from companion animals co-harbouring blaOXA-58, the tet39 region and other resistance genes on a single plasmid [PublishAheadOfPrint]

Besides Acinetobacter baumannii, A. pittii is an important nosocomial pathogen (1, 2)....

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Cloning and Expression of Novel Aminoglycoside Phosphotransferase Genes from Campylobacter and Their Role in the Resistance to Six Aminoglycosides [PublishAheadOfPrint]

Nine aph genes, including aph(2'')-Ib, Ic, Ig, If, If1, If3, Ih, aac(6')-Ie/aph(2'')-Ia, and aac(6')-Ie/aph(2'')-If2 were previously identified in Campylobacter. To measure the contribution of these alleles to aminoglycoside resistance, we cloned nine genes into the pBluescript and expressed them in E. coli DH5α. The nine aph expressed in E.coli showed varying levels of resistance to gentamicin, kanamycin and tobramycin. Three genes, aac(6'')-Ie/aph(2'')-Ia, aph2''-If1 and aph2''-Ig showed increased MICs to amikacin and five aph genes were transferrable.

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Environmental triazole induces cross-resistance to clinical drugs and affects morphophysiology and virulence of Cryptococcus gattii and C. neoformans [PublishAheadOfPrint]

Cryptococcus gattii and Cryptococcus neoformans are environmental fungi that cause cryptococcosis, which is usually treated with amphotericin B and fluconazole. However, therapeutic failure is increasing because of the emergence of resistant strains. Because these species are constantly isolated from vegetal materials and the usage of agrochemicals is growing, we postulate pesticides could be responsible for the altered susceptibility of these fungi to clinical drugs. Therefore, we evaluated the influence of the pesticide tebuconazole on the susceptibility to clinical drugs, morphophysiology, and virulence of C. gattii and C. neoformans strains. The results showed that tebuconazole exposure caused in vitro cross-resistance (CR) between the agrochemical and clinical azoles (fluconazole, itraconazole, ravuconazole), but not with amphotericin B. In some strains, CR was observed even after the exposure ceased. Further, tebuconazole exposure changed the morphology, including pseudohyphae formation in C. neoformans H99, and surface charge of the cells. Although the virulence of both species previously exposed to tebuconazole was decreased in mice, the tebuconazole-exposed colonies recovered from the lungs were more resistant to azole drugs than non-exposed cells. This in vivo CR was confirmed when fluconazole was not able to reduce the fungal burden in the lungs of mice. The tolerance to azoles could be due the increased of expression of the ERG11 in both species, and efflux pumps (AFR1 and MDR1) in C. neoformans. Our study supports the idea that agrochemical usage can significantly affect human pathogens present in the environment by affecting their resistance to clinical drugs.

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RISK FACTORS AND OUTCOMES FOR INEFFECTIVE EMPIRIC TREATMENT IN GRAM-NEGATIVE SEPSIS: STRATIFICATION BY ONSET OF INFECTION [PublishAheadOfPrint]

Sepsis and septic shock remain serious infections with reported mortality rates in excess of forty percent. Timely antibiotic therapy in sepsis and septic shock is recognized as an important determinant of outcome. However, the administration of ineffective empiric treatment (IET) (an initial antibiotic regimen that is not active against the identified pathogen(s) based on in vitro susceptibility testing) is associated with excess mortality compared to effective empiric treatment (EET). We examined all hospitalized patients between January 2010 and October 2015 at Barnes-Jewish Hospital with the presence of a sterile site (blood, or pleural, abdominal, cerebrospinal, synovial, and pericardial fluid) culture positive for Gram-negative (GN) bacteria combined with primary or secondary ICD-9-CM codes for severe sepsis (995.92) or septic shock (785.52). Variables significantly associated with early-onset (< 48 hours of hospitalization) IET of GN sterile site sepsis and septic shock included age, recent hospitalization and prior intravenous antibiotics. Late-onset IET was associated with increasing hospitalization days before infection onset and prior intravenous antibiotic administration. For patients with early-onset infection we found no difference in survival between patients receiving IET and EET. However, patients receiving IET in the late-onset infection group had a statistically lower survival compared to those receiving EET. These data suggest that risk factors and outcomes for IET can vary based on the onset of infection. Our results also highlight the importance of prior intravenous antibiotic exposure as a risk factor for IET in GN bacterial infections regardless of the onset on infection.

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Evaluation of Oritavancin Dosing Strategies against Vancomycin-Resistant Enterococcus faecium Isolates with or without Reduced Susceptibility to Daptomycin in an in vitro Pharmacokinetic/Pharmacodynamic Model. [PublishAheadOfPrint]

Clinical development of nonsusceptibility to the lipopeptide antibiotic daptomycin remains a serious concern during therapy for infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The long-acting lipoglycopeptide oritavancin exhibits potent in vitro activity against VREfm although its safety and efficacy in treating clinical VREfm infections have not been established. In this study, novel dosing regimens of daptomycin and oritavancin were assessed against both VREfm and daptomycin-nonsusceptible VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model.

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Overtreatment of Asymptomatic Candiduria among Hospitalized Patients: A Multi-institutional Study [PublishAheadOfPrint]

Candiduria is common in hospitalized patients and asymptomatic candiduria contributes to antifungal overuse. Guidelines for asymptomatic candiduria do not recommend antifungal use, rather the elimination of predisposing factors. It is unknown whether these recommendations are being followed. The primary objective of this study was to characterize candiduria management among hospitalized patients. This was a retrospective cohort study of a random sample of 305 hospitalized patients with candiduria at four U.S. medical centers from January 2010 to December 2013. Patients were classified as asymptomatic or symptomatic based on established criteria and data were collected by chart review. IDSA treatment guideline adherence and its association with clinical outcomes including candiduria recurrence (short- and long-term) and 30-day readmission were assessed. Eighty percent of patients were classified asymptomatic candiduria. Overall, 143 (47%) patients were not managed according to guidelines including 105/243 (43%) in the asymptomatic candiduria group and 38/62 (61%) in the symptomatic group (p=0.01). Discordance among asymptomatic patients was driven by overtreatment with an antifungal (98/105, 93%). Thirty-three percent of patients with asymptomatic candiduria not managed according to guidelines were treated for over 7 days, and 5% received over 14 days of therapy. Fluconazole was the most commonly used empiric antifungal among asymptomatic candiduria patients (96%) followed by micafungin (4%). Asymptomatic candiduria patients not managed according to guidelines had a trend toward higher 30-day readmission (35% vs. 26%, p=0.27). Inappropriate management of candiduria among hospitalized patients was high, leading to over-treatment with antifungal therapy.

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Combating multi-drug resistant pathogens with host-directed non-antibiotic therapeutics [PublishAheadOfPrint]

Earlier, we reported that 3 Food and Drug Administration-approved drugs, trifluoperazine (TFP, anti-psychotic), amoxapine (AXPN, anti-depressant), and doxapram (DXP, breathing stimulant), identified from an in vitro murine macrophage cytotoxicity screen, provided 40-60% protection to mice against pneumonic plague when administered at the time of infection for 1-3 days. In this study, the therapeutic potential of these drugs was further evaluated in mice when administered up to 48 h post-infection against pneumonic plague. While efficacy of TFP was somewhat diminished as treatment was delayed to 24 h, protection of mice with AXPN and DXP increased as treatment was progressively delayed to 24 h. At 48 h post infection, these drugs, when administered in combination with levofloxacin, provided significant, up to 100%, protection to animals against pneumonic or bubonic challenge. Likewise, when used in combination with vancomycin, all three drugs provided 80-100% protection from fatal oral Clostridium difficile infection in mice when administered 24 h post infection. Furthermore, AXPN provided 40-60% protection against respiratory infection with Klebsiella pneumoniae when administered at the time of infection or 24 h post infection. Using the same in vitro cytotoxicity assay, we identified additional 76/780 non-antibiotic drugs effective against K. pneumoniae. For Acinetobacter baumannii, 121 non-antibiotic drugs were identified to inhibit bacterial-induced cytotoxicity in murine macrophages. Of these 121 drugs, 13 inhibited macrophage cytotoxicity with two additional multiple-antibiotic resistant strains. Six of these drugs decreased intracellular survival of all three A. baumannii strains in macrophages. These results provided further evidence of the broad applicability and utilization of drug repurposing screening to identify new therapeutics to combat multi-drug resistant pathogens of public health concern.

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Comparative Assessment of Tedizolid Pharmacokinetics and Tissue Penetration Between Diabetic Patients with Wound Infections and Healthy Volunteers via In Vivo Microdialysis [PublishAheadOfPrint]

Herein, we present pharmacokinetic and tissue penetration data for oral tedizolid in hospitalized patients with diabetic foot infections (DFI) compared with healthy volunteers. Participants received oral tedizolid phosphate 200mg every 24 hours for 3 doses to achieve steady-state. A microdialysis catheter was inserted into the subcutaneous tissue near the margin of the wound for patients or into thigh tissue of volunteers. Following the 3^rd dose, 12 blood and 14 dialysate fluid samples were collected over 24 hours to characterize tedizolid concentrations in plasma and interstitial extracellular fluid of soft tissue. Mean ± SD tedizolid pharmacokinetic parameters in plasma for patients compared with volunteers, respectively, were: maximum concentration (C_max) = 1.5 ± 0.5 versus 2.7 ± 1.1 mg/L (p=0.005), time to C_max (T_max) [median (range)] = 5.9 (1.2-8.0) versus 2.5 (2.0-3.0 hours (p=0.003), half-life (t_1/2) = 9.1 ± 3.6 versus 8.9 ± 2.2 hours (p=0.932), and plasma area under the curve for the dosing interval (AUC_p) = 18.5 ± 9.7 versus 28.7 ± 9.6 mg_·h/L (p=0.004). The tissue AUC for the dosing interval was 3.4 ± 1.5 versus 5.2 ± 1.6 mg_·h/L (p=0.075). Tissue penetration, median (range) was 1.1 (0.3 - 1.6) versus 0.8 (0.7-1.0) (p=0.351). Despite lower plasma C_max and delayed T_max values for patients with DFI relative to healthy volunteers, the penetration and exposure into tissue were similar. Based on available pharmacodynamic thresholds for tedizolid, the plasma and tissue exposures using the oral 200mg once-daily regimen are suitable for further study in treatment of DFI.

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Activity of Meropenem-Vaborbactam in Mouse Models of Infection due to KPC-producing Carbapenem-Resistant Enterobacteriaceae (CRE) [PublishAheadOfPrint]

Meropenem-vaborbactam (Vabomere™) is highly active against Gram-negative pathogens, especially KPC-producing, carbapenem-resistant Enterobacteriaceae. The objective of these studies was to evaluate the efficacy of meropenem alone and in combination with vaborbactam in mouse thigh and lung infection models. Thighs or lungs of neutropenic mice were infected with KPC-producing carbapenem-resistant Enterobacteriaceae with meropenem MICs ranging from ≤ 0.06 – 8 mg/L in the presence of vaborbactam 8 mg/L. Mice were treated with meropenem alone or meropenem in combination with vaborbactam every 2 hours for 24 hours to provide exposures comparable to 2 g doses of each component in humans. Meropenem administered in combination with vaborbactam produced bacterial killing in all strains tested while treatment with meropenem alone either produced less than 0.5 log CFU/tissue of bacterial killing or none at all. In the thigh model, eleven strains were treated with the combination of meropenem plus vaborbactam (300 + 50 mg/kg). This combination produced between 0.8 to 2.89 logs of bacterial killing compared to untreated controls at the start of treatment. In the lung infection model, two strains were treated with the same dosage regimen of meropenem and vaborbactam. The combination produced more than 1.83 logs of bacterial killing against both strains tested compared to untreated controls at the start of treatment. Overall, these data suggest that meropenem-vaborbactam may have utility in the treatment of infections due to KPC-producing, carbapenem-resistant Enterobacteriaceae.

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Metabolic Mitigation of Staphylococcus aureus Vancomycin Intermediate-Level Susceptibility [PublishAheadOfPrint]

Staphylococcus aureus is a major human pathogen whose infections are increasingly difficult to treat due to increased antibiotic resistance, including resistance to vancomycin. Vancomycin intermediate-level susceptibility S. aureus (VISA) strains develop resistance to vancomycin through adaptive changes that are incompletely understood. Central to this adaptation are metabolic changes that permit growth in the presence of vancomycin. To define the metabolic changes associated with adaptive resistance to vancomycin in S. aureus, the metabolomes of a vancomycin sensitive and VISA strain pair isolated from the same patient shortly after vancomycin therapy began and following vancomycin treatment failure were analyzed. The metabolic adaptations included increased acetogenesis, carbon flow through the pentose phosphate pathway, wall teichoic acid and peptidoglycan precursor biosynthesis, and purine biosynthesis and decreased tricarboxylic acid (TCA) cycle activity. The significance of these metabolic pathways for vancomycin intermediate susceptibility was determined by assessing the synergist potential of human-use approved inhibitors of these pathways in combination with vancomycin against VISA strains. Importantly, inhibitors of amino sugar and purine biosynthesis acted synergistically with vancomycin to kill a diverse set of VISA strains, suggesting that combinatorial therapy could augment the efficacy of vancomycin even in patients infected with VISA strains.

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Circling Back for the Diagnosis

Foreword. In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors' commentary follows. Stage. A 28-year-old man presented to the…

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Case 33-2017: 22-Month-Old Conjoined Twins

Presentation of Case. Dr. Allan M. Goldstein: A pediatric surgeon at this hospital was contacted by a nonprofit organization to evaluate the possibility of surgical separation of conjoined twin girls. The twins were born by spontaneous vaginal delivery in East Africa. Because of the anticipated…

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Control of innate-like B cell location for compartmentalised IgM production

Lucy H Jackson-Jones | Cécile Bénézech

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Heme and hemolysis in innate immunity: adding insult to injury

Rui Martins | Sylvia Knapp

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Transcanal endoscopic ear surgery for perilymphatic fistula after electric acoustic stimulation

Transcanal endoscopic ear surgery (TEES) will become a very useful therapeutic option. A perilymphatic fistula (PLF) is defined as sudden sensorineural hearing loss and/or vertigo caused by leakage of the perilymph through a fistula from the oval window and/or round window. We report a case of PLF after electric acoustic stimulation (EAS), a kind of cochlear implant, successfully treated by TEES. A 38-year-old man presented to our hospital with vertigo and hearing loss (HL). His vertigo was induced by Valsalva maneuvers.

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Pneumomediastinum following a prolonged second stage of labor – an emphasis on early diagnosis and conservative management: a case report

Esophageal rupture is an extremely rare condition to occur to a pregnant or postnatal woman. Esophageal ruptures have been previously described in the literature; however, they are most common in the setting o...

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T Cell-Derived CD70 Delivers an Immune Checkpoint Function in Inflammatory T Cell Responses [TRANSPLANTATION]

The CD27–CD70 pathway is known to provide a costimulatory signal, with CD70 expressed on APCs and CD27 functions on T cells. Although CD70 is also expressed on activated T cells, it remains unclear how T cell–derived CD70 affects T cell function. Therefore, we have assessed the role of T cell–derived CD70 using adoptive-transfer models, including autoimmune inflammatory bowel disease and allogeneic graft-versus-host disease. Surprisingly, compared with wild-type T cells, CD70^–/– T cells caused more severe inflammatory bowel disease and graft-versus-host disease and produced higher levels of inflammatory cytokines. Mechanistic analyses reveal that IFN- induces CD70 expression in T cells, and CD70 limits T cell expansion via a regulatory T cell–independent mechanism that involves caspase-dependent T cell apoptosis and upregulation of inhibitory immune checkpoint molecules. Notably, T cell–intrinsic CD70 signaling contributes, as least in part, to the inhibitory checkpoint function. Overall, our findings demonstrate for the first time, to our knowledge, that T cell–derived CD70 plays a novel immune checkpoint role in inhibiting inflammatory T cell responses. This study suggests that T cell–derived CD70 performs a critical negative feedback function to downregulate inflammatory T cell responses.

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Long-Lived Innate IL-17-Producing {gamma}/{delta} T Cells Modulate Antimicrobial Epithelial Host Defense in the Colon [MUCOSAL IMMUNOLOGY]

Intestinal IL-17–producing cells, including Th17, / T, and innate lymphoid cells, are differentially distributed along the gastrointestinal tract. In this study, we show that the gut IL-17–producing / T (/ T17) cells develop before birth and persist in the tissue as long-lived cells with minimal turnover. Most colon / T17 cells express, together with V4 and CCR6, the scavenger receptor 2 and are mainly restricted to innate lymphoid follicles in the colon. Colon / T cells in mice that lack conventional dendritic cells 2 produced increased amounts of IL-17 with concomitant heightened epithelial antimicrobial response, such as the C-type lectins Reg3 and Reg3β. In the absence of / T cells or after IL-17 neutralization, this epithelial response was dramatically reduced, underlining the protective role of this unique subpopulation of innate / T17 cells in the colonic mucosa.

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A Specialist Macaque MHC Class I Molecule with HLA-B*27-like Peptide-Binding Characteristics [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

In different macaque species, the MHC A2*05 gene is present in abundance, and its gene products are characterized by low cell-surface expression and a highly conserved peptide-binding cleft. We have characterized the peptide-binding motif of Mamu-A2*05:01, and elucidated the binding capacity for virus-derived peptides. The macaque A2*05 allotype prefers the basic amino acid arginine at the second position of the peptide, and hydrophobic and polar amino acids at the C-terminal end. These preferences are shared with HLA-B*27 and Mamu-B*008, molecules shown to be involved in elite control in human HIV type 1 and macaque SIV infections, respectively. In contrast, however, Mamu-A2*05 preferentially binds 8-mer peptides. Retention in the endoplasmic reticulum seems to be the cause of the lower cell-surface expression. Subsequent peptide-binding studies have illustrated that Mamu-A2*05:01 is able to bind SIV-epitopes known to evoke a strong CD8⁺ T cell response in the context of the Mamu-B*008 allotype in SIV-infected rhesus macaques. Thus, the macaque A2*05 gene encodes a specialized MHC class I molecule, and is most likely transported to the cell surface only when suitable peptides become available.

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Inhibition of IRAK1 Ubiquitination Determines Glucocorticoid Sensitivity for TLR9-Induced Inflammation in Macrophages [INNATE IMMUNITY AND INFLAMMATION]

Inflammatory responses are controlled by signaling mediators that are regulated by various posttranslational modifications. Recently, transcription-independent functions for glucocorticoids (GC) in restraining inflammation have emerged, but the underlying mechanisms are unknown. In this study, we report that GC receptor (GR)–mediated actions of GC acutely suppress TLR9-induced inflammation via inhibition of IL-1R–associated kinase 1 (IRAK1) ubiquitination. β-TrCP–IRAK1 interaction is required for K48-linked ubiquitination of IRAK1 at Lys¹³⁴ and subsequent membrane-to-cytoplasm trafficking of IRAK1 interacting partners TNFR-associated factor 6 and TAK1 that facilitates NF-B and MAPK activation. Upon costimulation of macrophages with GC and TLR9-engaging ligand, GR physically interacts with IRAK1 and interferes with protein–protein interactions between β-TrCP and IRAK1. Ablation of GR in macrophages prevents GC-dependent suppression of β-TrCP–IRAK1 interactions. This GC-mediated suppression of IRAK1 activation is unique to TLR9, as GC treatment impairs TLR9 but not TLR4 ligand–induced K48-linked IRAK1 ubiquitination and trafficking of IRAK1 interacting partners. Furthermore, mutations in IRAK1 at Lys¹³⁴ prevent TLR9 ligand–induced activation of inflammatory signaling mediators and synthesis of proinflammatory cytokines to an extent comparable to GC-mediated inhibition. Collectively, these findings identify a transcription-independent, rapid, and nongenomic GC suppression of TLR9 ligand–mediated IRAK1 ubiquitination as a novel mechanism for restraining acute inflammatory reactions.

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Filamin A Regulates Neutrophil Adhesion, Production of Reactive Oxygen Species, and Neutrophil Extracellular Trap Release [INNATE IMMUNITY AND INFLAMMATION]

Neutrophils are of fundamental importance in the early immune response and use various mechanisms to neutralize invading pathogens. They kill endocytosed pathogens by releasing reactive oxygen species in the phagosome and release neutrophil extracellular traps (NETs) into their surroundings to immobilize and kill invading micro-organisms. Filamin A (FlnA) is an important actin cross-linking protein that is required for cellular processes involving actin rearrangements, such cell migration. It has also been shown to negatively regulate integrin activation and adhesion. However, its role in the regulation of β₂ integrin–dependent adhesion, as well as in other cellular functions in neutrophils, is poorly understood. Using a transgenic mouse model in which FlnA is selectively depleted in myeloid cells, such as neutrophils, we show that FlnA negatively regulates β₂ integrin adhesion to complement component iC3b and ICAM-1 in shear-free, but not shear-flow, conditions. FlnA deletion does not affect phagocytosis of Escherichia coli or Staphylococcus aureus or their intracellular killing. However, FlnA negatively regulates production of reactive oxygen species upon cell activation. Conversely, neutrophil activation through TLR4, as well as through activation by the Gram-negative bacteria E. coli, results in reduced NET production in FlnA-depleted neutrophils. Thus, FlnA is a negative regulator of β₂ integrin–dependent cell adhesion and reactive oxygen species production but is required for NET production in primary murine neutrophils.

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The Structure of the MHC Class I Molecule of Bony Fishes Provides Insights into the Conserved Nature of the Antigen-Presenting System [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

MHC molecules evolved with the descent of jawed fishes some 350–400 million years ago. However, very little is known about the structural features of primitive MHC molecules. To gain insight into these features, we focused on the MHC class I Ctid-UAA of the evolutionarily distant grass carp (Ctenopharyngodon idella). The Ctid-UAA H chain and β2-microglobulin (Ctid-β2m) were refolded in vitro in the presence of peptides from viruses that infect carp. The resulting peptide-Ctid-UAA (p/Ctid-UAA) structures revealed the classical MHC class I topology with structural variations. In comparison with known mammalian and chicken peptide-MHC class I (p/MHC I) complexes, p/Ctid-UAA structure revealed several distinct features. Notably, 1) although the peptide ligand conventionally occupied all six pockets (A–F) of the Ag-binding site, the binding mode of the P3 side chain to pocket D was not observed in other p/MHC I structures; 2) the AB loop between β strands of the α1 domain of p/Ctid-UAA complex comes into contact with Ctid-β2m, an interaction observed only in chicken p/BF2*2101-β2m complex; and 3) the CD loop of the α3 domain, which in mammals forms a contact with CD8, has a unique position in p/Ctid-UAA that does not superimpose with the structures of any known p/MHC I complexes, suggesting that the p/Ctid-UAA to Ctid-CD8 binding mode may be distinct. This demonstration of the structure of a bony fish MHC class I molecule provides a foundation for understanding the evolution of primitive class I molecules, how they present peptide Ags, and how they might control T cell responses.

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Endoplasmic Reticulum Transmembrane Proteins ZDHHC1 and STING Both Act as Direct Adaptors for IRF3 Activation in Teleost [INNATE IMMUNITY AND INFLAMMATION]

IFN regulatory factor (IRF)3 is a central regulator for IFN-β expression in different types of pathogenic infections. Mammals have various pathogenic sensors that are involved in monitoring pathogen intrusions. These sensors can trigger IRF3-mediated antiviral responses through different pathways. Endoplasmic reticulum–associated proteins stimulator of IFN gene (STING) and zinc finger DHHC-type containing 1 (ZDHHC1) are critical mediators of IRF3 activation in response to viral DNA infections. In this study, grass carp STING and ZDHHC1 were found to have some similar molecular features and subcellular localization, and both were upregulated upon stimulation with polyinosinic:polycytidylic acid, B-DNA, or Z-DNA. Based on these results, we suggest that grass carp STING and ZDHHC1 might possess some properties similar to their mammalian counterparts. Overexpression of ZDHHC1 and STING in Ctenopharyngodon idella kidney cells upregulated IFN expression, whereas knockdown of IRF3 inhibited IFN activation. In addition, coimmunoprecipitation and GST pull-down assays demonstrated that STING and ZDHHC1 can interact separately with IRF3 and promote the dimerization and nuclear translocation of IRF3. Furthermore, we also found that small interfering RNA–mediated knockdown of STING could inhibit the expression of IFN and ZDHHC1 in fish cells. Similarly, knockdown of STING resulted in inhibition of the IFN promoter. In contrast, ZDHHC1 knockdown also inhibited IFN expression but had no apparent effect on STING, which indicates that STING is necessary for IFN activation through ZDHHC1. In conclusion, STING and ZDHHC1 in fish can respond to viral DNA or RNA molecules in cytoplasm, as well as activate IRF3 and, eventually, trigger IFN expression.

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ARIH2 Ubiquitinates NLRP3 and Negatively Regulates NLRP3 Inflammasome Activation in Macrophages [INNATE IMMUNITY AND INFLAMMATION]

The nucleotide-binding oligomerization domain–like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a molecular platform that induces caspase-1 activation and subsequent IL-1β maturation, and is implicated in inflammatory diseases; however, little is known about the negative regulation of NLRP3 inflammasome activation. In this article, we identified an E3 ligase, Ariadne homolog 2 (ARIH2), as a posttranslational negative regulator of NLRP3 inflammasome activity in macrophages. ARIH2 interacted with NLRP3 via its NACHT domain (aa 220–575) in the NLRP3 inflammasome complex. In particular, we found that while using mutants of ARIH2 and ubiquitin, the really interesting new gene 2 domain of ARIH2 was required for NLRP3 ubiquitination linked through K48 and K63. Deletion of endogenous ARIH2 using CRISPR/Cas9 genome editing inhibited NLRP3 ubiquitination and promoted NLRP3 inflammasome activation, resulting in apoptosis-associated speck-like protein containing a caspase recruitment domain oligomerization, pro–IL-1β processing, and IL-1β production. Conversely, ARIH2 overexpression promoted NLRP3 ubiquitination and inhibited NLRP3 inflammasome activation. Our findings reveal a novel mechanism of ubiquitination-dependent negative regulation of the NLRP3 inflammasome by ARIH2 and highlight ARIH2 as a potential therapeutic target for inflammatory diseases.

http://ift.tt/2zm9CMN

Lipopolysaccharide Potentiates Insulin-Driven Hypoglycemic Shock [INNATE IMMUNITY AND INFLAMMATION]

Critically ill patients typically present with hyperglycemia. Treatment with conventional insulin therapy (targeting 144–180 mg/dl) improves patient survival; however, intensive insulin therapy (IIT) targeting normal blood glucose levels (81–108 mg/dl) increases the incidence of moderate and severe hypoglycemia, and increases mortality. Septic patients are especially prone to IIT-induced hypoglycemia, but the mechanism remains unknown. Here, we show that codelivery of insulin with otherwise sublethal doses of LPS induced hypoglycemic shock in mice within 1–2 h. LPS impaired clearance of insulin, which amplified insulin receptor signaling. These effects were mediated by caspase-11, TLR4, and complement, each of which trigger eicosanoid production that potentiates insulin signaling. Finally, in an animal model of sepsis, we observed that Salmonella typhimurium–infected mice exhibited simultaneous impaired insulin clearance coexisting with insulin resistance. Our results raise the possibility that septic patients have impaired insulin clearance, which could increase their susceptibility to hypoglycemia during IIT, contraindicating its use.

http://ift.tt/2zm9BIJ

Macrophage-Specific Expression of IL-37 in Hyperlipidemic Mice Attenuates Atherosclerosis [INNATE IMMUNITY AND INFLAMMATION]

Atherosclerosis, the progressive buildup of plaque within arterial blood vessels, can lead to fatal downstream events, such as heart attack or stroke. A key event contributing to the development of atherosclerosis is the infiltration of monocytes and its associated inflammation, as well as the formation of lipid-laden macrophage foam cells within the vessel wall. IL-37 is recognized as an important anti-inflammatory cytokine expressed especially by immune cells. This study was undertaken to elucidate the role of macrophage-expressed IL-37 in reducing the production and effects of proinflammatory cytokines, preventing foam cell formation, and reducing the development of atherosclerosis. Expression of human IL-37 was achieved with a macrophage-specific overexpression system, using the CD68 promoter in mouse primary bone marrow–derived macrophages via retroviral transduction. Macrophage IL-37 expression in vitro resulted in decreased mRNA (e.g., IL-1B, IL-6, and IL-12) and secreted protein production (e.g., IL-6, M-CSF, and ICAM-1) of key inflammatory mediators. IL-37 expression also inhibited macrophage proliferation, apoptosis, and transmigration, as well as reduced lipid uptake, compared with controls in vitro. The in vivo effects of macrophage-expressed IL-37 were investigated through bone marrow transplantation of transduced hematopoietic stem cells into irradiated atherosclerosis-prone Ldlr^–/– mice. After 10 wk on a high-fat/high-cholesterol diet, mice with IL-37–expressing macrophages showed reduced disease pathogenesis, which was demonstrated by significantly less arterial plaque development and systemic inflammation compared with control mice. The athero-protective effect of macrophage-expressed IL-37 has implications for development of future therapies to treat atherosclerosis, as well as other chronic inflammatory diseases.

http://ift.tt/2ybGuqg

Mechanisms of the Innate Defense Regulator Peptide-1002 Anti-Inflammatory Activity in a Sterile Inflammation Mouse Model [INNATE IMMUNITY AND INFLAMMATION]

Innate defense regulator (IDR) peptide-1002 is a synthetic host defense peptide derivative with strong anti-inflammatory properties. Extending previous data, IDR-1002 suppressed in vitro inflammatory responses in RAW 264.7 murine monocyte/macrophage cells challenged with the TLR4 agonist LPS and TLR2 agonists lipoteichoic acid and zymosan. To investigate the anti-inflammatory mechanisms of IDR-1002 in vivo, the PMA-induced mouse ear inflammation model was used. Topical IDR-1002 treatment successfully dampened PMA-induced ear edema, proinflammatory cytokine production, reactive oxygen and nitrogen species release, and neutrophil recruitment in the ears of CD1 mice. Advanced RNA transcriptomic analysis on the mouse ear transcriptome revealed that IDR-1002 reduced sterile inflammation by suppressing the expression of transmembrane G protein–coupled receptors (class A/1 rhodopsin-like), including receptors for chemokines, PGs, histamine, platelet activating factor, and anaphylatoxin. IDR-1002 also dampened the IFN- response and repressed the IFN regulatory factor 8–regulated network that controls central inflammatory pathways. This study demonstrates that IDR-1002 exhibits strong in vitro and in vivo anti-inflammatory activities, informs the underlying anti-inflammatory mechanisms, and reveals its potential as a novel therapeutic for inflammatory diseases.

http://ift.tt/2zm9Fbr

Revisiting the Road Map of Medullary Thymic Epithelial Cell Differentiation [IMMUNE SYSTEM DEVELOPMENT]

The basic two-step terminal differentiation model of the medullary thymic epithelial cell (mTEC) lineage from immature MHC class II (MHCII)^lo to mature MHCII^hi mTECs has recently been extended to include a third stage, namely the post-Aire MHCII^lo subset as identified by lineage-tracing models. However, a suitable surface marker distinguishing the phenotypically overlapping pre- from the post-Aire MHCII^lo stage has been lacking. In this study, we introduce the lectin Tetragonolobus purpureas agglutinin (TPA) as a novel cell surface marker that allows for such delineation. Based on our data, we derived the following sequence of mTEC differentiation: TPA^loMHCII^lo -> TPA^loMHCII^hi -> TPA^hiMHCII^hi -> TPA^hiMHCII^lo. Surprisingly, in the steady-state postnatal thymus TPA^loMHCII^lo pre-Aire rather than terminally differentiated post-Aire TPA^hiMHCII^lo mTECs were marked for apoptosis at an exceptionally high rate of ~70%. Hence, only the minor cycling fraction of the MHCII^lo subset (<20%) potentially qualified as mTEC precursors. FoxN1 expression inversely correlated with the fraction of slow cycling and apoptotic cells within the four TPA subsets. TPA also further subdivided human mTECs, although with different subset distribution. Our revised road map emphazises close parallels of terminal mTEC development with that of skin, undergoing an alternative route of cell death, namely cornification rather than apoptosis. The high rate of apoptosis in pre-Aire MHCII^lo mTECs points to a "quality control" step during early mTEC differentiation.

http://ift.tt/2zmAM64

The NF-{kappa}B-Responsive Long Noncoding RNA FIRRE Regulates Posttranscriptional Regulation of Inflammatory Gene Expression through Interacting with hnRNPU [INNATE IMMUNITY AND INFLAMMATION]

Long noncoding RNAs, a newly identified class of noncoding RNAs, are important regulators of gene expression in innate immunity. We report in this study that the transcription of FIRRE, a conserved long noncoding RNA between humans and mice, is controlled by NF-B signaling in macrophages and intestinal epithelial cells. Functionally, FIRRE appears to positively regulate the expression of several inflammatory genes in macrophages or intestinal epithelial cells in response to LPS stimulation via posttranscriptional mechanisms. Specifically, FIRRE physically interacts with heterogeneous nuclear ribonucleoproteins U, regulating the stability of mRNAs of selected inflammatory genes through targeting the AU-rich elements of their mRNAs in cells following LPS stimulation. Therefore, our data indicate a new regulatory role for NF-B–responsive FIRRE in the posttranscriptional regulation of inflammatory genes in the innate immune system.

http://ift.tt/2ycuQv5

Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-{kappa}B Signaling following Brain Injury [INNATE IMMUNITY AND INFLAMMATION]

Traumatic and nontraumatic brain injury results from severe disruptions in the cellular microenvironment leading to massive loss of neuronal populations and increased neuroinflammation. The progressive cascade of secondary events, including ischemia, inflammation, excitotoxicity, and free-radical release, contribute to neural tissue damage. NLRX1 is a member of the NLR family of pattern recognition receptors and is a potent negative regulator of several pathways that significantly modulate many of these events. Thus, we hypothesized that NLRX1 limits immune system signaling in the brain following trauma. To evaluate this hypothesis, we used Nlrx1^–/– mice in a controlled cortical impact (CCI) injury murine model of traumatic brain injury (TBI). In this article, we show that Nlrx1^–/– mice exhibited significantly larger brain lesions and increased motor deficits following CCI injury. Mechanistically, our data indicate that the NF-B signaling cascade is significantly upregulated in Nlrx1^–/– animals. This upregulation is associated with increased microglia and macrophage populations in the cortical lesion. Using a mouse neuroblastoma cell line (N2A), we also found that NLRX1 significantly reduced apoptosis under hypoxic conditions. In human patients, we identify 15 NLRs that are significantly dysregulated, including significant downregulation of NLRX1 in brain injury following aneurysm. We further demonstrate a concurrent increase in NF-B signaling that is correlated with aneurysm severity in these human subjects. Together, our data extend the function of NLRX1 beyond its currently characterized role in host–pathogen defense and identify this highly novel NLR as a significant modulator of brain injury progression.

http://ift.tt/2yaGS8w

Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis [IMMUNE SYSTEM DEVELOPMENT]

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates biological responses to endogenous and environmental chemical cues. Increasing evidence shows that the AHR plays physiological roles in regulating development, homeostasis, and function of a variety of cell lineages in the immune system. However, the role of AHR in human B cell development has not been investigated. Toward this end, an in vitro feeder-free human B cell developmental model system was employed using human cord blood CD34⁺ hematopoietic stem/progenitor cells. Using this model, we found that AHR activation by the high-affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin significantly suppressed the generation of early B cells and pro-B cells from hematopoietic stem/progenitor cells, indicating the impairment of B cell lineage specification and commitment. Addition of an AHR antagonist reversed 2,3,7,8-tetrachlorodibenzo-p-dioxin–elicited suppression of early B and pro-B cells, suggesting a role of AHR in regulating B lymphopoiesis. Gene expression analysis revealed a significant decrease in the messenger RNA level of early B cell factor 1 (EBF1) and paired box 5, two critical transcription factors directing B cell lineage specification and commitment. Additionally, binding of the ligand-activated AHR to the putative dioxin response elements in the EBF1 promoter was demonstrated by EMSAs and chromatin immunoprecipitation analysis, suggesting transcriptional regulation of EBF1 by AHR. Taken together, this study demonstrates a role for the AHR in regulating human B cell development, and it suggests that transcriptional alterations of EBF1 by the AHR are involved in the underlying mechanism.

http://ift.tt/2y8GEPd

Maternal High Fiber Diet during Pregnancy and Lactation Influences Regulatory T Cell Differentiation in Offspring in Mice [IMMUNE SYSTEM DEVELOPMENT]

Short-chain fatty acids (SCFAs), the end products of dietary fiber, influence the immune system. Moreover, during pregnancy the maternal microbiome has a great impact on the development of the offspring's immune system. However, the exact mechanisms by which maternal SCFAs during pregnancy and lactation influence the immune system of offspring are not fully understood. We investigated the molecular mechanisms underlying regulatory T cell (T_reg) differentiation in offspring regulated by a maternal high fiber diet (HFD). Plasma levels of SCFAs in offspring from HFD-fed mice were higher than in those from no fiber diet–fed mice. Consequently, the offspring from HFD-fed mice had higher frequencies of thymic T_reg (tT_reg) and peripheral T_regs. We found that the offspring of HFD-fed mice exhibited higher autoimmune regulator (Aire) expression, a transcription factor expressed in the thymic microenvironment, suggesting SCFAs promote tT_reg differentiation through increased Aire expression. Notably, the receptor for butyrate, G protein–coupled receptor 41 (GPR41), is highly expressed in the thymic microenvironment and Aire expression is not increased by stimulation with butyrate in GPR41-deficient mice. Our studies highlight the significance of SCFAs produced by a maternal HFD for T_reg differentiation in the thymus of offspring. Given that Aire expression is associated with the induction of tT_regs, the maternal microbiome influences T_reg differentiation in the thymus of offspring through GPR41-mediated Aire expression.

http://ift.tt/2zmAJqU

Rab27-Dependent Exosome Production Inhibits Chronic Inflammation and Enables Acute Responses to Inflammatory Stimuli [INNATE IMMUNITY AND INFLAMMATION]

Extracellular vesicles, including exosomes, have recently been implicated as novel mediators of immune cell communication in mammals. However, roles for endogenously produced exosomes in regulating immune cell functions in vivo are just beginning to be identified. In this article, we demonstrate that Rab27a and Rab27b double-knockout (Rab27DKO) mice that are deficient in exosome secretion have a chronic, low-grade inflammatory phenotype characterized by elevated inflammatory cytokines and myeloproliferation. Upon further investigation, we found that some of these phenotypes could be complemented by wild-type (WT) hematopoietic cells or administration of exosomes produced by GM-CSF–expanded bone marrow cells. In addition, chronically inflamed Rab27DKO mice had a blunted response to bacterial LPS, resembling endotoxin tolerance. This defect was rescued by bone marrow exosomes from WT, but not miR-155^–/–, cells, suggesting that uptake of miR-155–containing exosomes is important for a proper LPS response. Further, we found that SHIP1 and IRAK-M, direct targets of miR-155 that are known negative regulators of the LPS response, were elevated in Rab27DKO mice and decreased after treatment with WT, but not miR-155^–/–, exosomes. Together, our study finds that Rab27-dependent exosome production contributes to homeostasis within the hematopoietic system and appropriate responsiveness to inflammatory stimuli.

http://ift.tt/2zmWbwd

STAT4 Regulates the CD8+ Regulatory T Cell/T Follicular Helper Cell Axis and Promotes Atherogenesis in Insulin-Resistant Ldlr-/- Mice [IMMUNE REGULATION]

The metabolic syndrome and diabetic conditions support atherosclerosis, but the exact mechanisms for accelerated atherogenesis remain unclear. Although the proinflammatory role of STAT4 in atherosclerosis and diet-induced insulin resistance (IR) was recently established, the impact of STAT4 on atherogenesis in conditions of IR is not known. In this study, we generated Stat4^–/–Ldlr^–/– mice that were fed a diabetogenic diet with added cholesterol (DDC). DDC-fed Stat4^–/–Ldlr^–/– mice demonstrated improved glucose tolerance, insulin sensitivity, and a 36% reduction in atherosclerosis compared with Ldlr^–/– controls. Interestingly, we detected a reduction in T follicular helper (Tfh) cells and plasma B cells but a sharp elevation in CD8⁺ regulatory T cells (Tregs) in spleens and aortas of Stat4^–/–Ldlr^–/– mice compared with Ldlr^–/– mice. Similarly, STAT4 deficiency supported CD8⁺ Treg differentiation in vitro. STAT4-deficient CD8⁺ Tregs suppressed Tfh cell and germinal center B cell development upon immunization with keyhole limpet hemocyanin, indicating an important role for STAT4 in CD8⁺ Treg functions in vivo. Furthermore, adoptive transfer of Stat4^–/–Ldlr^–/– CD8⁺ Tregs versus Ldlr^–/– CD8⁺ Tregs resulted in a significant reduction in plaque burden and suppression of Tfh cell and germinal center B cells in DDC-fed Ldlr^–/– recipients. STAT4 expression in macrophages (Ms) also affected the Tfh/CD8⁺ Treg axis, because conditioned media from Stat4^–/–Ldlr^–/– Ms supported CD8⁺ Treg differentiation, but not Tfh cell differentiation, in a TGF-β–dependent manner. These findings suggest a novel mechanism by which STAT4 supports atherosclerosis in IR Ldlr^–/– mice via STAT4-dependent Ms, as well as cell-intrinsic suppression of CD8⁺ Treg generation and functions and maintenance of Tfh cell generation and the accompanying humoral immune response.

http://ift.tt/2yaH3Re

Nonclassical Monocytes Mediate Secondary Injury, Neurocognitive Outcome, and Neutrophil Infiltration after Traumatic Brain Injury [INNATE IMMUNITY AND INFLAMMATION]

Traumatic brain injury (TBI) results in rapid recruitment of leukocytes into the injured brain. Monocytes constitute a significant proportion of the initial infiltrate and have the potential to propagate secondary brain injury or generate an environment of repair and regeneration. Monocytes are a diverse population of cells (classical, intermediate, and nonclassical) with distinct functions, however, the recruitment order of these subpopulations to the injured brain largely remains unknown. Thus, we examined which monocyte subpopulations are required for the generation of early inflammatory infiltrate within the injured brain, and whether their depletion attenuates secondary injury or neurocognitive outcome. Global monocyte depletion correlated with significant improvements in brain edema, motor coordination, and working memory, and abrogated neutrophil infiltration into the injured brain. However, targeted depletion of classical monocytes alone had no effect on neutrophil recruitment to the site of injury, implicating the nonclassical monocyte in this process. In contrast, mice that have markedly reduced numbers of nonclassical monocytes (CX3CR1^–/–) exhibited a significant reduction in neutrophil infiltration into the brain after TBI as compared with control mice. Our data suggest a critical role for nonclassical monocytes in the pathology of TBI in mice, including important clinical outcomes associated with mortality in this injury process.

http://ift.tt/2zm9kpb

Reactive Oxygen Species Regulate the Inflammatory Function of NKT Cells through Promyelocytic Leukemia Zinc Finger [IMMUNE REGULATION]

Reactive oxygen species (ROS) are byproducts of aerobic metabolism and contribute to both physiological and pathological conditions as second messengers. ROS are essential for activation of T cells, but how ROS influence NKT cells is unknown. In the present study, we investigated the role of ROS in NKT cell function. We found that NKT cells, but not CD4 or CD8 T cells, have dramatically high ROS in the spleen and liver of mice but not in the thymus or adipose tissues. Accordingly, ROS-high NKT cells exhibited increased susceptibility and apoptotic cell death with oxidative stress. High ROS in the peripheral NKT cells were primarily produced by NADPH oxidases and not mitochondria. We observed that sorted ROS-high NKT cells were enriched in NKT1 and NKT17 cells, whereas NKT2 cells were dominant in ROS-low cells. Furthermore, treatment of NKT cells with antioxidants led to reduced frequencies of IFN-– and IL-17–expressing cells, indicating that ROS play a role in regulating the inflammatory function of NKT cells. The transcription factor promyelocytic leukemia zinc finger (PLZF) seemed to control the ROS levels. NKT cells from adipose tissues that do not express PLZF and those from PLZF haplodeficient mice have low ROS. Conversely, ROS were highly elevated in CD4 T cells from mice ectopically expressing PLZF. Thus, our findings demonstrate that PLZF controls ROS levels, which in turn governs the inflammatory function of NKT cells.

http://ift.tt/2yaogFE

Practice and Safety of Allergen Specific Immunotherapy for Allergic Rhinitis in the UK National Health Service: A report of ‘real world’ clinical practice

Abstract

Allergen specific immunotherapy (SIT) alleviates symptoms, improves health-related quality of life and alters the natural course of the disease in patients suffering from allergic rhinitis. It is currently delivered in the UK National Health Service (NHS) via 2 modalities namely subcutaneous injection immunotherapy (SCIT) and sublingual immunotherapy (SLIT). The latter has a superior safety profile – anaphylaxis is a rare occurrence. Most vaccines currently employed for SIT in the UK NHS are unlicensed and available on a named-patient basis and prescribed in secondary care by a specialist.

This article is protected by copyright. All rights reserved.

http://ift.tt/2h9cFzL

Axilläre und perimamilläre Fox-Fordyce-Erkrankung (apokrine Miliaria) bei einer 19-jährigen Patientin

Zusammenfassung

Die Fox-Fordyce-Erkrankung (FFD), auch bekannt als apokrine Miliaria, ist eine seltene, chronische Dermatose, die durch hautfarbene bis hellbraune oder gelbliche Papeln und Juckreiz v. a. in Bereichen mit apokrinen Drüsen charakterisiert ist. Typischerweise sind postpubertale Mädchen und Frauen zwischen 13 und 35 Jahren betroffen. Die Ätiologie ist bisher nicht gänzlich geklärt, wobei eine hormonelle Komponente diskutiert wird. Des Weiteren wurden verschiedene Exazerbationsfaktoren beschrieben, unter anderem lasergestützte Epilationen sowie eine Hyperhidrose. Die Behandlung der FFD gestaltet sich als relativ schwierig, die bisher beschriebenen Therapien zeigten unterschiedliche Erfolge.

http://ift.tt/2Amu54a

Dietary and metabolic modulators of hepatic immunity

Abstract

The liver is the central metabolic organ of the organism and is thus constantly exposed to gut-derived dietary and microbial antigens. The liver maintains homoeostatic tolerance to these mostly harmless antigens. However, the liver also functions as a barrier organ to harmful pathogens and is thus permissive to liver inflammation. The regulation of the delicate balance between liver tolerance and liver inflammation is of vital importance for the organism. In recent years, a general role for dietary components and metabolites as immune mediators has been emerging. However, although the liver is exposed to a great deal of metabolic mediators, surprisingly, little is known about their actual role in the regulation of hepatic immune responses. Here, we will explore the possible impacts of metabolic mediators for homoeostatic and pathological immunity in the liver, by highlighting selected examples of metabolic immune regulation in the liver.

http://ift.tt/2AoycwM

The Effect of Visual Contrast on Human Vestibulo-Ocular Reflex Adaptation

Abstract

The vestibulo-ocular reflex (VOR) is the main retinal image stabilising mechanism during rapid head movement. When the VOR does not stabilise the world or target image on the retina, retinal image slip occurs generating an error signal that drives the VOR response to increase or decrease until image slip is minimised, i.e. VOR adaptation occurs. Visual target contrast affects the human smooth pursuit and optokinetic reflex responses. We sought to determine if contrast also affected VOR adaptation. We tested 12 normal subjects, each over 16 separate sessions. For sessions 1–14, the ambient light level (lx) during adaptation training was as follows: dark, 0.1, 0.2, 0.3, 0.5, 0.7, 1, 2, 8, 16, 32, 64, 128 and 255 lx (light level for a typical room). For sessions 15–16, the laser target power (related to brightness) was halved with ambient light at 0 and 0.1 lx. The adaptation training lasted 15 min and consisted of left/right active head impulses. The VOR gain was challenged to increment, starting at unity, by 0.1 every 90 s for rotations to the designated adapting side and fixed at unity towards the non-adapting side. We measured active and passive VOR gains before and after adaptation training. We found that for both the active and passive VOR, there was a significant increase in gain only towards the adapting side due to training at contrast level 1.5 k and above (2 lx and below). At contrast level 261 and below (16 lx and above), adaptation training resulted in no difference between adapting and non-adapting side gains. Our modelling suggests that a contrast threshold of ~ 1000, which is 60 times higher than that provided by typical room lighting, must be surpassed for robust active and passive VOR adaptation. Our findings suggest contrast is an important factor for adaptation, which has implication for rehabilitation programs.

http://ift.tt/2j3BbX5

The Effect of Visual Contrast on Human Vestibulo-Ocular Reflex Adaptation

Abstract

The vestibulo-ocular reflex (VOR) is the main retinal image stabilising mechanism during rapid head movement. When the VOR does not stabilise the world or target image on the retina, retinal image slip occurs generating an error signal that drives the VOR response to increase or decrease until image slip is minimised, i.e. VOR adaptation occurs. Visual target contrast affects the human smooth pursuit and optokinetic reflex responses. We sought to determine if contrast also affected VOR adaptation. We tested 12 normal subjects, each over 16 separate sessions. For sessions 1–14, the ambient light level (lx) during adaptation training was as follows: dark, 0.1, 0.2, 0.3, 0.5, 0.7, 1, 2, 8, 16, 32, 64, 128 and 255 lx (light level for a typical room). For sessions 15–16, the laser target power (related to brightness) was halved with ambient light at 0 and 0.1 lx. The adaptation training lasted 15 min and consisted of left/right active head impulses. The VOR gain was challenged to increment, starting at unity, by 0.1 every 90 s for rotations to the designated adapting side and fixed at unity towards the non-adapting side. We measured active and passive VOR gains before and after adaptation training. We found that for both the active and passive VOR, there was a significant increase in gain only towards the adapting side due to training at contrast level 1.5 k and above (2 lx and below). At contrast level 261 and below (16 lx and above), adaptation training resulted in no difference between adapting and non-adapting side gains. Our modelling suggests that a contrast threshold of ~ 1000, which is 60 times higher than that provided by typical room lighting, must be surpassed for robust active and passive VOR adaptation. Our findings suggest contrast is an important factor for adaptation, which has implication for rehabilitation programs.

http://ift.tt/2j3BbX5

Acne inversa/Hidradenitis suppurativa: Eine Herausforderung für die Zukunft

Zusammenfassung

Acne inversa (AI) ist eine chronisch rezidivierende, entzündliche Dermatose mit dem Charakter einer Systemerkrankung. AI ist durch typische Hautveränderungen in Körperarealen mit apokrinen Drüsen gekennzeichnet. Die Versorgung der AI-Patienten ist in Deutschland nach wie vor unzureichend. Diese Situation lässt sich durch folgende Anstrengungen wahrscheinlich maßgeblich verbessern: 1) die Verkürzung der Zeitspanne zwischen der ersten Manifestation der Erkrankung und Diagnosestellung/Beginn der Therapie; 2) die fundierte Erforschung der AI-Pathogenese mit dem Ziel der Identifizierung von Therapietargets und Blutbiomarkern; 3) die Etablierung einer Methode zur Quantifizierung des Schweregrads der Erkrankung, die sowohl die klinische Beurteilung als auch objektive Laborparameter und die Selbsteinschätzung des Patienten (z. B. Dermatology Life Quality Index [DLQI]) berücksichtigt; 4) die Erarbeitung eines klaren Algorithmus für die interdisziplinäre Behandlung der Patienten, die neben der Therapie der Hautläsionen auch lebensstiländernde Maßnahmen einschließt und die systemischen Veränderungen bei AI berücksichtigt. Dieser Beitrag beschreibt die aktuellen Probleme der medizinischen Versorgung der AI-Patienten und zeichnet Wege auf, wie wir die beschriebenen Ziele erreichen können.

http://ift.tt/2yB8iJ2

A multicenter study of malignant oral and maxillofacial lesions in children and adolescents

Publication date: December 2017
Source:Oral Oncology, Volume 75
Author(s): José Alcides Almeida de Arruda, Leni Verônica de Oliveira Silva, Camila de Nazaré Alves de Oliveira Kato, Lauren Frenzel Schuch, Aline Carvalho Batista, Nádia Lago Costa, Sandra Beatriz Chaves Tarquinio, Elena Riet Correa Rivero, Vinícius Coelho Carrard, Manoela Domingues Martins, Ana Paula Veras Sobral, Ricardo Alves Mesquita
ObjectivesTo investigate the frequency of malignant oral and maxillofacial lesions among children and adolescents from representative geographic regions of Brazil.Materials and MethodsA retrospective study was conducted on biopsies obtained from 1990 to 2016 at six Brazilian oral and maxillofacial pathology referral centers. A total of 85,105 biopsy specimens from children and adolescents were analyzed. Gender, age, anatomical location, symptomatology and histopathological diagnosis were evaluated. Data were analyzed using descriptive statistical methods.ResultsFifty-eight (0.06%) malignant oral and maxillofacial lesions were diagnosed in children (19%) and adolescents (81%). The lesions were more frequent among females (60.3%) and adolescents. The most prevalent lesions were mucoepidermoid carcinomas (22.4%), osteosarcomas (13.8%), squamous cell carcinomas (12.1%), and Burkitt's lymphomas (12.1%). The most commonly affected sites were the palate (19%), mandible (13.8%), and maxilla (13.8%). Almost half the patients were asymptomatic.ConclusionPediatric oral and maxillofacial malignant lesions were infrequent and showed wide diversity, with a prevalence of mucoepidermoid carcinomas. Analysis of malignant lesions in children and adolescents helps pediatric dentists and oncologists to obtain a better understanding of such lesions and to reduce the time for diagnosis, with a consequent improvement of prognosis.



http://ift.tt/2zhweQZ

Results of a phase II randomized controlled clinical trial comparing efficacy of Cabazitaxel versus Docetaxel as second line or above therapy in recurrent head and neck cancer

Publication date: December 2017
Source:Oral Oncology, Volume 75
Author(s): Amit Joshi, Vijay Patil, Vanita Noronha, Sachin Dhumal, Nikhil Pande, Arun Chandrasekharan, Siddharth Turkar, Hollis DSouza, Sameer Shrirangwar, Abhishek Mahajan, Supreeta Arya, Shashikant Juvekar, Atanu BhattaCharjee, Kumar Prabhash
BackgroundCabazitaxel has shown activity in squamous cancer cell lines and in taxane resistant cell lines. Hence we planned a phase 2 study to evaluate the efficacy of cabazitaxel against Docetaxel in recurrent head and neck cancer, post first line treatment.MethodsThis was a phase 2, investigator initiated, randomized controlled trial of Docetaxel (75 mg/m²) versus Cabazitaxel (20 mg/m²), in patients with head and neck cancer with ECOG performance status 0–2 who have been exposed to at least one line of chemotherapy, involving a sample size of 92 (46 per group)(CTRI/2015/06/005848). Disease control rate at 6 weeks was assessed and compared using the chi-square test.ResultsThe disease control rate at 6 weeks was better in the Docetaxel arm over the cabazitaxel arm (52.3% versus 13.6%, p = 0.017). The median progression free survival was 21 days (95% CI 5.28 to 36.72 days) in the cabazitaxel arm versus 61 days (95% CI 21.39 to 100.60 days) in the Docetaxel arm (HR-1.455, 95% CI 0.919–2.304, p = 0.100). The median overall survival was 115 days (95% CI 74.04 to 155.95 days) in the cabazitaxel arm versus 155 days (95% CI 148.6 to 161.40 days) in the Docetaxel arm (HR-1.464, 95% CI 0.849–2.523, p = 0.170).ConclusionDocetaxel had a superior disease control rate at 6 weeks compared to cabazitaxel.



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Evaluation of the diagnostic efficacy and spectrum of autofluorescence of benign, dysplastic and malignant lesions of the oral cavity using VELscope

Publication date: December 2017
Source:Oral Oncology, Volume 75
Author(s): Ravikant S. Ganga, Dipali Gundre, Shivani Bansal, Pankaj M. Shirsat, Pooja Prasad, Rajiv S. Desai
ObjectivesConventional oral examination and biopsy are the only reliable methods for the early detection of oral cancer at present. Autofluorescence examination of oral tissues using the VELscope has been suggested as an adjunctive tool for cancer detection and diagnosis. The aim of our study was to evaluate the efficacy of the VELscope in recognizing dysplastic and/or neoplastic changes in oral mucosal lesions that were identified on conventional oral examination.Materials and methodsTwo hundred patients with oral mucosal lesions were subjected to conventional oral examination followed by VELscope examination and their autofluorescence characteristics were compared with the histopathological diagnosis. The sensitivity, specificity, positive and negative predictive values of the VELscope examination was calculated.ResultsThe VELscope examination showed sensitivity and specificity values of 76% (95% CI: 54.87–90.64%) and 66.29% (95% CI: 58.76–73.24%) respectively while the positive and negative predictive values were 24.36% (95% CI: 19.22–30.36%) and 95.08% (95% CI: 90.52–97.51%) respectively.ConclusionThe VELscope examination alone cannot provide a definitive diagnosis as to the presence of dysplastic tissue change. In spite of having a reasonable sensitivity, the high number of false-positive results limits its efficiency as an adjunct. However, a high negative predictive value can serve to alleviate patient anxiety regarding suspicious mucosal lesions in a general practice setting.



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Humidification mitigates acute mucosal toxicity during radiotherapy when factoring volumetric parameters. Trans Tasman Radiation Oncology Group (TROG) RadioHUM 07.03 substudy

Publication date: December 2017
Source:Oral Oncology, Volume 75
Author(s): A. Macann, F. Fauzi, J. Simpson, G. Sasso, H. Krawitz, C. Fraser-Browne, J. Manitz, A. Raith
Purpose/Objective(s)To model in a subset of patients from TROG 07.03 managed at a single site the association between domiciliary based humidification use and mucositis symptom burden during radiotherapy (RT) for head and neck cancer (HNC) when factoring in volumetric radiotherapy parameters derived from tumour and normal tissue regions of interest.Materials/MethodsFrom June 2008 through June 2011, 210 patients with HNC receiving RT were randomised to either a control arm or humidification using the Fisher & Paykel Healthcare MR880 humidifier. This subset analysis involves patients recruited from Auckland City Hospital treated with a prescribed dose of ≥70 Gy. Regression models included control variables for Planning Target Volume 70 GY (PTV70Gy); Equivalent Uniform Dose (EUD) MOIST and TSV (surrogates of total mucosal and total swallowing volumes respectively).ResultsThe analysis included 39 patients (humidification 20, control 19). There was a significant odds reduction in CTCAE v3.0 functional mucositis score of 0.29 associated with the use of humidification (p<.001). Within the parameters of the model therefore, the risk of a humidification patient being scored as experiencing a one-step increase in functional mucositis was 3.45 times lower (1/0.29) than for control patients. A control patient was 4.17 times more likely to receive an unfavourable nutritional mode score (p<.001). The risk of being admitted to hospital decreased by a factor of 11.11 for humidification patients (p=.013).ConclusionThe results support the hypothesis that humidification can help mitigate mucositis symptom burden. Radiotherapy dosimetric parameters assist in the evaluation of toxicity interventions.



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Plasticity of oral mucosal cell sheets for accelerated and scarless skin wound healing

Publication date: December 2017
Source:Oral Oncology, Volume 75
Author(s): Jong-Lyel Roh, Jaewang Lee, Eun Hye Kim, Daiha Shin
ObjectivesWound healing is generally faster and associated with less scarring in the oral mucosa than in the skin. Although rarely studied, oral mucosa equivalents may contribute to rapid, scarless cutaneous wound healing. Therefore, we examined the potential utility of our newly developed oral mucosal cell sheet in skin wound healing.Materials and methodsOral mucosa and skin samples were obtained from surgical patients and Sprague-Dawley rats. Keratinocytes and fibroblasts were primarily cultured for in vitro cell expansion. Mucosa and skin equivalents were produced with a mixture of cultured fibroblasts and autologous fibrin from plasma and seeding keratinocytes. Mucosal and skin cell sheets were transplanted in full-thickness excisional wounds of rat skin with control wounds. Gross, histological, and molecular characteristics of wound healing according to different postsurgical days were compared in control and cell sheet-covered wounds.ResultsKeratinocytes and fibroblasts derived from the oral mucosa were cultured faster than those derived from the skin. The in vitro-engineered oral mucosa and skin equivalents were successfully produced using complete autologous mucosa or skin and plasma fibrin, showing similarity to the histological characteristics of the skin or mucosa. In the in vivo rat model, the oral mucosal and skin cell sheet promoted wound healing with early wound closure and less scarring. The cell sheet-treated wounds showed lower TGF-β1, α-smooth muscle actin, and fibronectin mRNA expression than the control wounds.ConclusionsThe oral mucosal cell sheet demonstrated in vivo tissue plasticity through good adaptation to skin wounds, contributing to accelerated and scarless healing.
This study examined the potential utility of a newly developed oral mucosal cell sheet in skin excisional wounds. The oral mucosal cell sheet promoted wound healing with early wound closure and less scarring and demonstrated in vivo tissue plasticity through good adaptation in cutaneous wounds.


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Head and neck reconstruction with free flaps based on the thoracodorsal system

Publication date: December 2017
Source:Oral Oncology, Volume 75
Author(s): John Edward O'Connell, Mandeep S Bajwa, Andrew G. Schache, Richard J. Shaw
The advent or micro-vascular free tissue transfer has facilitated the reconstruction of increasingly complex head and neck defects. There are multiple donor sites available, each with its' own advantages and disadvantages. However, the subscapular system, including the thoracodorsal system, provides the widest array of soft tissue and osseous flaps, as well as chimeric options. Its advantages include a long pedicle, independently mobile tissue components, relative sparing from atherosclerosis, and minimal donor site morbidity. The soft tissue flaps available from the thoracodorsal system include the Latissimus Dorsi, and Thoracodorsal Artery Perforator flaps, while the Tip of Scapula provides the osseous component. This review paper outlines the anatomical basis for these flaps, as well as describing their utility in head and neck reconstruction.



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Head and neck free flap reconstruction: What is the appropriate post-operative level of care?

Publication date: December 2017
Source:Oral Oncology, Volume 75
Author(s): Varun V. Varadarajan, Hassan Arshad, Peter T. Dziegielewski
Patients undergoing head and neck reconstruction require complex, multidisciplinary postoperative care which may include wound care, flap monitoring, tracheostomy management, and management of comorbid conditions. Historically, patients undergoing major resection of a head and neck or aerodigestive tract malignancy with regional or free flap reconstruction were routinely admitted to the ICU. Although head and neck cancer patients may have multiple medical comorbidities that may require postoperative critical care, the current trend in many institutions is to transfer stable and less medically complex patients to non-intensive care-level units with specialty trained nursing staff. These units have been shown to decrease the total cost of care without compromising the quality of care, length of stay, or postoperative complications.



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Assessing the role of immune system in cancer progression from minimal residual disease

Publication date: Available online 6 November 2017
Source:Oral Oncology
Author(s): A. Thirumal Raj, Shankargouda Patil, Chandini Rajkumar, Sachin Sarode




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The effects of storage time and temperature on the stability of salivary phosphatases, transaminases and dehydrogenase

Publication date: January 2018
Source:Archives of Oral Biology, Volume 85
Author(s): Damaris Raissa dos Santos, Rayne Oliveira Souza, Layani Bertaglia Dias, Tayná Buffulin Ribas, Luis Cezar Farias de Oliveira, Doris Hissako Sumida, Rita Cássia Menegati Dornelles, Ana Cláudia de Melo Stevanato Nakamune, Antonio Hernandes Chaves-Neto
ObjectivesTo investigate the influence of temperature and storage time on salivary acid phosphatase (ACP), tartrate-resistant acid phosphatase (TRAP), alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and lactate dehydrogenase (LDH).DesignUnstimulated whole expectorated saliva was collected from healthy men and women subjects (n=26) between 8 and 10a.m. The saliva samples were centrifuged, and the supernatants were measured for ACP, TRAP, ALP, AST, ALT and LDH activities immediately (without freezing) [baseline values] and after time intervals of 3, 7, 14 and 28days (d) of storage at −20°C and −80°C using spectrophotometric methods The influence of storage time was analyzed by one-way ANOVA followed by the Dunnett post-test, while the paired Student's-t-test was used to compare the differences between the temperature (p<0.05).ResultsThere was significant decline in the activities of all enzymes at −20°C with increasing storage time. This decrease was relevant from day 14 onward for the majority of the enzymes, with the exception of AST. After day 28, the more sensitive enzymes were ALP and LDH, which showed residual activity of 39% and 16%, respectively, compared with baseline values. There were considerable, but insignificant changes, in the activities of all enzymes after storage at −80°C for 28days.ConclusionsFrozen samples should be kept at −80°C to preserve these activities, but there are restrictions for the enzymes ALP, ALT and LDH. Storage of samples at −20°C could introduce high error variance in measured activities.



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Effectiveness of three age estimation methods based on dental and skeletal development in a sample of young Brazilians

Publication date: January 2018
Source:Archives of Oral Biology, Volume 85
Author(s): Marcelo Afonso Machado, Eduardo Daruge Júnior, Mário Marques Fernandes, Igor Felipe Pereira Lima, Graziela Oro Cericato, Ademir Franco, Luiz Renato Paranhos
ObjectiveThis study compared three methods designed for age estimation.MethodsA sample of 468 radiographs (234 panoramic and 234 carpal radiographs) collected from patients ranging from 5 to 14 years old (mean age: 11.27years old±2.27years) was used. Three age estimation methods: were applied: one founded on dental development, one founded on hand and wrist development, and a method combining both measurements. For each method, the mean error (ME), mean absolute error (MAE), root mean square error (RMSE), and mean percentage of absolute error (MPAE) were quantified. The methods: were compared based on their effectiveness for estimating age in relation to sex and age range.ResultsThe data show that the method exclusively using the development of the hand and wrist had the highest error rates (ME: 1.28M, 1.85F; MAE: 1.64M, 1.96F; RMSE: 1.94M, 2.32F) for both males (M) and females (F). In males, the method combining dental and skeletal development obtained outcomes that were slightly better than the method founded on only dental development (MPAE: 6.99% and 7.47%, respectively). In females, the opposite result was observed (MPAE: 8.48% and 6.59%, respectively). The method founded exclusively on skeletal development significantly overestimated (p=0.001) the age (mean chronological and estimated ages: 11.27 and 12.88, respectively).ConclusionThe methods involving dental development provided more accurate age estimates of chronological age. The method exclusively based on hand and wrist development resulted in outcomes that were highly discrepant from the chronological age.



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L-mimosine and hypoxia enhance angiopoietin-like 4 production involving hypoxia-inducible factor-1alpha: Insights from monolayer and spheroid cultures of dental pulp-derived cells and tooth slice cultures

Publication date: January 2018
Source:Archives of Oral Biology, Volume 85
Author(s): Klara Janjić, Umar Alhujazy, Andreas Moritz, Hermann Agis
ObjectiveAngiopoietin-like 4 (Angptl4) is an angiogenesis modulating signaling factor and as such involved in blood vessel formation but also in hard tissue resorption. Here we hypothesized that the hypoxia mimetic agent L-mimosine (L-MIM) and hypoxia stimulate the production of Angptl4 in the dental pulp.Material and methodsMonolayer and spheroid cultures of primary human dental pulp-derived cells (DPC) were treated with L-MIM or hypoxia. Furthermore, tooth slice cultures were performed. The production of Angptl4 was assessed at mRNA and protein levels using reverse transcription qPCR and immunoassays, respectively. To assess the involvement of hypoxia inducible factor (HIF)-1α (HIF-1signaling, inhibitor studies with echinomycin and Western Blot analysis for HIF-1α were performed in DPC monolayer cultures.(HIF-1ResultsL-MIM and hypoxia increased production of Angptl4 at mRNA and protein levels in monolayer cultures of DPC. The increase of Angptl4 was paralleled by an increase of HIF-1α and inhibited by echinomycin. Angptl4 protein levels were also elevated in spheroid cultures. In tooth slice cultures, the pulp tissue expressed and released Angptl4 under normoxic and hypoxic conditions and in the presence of L-MIM. There was a trend for an increase in Angptl4 mRNA levels and a trend for a decrease in the protein levels of the supernatants.ConclusionsOur results suggest that the hypoxia mimetic agent L-MIM and hypoxia can increase Angptl4 production in DPC involving HIF-1α. However, the increase in the cell culture supernatants does not translate in an increased release in tooth slice organ cultures.



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Evaluation of the bisphosphonate effect on stem cells derived from jaw bone and long bone rabbit models: A pilot study

Publication date: January 2018
Source:Archives of Oral Biology, Volume 85
Author(s): Jun-Beom Park, Seung-Hyun Cho, InSoo Kim, Won Lee, Seung-Hwan Kang, Heesung Kim
Background and objectiveBisphosphonates have been widely used and the number of patients experiencing medication-related osteonecrosis of the jaw (MRONJ) has been increasing. This study was designed to evaluate the effect of zoledronate on stem cells derived from different tissues.DesignStem cells derived from four different tissues were compared using rabbit models (JPO: periosteum from the jaw bone (mandible), JBM: bone marrow from the jaw bone, LPO: periosteum from long bone (tibia), and LBM: bone marrow from long bone). Stem cells were grown in the presence of zoledronate at final concentrations ranging from 10⁻⁶M to 10⁻¹⁰M. Morphology was viewed under an inverted microscope, and the analysis of cell proliferation was performed using a Cell Counting Kit-8 (CCK-8) on days 1, 2, 4, and 7.ResultsThe CCK-8 results for LBM showed that the increase of CCK-8 values was correlated with a longer incubation time. Compared to the untreated control, growth in the presence of zoledronate at 10⁻¹⁰M and 10⁻⁸M resulted in decreased CCK-8 values for LBM on day 7 (P<0.05). The CCK-8 results for JBM, LPO, and JPO on days 1, 2, 4, and 7 showed that the presence of zoledronate did not produce statistically significant changes compared with the untreated control.ConclusionZoledronate in the tested concentrations from JBM, LPO, and JPO did not produce noticeable alterations in the viability of mesenchymal stem cells. This in vitro experiment suggests that the occurrence of MRONJ solely in the oral cavity is not due to differences in the cellular proliferation of stem cells in the response to zoledronate.



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Three-dimensional mammalian tooth development using diceCT

Publication date: January 2018
Source:Archives of Oral Biology, Volume 85
Author(s): Qamariya Nasrullah, Marilyn B. Renfree, Alistair R. Evans
ObjectiveThis study aims to develop the Diffusible Iodine-based Contrast-Enhanced CT (diceCT) method for non-destructive imaging of both soft and mineralised tissues. We sought to document the 3D spatio-temporal pattern of mammalian tooth development including multiple tooth classes and generations, using the tammar wallaby (Macropus eugenii) as a model species.DesignWe took microCT scans of developing fetuses and pouch young stained using Lugol's Iodine (I2KI) contrast agent. Stained versus unstained specimen comparisons were then made to investigate whether staining had improved visualisation of structures. Scan slices were compared to histological sections to confirm the identity of tissues and structures. Tissue layers were digitally segmented to create 3D models.ResultsDiceCT dramatically enhanced visual contrast of soft tissues, allowing differentiation between epithelial and mesenchymal layers. Subvolume scans at higher magnification achieved single-cell layer resolution within relatively large intact heads. We observed in-situ initiating teeth, which progressed through major stages of tooth development including morphogenesis and mineralisation. In addition, we traced the development of other mineralized and unmineralised tissues, such as the cranial bones and the brain, eye and olfactory system.ConclusionsDiceCT was time- and cost-effective in producing complex 3D models of the entire dentition of the tammar wallaby at each developmental stage with tissue-level resolution. The 3D view of soft and mineralised tooth structures allowed us to define tooth class and generation from a developmental perspective. Additionally, the development of other organs can also be documented using the same scans, demonstrating the efficiency and versatility of this technique.



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Presence of dental signs of congenital syphilis in pre-modern specimens

Publication date: January 2018
Source:Archives of Oral Biology, Volume 85
Author(s): Stella Ioannou, Renata J. Henneberg, Maciej Henneberg
ObjectiveTooth morphology can vary due to genetic factors, infectious diseases and other environmental stresses. Congenital syphilis is known to interrupt tooth formation i.e. odontogenesis and amelogenesis, producing specific dental characteristics. Variation of those characteristics can occur, resulting in dental signs "not typical" of the disease, however, they are described in the 19th century literature. Past treatments of congenital syphilis with mercury also interrupted dental processes resulting in significantly different dental signs. The aim of this study is to examine the dentition of the oldest (pre 15th century) cases attributed to congenital syphilis to determine whether their dental processes have been affected by either congenital syphilis itself, its treatments (mercury) or a combination of both (syphilitic-mercurial).DesignComparisons of dental signs of congenital syphilis and its mercuric treatments as described by Hutchinson, Moon and Fournier in the 1800s and in standardised methods as established by modern studies, are made with the dentition of specimens found in archaeological sites in Mexico, Italy, Turkey and Austria dating back to the Terminal Formative Period, Classical Antiquity, Byzantine times and Middle Ages.ResultsThe dentitions of a child from Oaxaca, Mexico, St. Pölten, Austria, and two juveniles from Classical Antiquity site Metaponto, Italy, show signs attributed to syphilis only. One adolescent from Byzantine site Nicaea, Turkey, shows dental signs characterised as syphilitic-mercurial.ConclusionsDental abnormalities observed in Mediterranean individuals match a range of signs attributable to congenital syphilis and its treatments, more so than the New World case. Therefore, it is likely that these individuals suffered from congenital syphilis.



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Researchers Report First-Ever Protein Hydrogels Made in Living Cells

Johns Hopkins cell biologists report what they believe is the first-ever creation of tiny protein-based gelatin-like clumps called hydrogels inside living cells. The ability to create hydrogels on demand, they say, should advance the long scientific struggle to study the elusive structures—which form in nature when proteins or other molecules aggregate under certain conditions—and to uncover their suspected contributions to human diseases.

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Quality of questionnaires for the assessment of otitis media with effusion in children

Abstract

Introduction

Audiometric tests provide information about hearing in otitis media with effusion (OME). Questionnaires can supplement this information by supporting clinical history-taking as well as potentially providing a standardized and comprehensive assessment of the impact of the disease on a child. There are many possible candidate questionnaires. This study aimed to assess the quality and usability of parent / child questionnaires in OME assessment.

Methods

Fifteen, published questionnaires, commonly used in audiological departments (ABEL, CHAPS, CHILD, COW, ECLiPS, ELF, FAPC, HL-7, LIFE-R Student, LIFE-UK IHP, LittlEARS, LSQ, OM-6, OMQ-14, PEACH) were assessed according to the following 8 criteria: conceptual clarity, respondent burden, reliability, validity, normative data, item bias, ceiling/ floor effects, and administrative burden.

Results

ECLiPS, LittlEARS and PEACH scored highest overall based on the assessment criteria established for this study. None of the questionnaires fully satisfied all 8 criteria. Although all questionnaires assessed issues considered to be of at least adequate relevance to OME, the majority had weaknesses with respect to the assessment of psychometric properties, such as item bias, floor/ceiling effects or measurement reliability and validity. Publications reporting on the evaluation of reliability, validity, normative data, item bias and ceiling/floor effects were not available for most of the questionnaires.

Conclusion

This formal evaluation of questionnaires, currently available to clinicians, highlights three questionnaires as potentially offering a useful adjunct in the assessment of OME in clinical or research settings. These were the ECLiPS, which is suitable for children aged 6 years and older, and either the LittlEARS or the PEACH for younger children. The latter two are narrowly focused on hearing, whereas ECLiPS has a broader focus on listening, language and social difficulties.

This article is protected by copyright. All rights reserved.

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Evolution of soft palate surgery techniques for Obstructive Sleep Apnea patients: A comparative study for single level palatal surgeries

Abstract

Objectives

to compare the results of tissue preservation techniques of soft palate surgeries including expansion sphincter pharyngoplasty (ESP) and barbed reposition pharyngoplasty (BRP) for patients suffering from obstructive sleep apnea (OSA) with the traditional uvulopalatopharyngoplasty (UPPP).

Design

interventional comparative study.

Setting

Morgagni- Pierantoni Hospital.

Participants

seventy five patients were included in the study, divided into three groups with 25 patients per group: UPPP, ESP or BRP.

Main outcomes measures

Polysomnography was done for all patients pre- and post-operatively, the post-operative results were recorded at least six months after surgery. All patients were assessed pre-operatively using drug induced sleep endoscopy. Epworth Sleepiness scale and body mass index were registered for all patients before and after surgery.

Results

the mean of pre- and post-operative differences of apnea hypopnea index values were higher in BRP group than ESP: 15.76±14.5 Vs 10.13±5.3; P <0.05 and UPPP groups: 15.76± 14.5 Vs 6.08±5.5; P <0.0005. The mean of differences of oxygen desaturation index values was higher in BRP group than UPPP group: 15.09±17.6 Vs 7.13±6.8; P <0.0005, but not significantly higher than ESP group: 15.09± 17.6 Vs 6.48±7.9; P >0.05. The mean of differences of ESS values was higher in BRP group than ESP group: 5.52 ±4.1 Vs 4.84±3.3; P <0.005 and UPPP groups: 5.52 ±4.1Vs 1.36±1.9; P <0.005. Finally, the pre- and post-operative mean of differences of lowest oxygen saturation values were not statistically significant among the three groups (P >0.05).

Conclusion

BRP can be considered an effective procedure on the basis of the post-operative outcomes. ESP still proves to be a good technique especially when performed by experienced surgeons. Both techniques proved to be superior to UPPP.

This article is protected by copyright. All rights reserved.

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Higher prevalence and increased severity of sleep-disordered breathing in male patients with chronic tinnitus: our experience with 173 cases

Tinnitus and sleep are closely related. One of the most important aspects of tinnitus is its association with sleep disturbance. According to the literature, up to 71% of patients with tinnitus report sleep problems (1); furthermore, insomnia is also associated with more distressing tinnitus (2). Conversely, sleep disturbance was proposed as one of the causes of chronic tinnitus (3). The relationship of tinnitus with sleep-disordered breathing (SDB) and obstructive sleep apnea (OSAS) has rarely been mentioned (4). In a recent population-based case-control study, the risk of tinnitus was found to increase 1.36 times in patients with OSAS. However, no detailed grading or severity of SDB (or OSAS) and tinnitus was provided. The purpose of this study was to investigate the exact relationship between tinnitus and SDB and delineate the incidence and severity of SDB in patients with chronic tinnitus; moreover, our study reports the preliminary outcome of tinnitus after intervention with continuous positive airway pressure (CPAP) in selected patients with moderate to severe SDB.

This article is protected by copyright. All rights reserved.

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An ENT smartphone Handbook: adopting new practice for induction

There should be continued support and drive for innovation and implementation of smartphone-based access to local guidelines.

This is the first study, that we're aware of, assessing the use of a smartphone-based clinical handbook in ENT surgery.

Use of a smartphone-based handbook is superior to printed or intranet-based guidelines.

Use of smartphone apps can support junior doctors with delivery of care.

Smartphone-based access to guidelines encourage learning and education to improve the induction process for new doctors.

This article is protected by copyright. All rights reserved.

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Immunohistochemical expression of vitamin D receptor in melanocytic nevi and cutaneous melanoma. A case-control study

Abstract

Background

Vitamin D (VD) deficiency is associated with higher risk of cancer, possibly due to anti-proliferative, anti-angiogenic, pro-apoptotic, cell-differentiating and anti-invasive effects. The anti-carcinogenic role of VD in melanoma is still a matter of debate. Loss of nuclear and cytoplasmic vitamin D Receptor (VDR) expression in melanoma cells has been reported.

Objective

To analyze VDR immunohistochemical expression in benign dermal nevi (DN) and MM.

Methods

A case-control study evaluated nuclear and cytoplasmic VDR immunohistochemical staining in 54 DN and 55 MM tissue samples.

Results

There was a significantly higher cytoplasmic VDR-positivity in DN compared with MM (59% vs. 16%, P<0.0001). The mean VDR cytoplasmic expression was also higher in DN vs. MM (P<0.0001). No differences in nuclear VDR-positivity were observed between groups, but mean nuclear VDR expression was significantly lower in DN vs. MM (P=0.02). The loss of cytoplasmic VDR in MM was associated with Clark level, Tumor staging and pTNM AJCC staging (P=0.004, P=0.009 and P=0.02, respectively).

Conclusion

Alterations in VDR expression and localization are found in MM compared with DN. Loss of cytoplasmic VDR was associated with melanoma tumor size, suggesting that loss of cytoplasmic VDR may be a prognostic factor.

This article is protected by copyright. All rights reserved.

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Prevalence and incidence of chronic spontaneous urticaria in the entire Korean adult population

Abstract

Ethnic differences and temporal trends in the epidemiology of chronic spontaneous urticaria (CSU) are not well understood, especially in East Asia.^1-3 The aim of our study was to investigate trends in the prevalence and incidence of CSU among adult Korean subjects from 2006 to 2014 using a nationwide, population-based study.

This article is protected by copyright. All rights reserved.

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A systematic review of diagnostic criteria for psoriasis in adults and children: Evidence from studies with a primary aim to develop or validate diagnostic criteria

Abstract

Background

The diagnosis of psoriasis in adults and children is made clinically, for both patient management and the selection of participants in research. Diagnostic criteria provide a structure for clinical assessment, which in turn helps standardise patient recruitment into clinical trials and case definitions in observational studies.

Objective

The aim of this systematic review was to identify and critically appraise the published studies to date that had a primary research aim to develop or validate diagnostic criteria for psoriasis.

Method

A search of Ovid MEDLINE and Ovid Embase was conducted in October 2016. The primary objective was sensitivity and specificity of diagnostic criteria for psoriasis. Secondary objectives included diagnostic recommendations, applicability to children and study characteristics. Diagnostic accuracy studies were critically appraised for risk of bias using the QUADAS-2 tool.

Results

Twenty-three studies met the inclusion criteria.None detailed clinical examination-based diagnostic criteria. The included criteria varied from genetic and molecular diagnostic models to skin imaging, histopathology, questionnaire-based, computer-aided and traditional Chinese medicine criteria. High sensitivity and specificity (>90%) were reported in many studies. However, the study authors often did not specify how criteria would be used clinically or in research. This review identified studies with varyingrisk of bias and due to each study developing separate criteria meta-analysis was not possible.

Conclusion

Clinical examination-based diagnostic criteria are currently lacking for psoriasis. Future research could follow an international collaborative approach and employ high quality diagnostic accuracy study design. Existing and newly developed criteria require validation.

This article is protected by copyright. All rights reserved.

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HIFU Reapplication in Benign Nodules

Condition:   Thyroid Nodule
Intervention:   Device: Echopulse
Sponsor:   The University of Hong Kong
Recruiting

http://ift.tt/2Ad3Wnx

Phase III Study: Modulated Electro-Hyperthermia Plus Chemo-radiation for Cervical Cancer Patients in South Africa

Condition:   Cervical Cancer
Interventions:   Device: Modulated electro-hyperthermia;   Radiation: External beam radiation;   Drug: Cisplatin;   Radiation: Brachytherapy
Sponsors:   Jeffrey Kotzen;   National Research Foundation of South Africa;   NTP Radioisotopes SOC Ltd
Recruiting

http://ift.tt/2hLy2rx

A Pilot Study to Evaluate the Feasibility and Potential Effectiveness of the Flexitouch System Head and Neck Treatment

Conditions:   Head and Neck Neoplasms;   Head and Neck Cancer;   Head and Neck Lymphedema
Interventions:   Device: Flexitouch head and neck lymphedema treatment system;   Other: Standard home lymphedema care
Sponsors:   Tactile Medical;   Vanderbilt University
Not yet recruiting

http://ift.tt/2AdquER

High-flow Nasal Cannula Oxygenation Decrease Hypoxia in Gastroscopy Sedated by Propofol

Conditions:   Hypoxia;   Gastric Cancer;   Esophagus Cancer;   Adverse Event
Intervention:   Device: High-flow nasal cannula oxygenation
Sponsors:   RenJi Hospital;   Shanghai Pudong New Area People's Hospital;   Shanghai Tongji Hospital, Tongji University School of Medicine
Recruiting

http://ift.tt/2hMbo2h

Comparison of Two Concomitant Administration of RT With Cisplatin in Standard Infusion or Fractional Infusion

Condition:   Squamous Cell Carcinoma of the Head and Neck
Interventions:   Drug: Split Cisplatin;   Drug: Cisplatin;   Radiation: Radiotherapy
Sponsor:   Groupe Oncologie Radiotherapie Tete et Cou
Recruiting

http://ift.tt/2Ad3SEj

A Study of CDX-1140 in Patients With Advanced Solid Tumors

Conditions:   Melanoma;   Non-small Cell Lung Cancer;   Breast Cancer;   Gastric Cancer;   Renal Cell Carcinoma;   Ovarian Cancer;   Cholangiocarcinoma;   Bladder Urothelial Carcinoma;   Pancreatic Adenocarcinoma;   Colorectal Cancer;   Esophageal Cancer;   Hepatic Cancer;   Head and Neck Cancer
Intervention:   Drug: CDX-1140
Sponsor:   Celldex Therapeutics
Not yet recruiting

http://ift.tt/2hLffMX