Why Aren't There More Female Pain Medicine Physicians?

Despite a growing awareness about the importance of gender equity and the rising number of women in medicine, women remain persistently underrepresented in pain medicine and anesthesiology. Pain medicine ranks among the bottom quartile of medical specialties in terms of female applicants, female trainees, and proportion of female practitioners. Female pain medicine physicians are also notably disadvantaged compared with their male colleagues in most objective metrics of gender equity, which include financial compensation, career advancement, public recognition, and leadership positions. Increased gender diversity among pain medicine physicians is vital to fostering excellence in pain research, education, and clinical care, as well as creating a high-quality work environment. Pain medicine stands at a crossroads as a specialty, and must examine reasons for its current gender gap and consider a call to action to address this important issue. Accepted for publication December 24, 2017. Address correspondence to: Tina L. Doshi, MD, Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 550 N Broadway, Suite 309C, Baltimore, MD 21205 (e-mail: tina.doshi@jhmi.edu). The authors have no sources of funding to declare for this article. The authors declare no conflict of interest. Copyright © 2018 by American Society of Regional Anesthesia and Pain Medicine.

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Monoclonal Antibody Against HA Protein of the European Avian-Like H1N1 Swine Influenza Virus

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy, Ahead of Print.


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47-mG2a: A Mouse IgG2a-Type of PcMab-47 Useful for Detecting Podocalyxin in Esophageal Cancers by Immunohistochemistry

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy, Ahead of Print.


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Surgical Anatomy of the Upper Face and Forehead

Facial plast Surg 2018; 34: 109-113
DOI: 10.1055/s-0038-1637727

Aesthetic ideals regarding proportion and balance of the face have existed for centuries. The upper third of the face, including the brow, forehead, and temple, provides an important contribution to the overall facial aesthetic. This is especially true given how the brow frames the eyes, and the eyes serve as the key focal point in our interactions with others. There exists a variety of surgical and nonsurgical procedures aimed at improving the aesthetic of the upper portion of the face, and a thorough knowledge of the surgical anatomy of the upper face and forehead is critical to their successful execution.
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An Unexpected Donor Site Complication after Aesthetic Rhinoplasty: Arteriovenous Fistula of the Superficial Temporal Artery

Facial plast Surg 2018; 34: 235-236
DOI: 10.1055/s-0038-1636934

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Halos and Asymmetric Triangles: Designing the Eyelids with Volume Using Fillers and/or Fat

Facial plast Surg 2018; 34: 173-177
DOI: 10.1055/s-0038-1636902

Periorbital aging is mainly a product of volume loss, which can be addressed with fillers and/or fat grafting. This stands in contrast to the lower face where a lifting procedure can be the principal method to improve moderate-to-significant aging. New models to explain these concepts of periorbital rejuvenation to both the surgeon and the prospective patient are outlined herein, namely, three facial halos (around the eyes, around the perimeter of the face, and around the mouth) and asymmetric triangles around the eyes. Specific techniques for fillers and fat grafting are also covered separately in detail in this article.
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The Aesthetics of the Upper Face and Brow: Male and Female Differences

Facial plast Surg 2018; 34: 114-118
DOI: 10.1055/s-0038-1636935

A hallmark of the modern era of facial plastic surgery is the increasing demand for upper facial rejuvenation by both genders and the growing variety of such options, including both surgical and non-surgical modalities. Thus, now more than ever, differentiating these aesthetic ideals between the two genders and understanding their nuances has become a necessity for the facial cosmetics community. In this article, a detailed comparison of the the pertinent anatomical and topographical differences is presented, followed by a review of the historical evolution of these aesthetic trends.
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Aesthetics and Rejuvenation of the Temple

Facial plast Surg 2018; 34: 159-163
DOI: 10.1055/s-0038-1636921

The temples are an often overlooked, but important element of facial rejuvenation. The anatomy of the temple should be understood prior to any intervention in this location. Multimodal treatment to re-establish youthful convexity, proper hairline position, and correct actinic damage is recommended for optimal results. Important anatomy, aesthetic goals, and methods of rejuvenation are reviewed in detail.
[...]

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Rejuvenation of the Upper Face and Brow: Neuromodulators and Fillers

Facial plast Surg 2018; 34: 119-127
DOI: 10.1055/s-0038-1637004

Facial aging involves a combination of volume loss and descent, loss of skin elasticity, dynamic lines due to facial mimetic muscle action, and development of static rhytids. Although surgery remains an option for treatment, minimally invasive aesthetic procedures continue to gain popularity with the use of neuromodulators and soft tissue fillers being the most sought-after procedures. Although these may be used in isolation to treat specific concerns, they are often combined to address multiple facets of aging. Multiple different neuromodulators and fillers are commercially available. Although relatively effective and safe, a thorough understanding of their indications, compositions, and potential adverse effects is paramount. This article will review the available aesthetic products for minimally invasive periorbital rejuvenation with botulinum toxin and injectable fillers. Although it will not focus on other therapies aimed at facial rejuvenation, such as resurfacing techniques or surgical interventions, it is important to note that an individualized treatment plan may combine multiple therapies to optimize patient outcomes and satisfaction.
[...]

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Upper Blepharoplasty: Management of the Upper Eyelid and Brow Complex via Transblepharoplasty Approach

Facial plast Surg 2018; 34: 183-193
DOI: 10.1055/s-0038-1636918

Upper blepharoplasty is one of the more common facial plastic procedures. The upper lid and brow complex are managed together. Whether upper blepharoplasty is performed for medical or cosmetic reasons, the aim is to improve appearance while retaining natural shape and maintaining (or improving) function. For optimal results, it is important to understand relevant eyelid anatomy and the concept of maintaining youthful volume and position of the eyelid brow orbit complex. Management of patient expectations, meticulous planning, and a degree of surgical finesse all contribute to the desired outcome. The article will focus on the assessment, techniques, and complications of upper blepharoplasty, which involve management of the skin, orbicularis oculi, preaponeurotic fat, levator aponeurosis and muscle as related to concomitant ptosis, and lateral brow complex via transblepharoplasty (internal) brow lift and fixation.
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The Open Browlift

Facial plast Surg 2018; 34: 128-138
DOI: 10.1055/s-0038-1637003

The eyes and periorbital areas are critical components for the harmonious treatment of the aging face. The authors prefer the open browlift for rejuvenation of the forehead area. The open browlift is the most versatile, effective, and long-lasting method for the treatment of the forehead. The analysis of the forehead area, alternative treatments, variations in incisions, and key components of the surgical procedure are to be reviewed.
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Hairline Restoration: Difference in Men and Woman—Length and Shape

Facial plast Surg 2018; 34: 155-158
DOI: 10.1055/s-0038-1636905

Hair restoration has become increasingly popular in recent years with both men and women. New technologies such as follicular unit extraction and grafting have made it possible for patients to get a natural looking result with minimal downtime. Men usually experience hairline recession as a result of androgenic alopecia, while women most commonly experience thinning of the crown and vertex, with the preservation of the hairline. However, there is a growing population of women who wish to advance their hairline forward because of congenital high hairline, traction alopecia, or previous facial cosmetic surgery. There are several key differences between the female and male hairline. Understanding such differences and following certain guidelines will help the facial plastic surgeon to obtain beautiful and natural appearing results.
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Endoscopic Browplasty

Facial plast Surg 2018; 34: 139-144
DOI: 10.1055/s-0038-1637728

The endoscopic brow lift has become an established procedure that can safely and reliably rejuvenate the upper third of the face. The authors discuss relevant anatomy and considerations for patient selection to optimize surgical outcomes. A detailed review of surgical technique is presented, and the potential complications and means to reduce them are discussed.
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Fat Grafting Volume Restoration to the Brow and Temporal Regions

Facial plast Surg 2018; 34: 164-172
DOI: 10.1055/s-0038-1636922

Primary manifestations of facial aging are the reduction in subcutaneous tissue volume, especially the atrophy of fat as well as bone volume depletion which directly contribute to loss of support and laxity of the skin. Depressions and hollows develop with a visible disruption of the cosmetic facial aesthetic units resulting in harsh shadows. This is especially evident in the eyebrow and temporal regions which accentuate the appearance of brow ptosis and a hollow, almost cadaveric look to the temple. Restoration of volume to these areas has been shown to rejuvenate the upper face creating a softer, fuller, and more youthful appearance. Fat grafting by itself or in combination with upper facial surgical procedures plays a major role in the restoration of youthful facial qualities in this region.
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Scalp Advancement and the Pretrichial Brow Lift

Facial plast Surg 2018; 34: 145-149
DOI: 10.1055/s-0038-1636920

This article will review considerations for scalp advancement, or forehead shortening, when done in combination with a brow lift. The author's technique for anterior hairline reshaping is presented with particular focus on simultaneous reduction of temporal recession.
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Effect of Orbicularis Muscle Resection during Blepharoplasty on the Position of the Eyebrow

Facial plast Surg 2018; 34: 178-182
DOI: 10.1055/s-0038-1636904

Dermatochalasis is a skin excess in the upper eyelid which may be associated with either an aesthetic and functional defect, blocking the peripheral vision. Upper blepharoplasty is the gold standard procedure for correction of dermatochalasis and to restore youthful contours to the periorbita. It is one of the most commonly performed procedures in aesthetic plastic surgery; however, there is still a lack of consensus about this procedure. The excess skin is sometimes removed alone or in conjunction with a strip of orbicularis oculi muscle. The rationale for both muscle and skin resection or skin alone preserving the muscle is uncertain. Some authors have studied the aging influence in brow position, and a few studies pointed out the influence of the upper blepharoplasty on brow height. The true effects, regarding the position of the eyebrow, of both techniques, with or without resection of the preseptal orbicularis oculi muscle, are unclear. The authors present a review of the literature to find the rationale for resecting or preserving the orbicularis oculi muscle in upper eyelid blepharoplasty and its relation to eyebrow position.
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The Trichophytic and Lateral Temporal Lifts: Application to the Focal Elevation of the Aging Lateral Eyebrow

Facial plast Surg 2018; 34: 150-154
DOI: 10.1055/s-0038-1636928

Rejuvenation of the upper face is a key component of overall facial rejuvenation. The upper face is probably the most important purveyor of our sense of well-being and our primary transmittal of nonverbal social interaction. There are many aspects to the aging changes in the area. Central to these concerns is the level and shape of the eyebrow. Ptosis of the lateral brow begins at a relatively young age and tends to worsen over time. This article describes an adaptation of modifiable techniques to address focal issues of the lateral eyebrow.
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The Aesthetics of the Upper Face: Forehead, Brow, and Upper Eyelid

Facial plast Surg 2018; 34: 107-108
DOI: 10.1055/s-0038-1636923

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Manipulation of the Periorbital Musculature

Facial plast Surg 2018; 34: 194-200
DOI: 10.1055/s-0038-1636919

The resting and expressive states of the periorbital region contribute to perceived age, emotion, gender, race, and countenance. A thorough understanding of the periorbital musculature is essential for comprehensive facial rejuvenation. Surgical and nonsurgical manipulation of these muscles can lead to alterations in brow elevation, resting brow position, and dynamic periorbital rhytids. Both surgical and nonsurgical techniques can produce desired effects, and they are often used concomitantly to obtain optimal results.
[...]

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Understanding echinocandin resistance in the emerging pathogen Candida auris [PublishAheadOfPrint]

Candida auris has emerged simultaneously on five continents as a fungal pathogen causing nosocomial outbreaks. One of the challenges in the treatment of C. auris infections is variable antifungal susceptibility profiles among clinical isolates and the development of resistance to single or multiple classes of available antifungal drugs. Here, in vitro susceptibility to echinocandin antifungal drugs and FKS1 sequencing was performed on 106 C. auris clinical isolates. Four isolates were identified as resistant to all tested echinocandins (MIC ≥ 4 mg/l) and harbored a S639F mutation in FKS1 HS1. All remaining isolates were FKS wildtype (WT) and echinocandin-susceptible with micafungin being the most potent echinocandin (MIC₅₀= 0.125 mg/l). Antifungal susceptibility testing with caspofungin was challenging due to the fact that all FKS1 WT isolates exhibited an 'Eagle effect' (also known as paradoxical growth effect), of varying intensity. To assess whether the 'Eagle effect' resulted in pharmacodynamics resistance, 8 representative isolates were evaluated for in vivo drug response in a murine model of invasive candidiasis. All isolates were susceptible to caspofungin at a human therapeutic dose, except for those harboring the S639F mutation. The data suggest that only isolates carrying mutations in FKS1 are echinocandin-resistant and that routine in vitro susceptibility testing of C. auris isolates with caspofungin by broth microdilution method should be cautiously viewed or avoided.

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Report of erm(B)+ Campylobacter jejuni in the United States [PublishAheadOfPrint]

Campylobacter is a leading cause of foodborne illness in the United States, causing an estimated 1.3 million illnesses annually (1)....

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Measurement of Skeletal Muscle Area Improves Estimation of Aminoglycoside Clearance Across Body Size [PublishAheadOfPrint]

A consistent approach to the dosing of aminoglycosides across the modern body size distribution has been elusive. We evaluated whether radiologically-derived measures of body composition could explain more of the inter-patient variability in aminoglycoside pharmacokinetics (PK) than standard body size metrics. This retrospective study included adult patients treated with gentamicin or tobramycin with at least three drug concentrations and computed tomography (CT) imaging available. Aminoglycoside volume and clearance (CL) estimates were computed using a two-compartment model by Bayesian analysis. Morphomic data were extracted from CT images using a custom algorithm. Bivariable and multivariable linear regression were used to assess relationships between PK parameters and covariates. A total of 335 patients were included with a median (min, max) of 4 (3, 16) aminoglycoside concentrations per patient. The median (min, max) age, height, and weight of included patients was 57 (21, 93) years, 170 (145, 203) centimeters, and 81 (42, 187) kilograms. Both standard and morphomic measures poorly explained variability in volume (R² < 0.06). Skeletal muscle area and volume explained more of the inter-patient variability in CL than weight or sex. Higher precision was observed using a modified Cockcroft-Gault equation with skeletal muscle area at L3 (R² = 0.38) or L4 (R² = 0.37) than the standard Cockcroft-Gault equation using lean (R² = 0.23), adjusted (R² = 0.23), or total body weights (R² = 0.22). These results highlight that skeletal muscle measurements from CT images obtained in the course of care can improve the precision of aminoglycoside CL estimation over current body size scalars.

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Defining substrate specificity in the CTX-M family: the role of Asp240 in ceftazidime hydrolysis [PublishAheadOfPrint]

The natural diversification of CTX-M β-lactamases led to the emergence of Asp240Gly variants in the clinic that confer reduced susceptibility to ceftazidime (CAZ). In this study, we compared the impact of this substitution on CAZ and ceftazidime/avibactam (CZA) MICs against isogenic Escherichia coli strains with different porin deficiencies. Our results show a noticeable increase in CAZ resistance in clones expressing Asp240Gly-harboring CTX-M when combined with OmpF porin deficiency. Kinetic analysis revealed that the k_cat/K_m for CAZ was 5-15-fold higher for all Asp240Gly variants, but remained 200-725-fold lower than that for cefotaxime (CTX). In vitro selection of CAZ resistant clones yielded non-susceptible CTX-M-producers (MIC>16 μg/ml) only after overnight incubation; the addition of avibactam (AVI) decreased MICs to a susceptible range against these variants. In contrast, the use of CZA as a selective agent did not yield resistant clones. AVI inactivated both CTX-M-12 and CTX-M-96 with K_iapp comparable to SHV-2 and 1,000-fold greater than PER-2 and CMY-2; k₂/K for CTX-M-12 was 24- and 35-fold higher than CTX-M-96 and CTX-M-15, respectively. Molecular modelling suggests that AVI interacts similarly with CTX-M-96 and CTX-M-15. We conclude that the impact of Asp240Gly in resistance may arise when other mechanisms are also present (i.e. OmpF deficiency). Additionally, CAZ selection could favor the emergence of CAZ-resistant sub-populations. These results define the role of Asp240 and the impact of the -Gly substitution and allow us to hypothesize that the use of CZA could be an effective preventive strategy to delay the development of resistance in this family of ESBLs.

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A novel polyaminocarboxylate compound to treat murine pulmonary aspergillosis by interfering with zinc metabolism [PublishAheadOfPrint]

Aspergillus fumigatus can cause pulmonary aspergillosis in immunocompromised patients and is associated with a high mortality rate due to the lack of reliable treatment options. This opportunistic pathogen requires zinc in order to grow and cause disease. Novel compounds that interfere with fungal zinc metabolism may therefore be of therapeutic interest. We screened chemical libraries containing 59223 small molecules using a resazurin assay that compared their effects on an A. fumigatus wild type strain grown under zinc-limiting conditions and on a zinc transporter knockout strain grown under zinc-replete conditions to identify compounds affecting zinc metabolism. After a first screen 116 molecules were selected whose inhibitory effect on fungal growth was further tested by using luminescence assays and hyphal length measurements to confirm their activity, as well as to toxicity assays on HeLa cells and mice. Six compounds were selected following a re-screening, two of which were pyrazolones, two were porphyrins and two were polyaminocarboxylates. All three groups showed good in vitro activity but only one of the polyaminocarboxylates was able to significantly improve the survival of immunosuppressed mice suffering from pulmonary aspergillosis. This two-tier screening approach led us to the identification of a novel small molecule with in vivo fungicidal effects and low murine toxicity that may lead to the development of new treatment options for fungal infections either by administration of this compound as a monotherapy or as part of a combination therapy.

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Aspergillus fumigatus cyp51A polymorphisms, an insight on their significance. [PublishAheadOfPrint]

Triazole antifungal compounds are the first treatment choice for invasive aspergillosis. However, in the last decade Aspergillus fumigatus azole resistance has increased notoriously. The main resistance mechanisms are well-defined and mostly related to point mutations of the azole target, 14-α sterol demethylase (cyp51A), with or without tandem repeat integrations in the cyp51A promoter. Furthermore, different combinations of five Cyp51A mutations (F46Y, M172V, N248T, D255E and E427K) have been reported worldwide in around 10% of the total A. fumigatus isolated. The azole susceptibility profile of these strains shows elevated azole minimum inhibitory concentrations, although based on azole susceptibility breakpoints these strains are not considered as azole resistant. The purpose of the study was to determine whether these cyp51A polymorphisms (SNPs) are responsible for the azole susceptibility profile and whether they are reflected in a poorer azole treatment response in vivo that could compromise patient treatment and outcome. A cyp51A deleted mutant was generated, becoming fully susceptible to all azoles tested. Also, three gene constructions with different combinations of cyp51A-SNPs were generated and re-introduced in an azole susceptible wild-type (WT) strain (akuB^KU80). The alternative model host Galleria mellonella was used to compare virulence and voriconazole response of infected larvae with A. fumigatus cyp51A-WT or cyp51A-SNP strains. All strains were pathogenic in G. mellonella although they did not respond similarly to voriconazole therapeutic doses. Finally, these strains were full genome sequenced and analyzed in comparison with A. fumigatus-WT strains, revealing that they belong to different strain clusters or lineages.

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Imidazopyridine compounds inhibit mycobacterial growth by depleting ATP levels [PublishAheadOfPrint]

The imidazopyridines are a promising new class of anti-tubercular agents with potent activity in vitro and in vivo. We isolated resistant mutants of Mycobacterium tuberculosis to a representative imidazopyridine; mutants had large shifts (>20-fold) in MIC (minimum inhibitory concentration). Whole genome sequencing revealed mutations in Rv1339, a hypothetical protein of unknown function. We isolated mutants to three further compounds from the series; mutants with single nucleotide polymorphisms in Rv1339 were isolated against two compounds. Mutants with single nucleotide polymorphisms in QcrB, the proposed target for this series, were isolated against one compound. All strains were resistant to two compounds, regardless of the mutation and a strain carrying the QcrB T313I mutation was resistant to all of the imidazopyridine derivatives tested, confirming cross-resistance. We confirmed that compounds from this series were targeting QcrB by monitoring pH homeostasis and ATP generation; imidazopyridines disrupted pH homeostasis and depleted ATP, providing further evidence of an effect on the electron transport chain. A representative compound was bacteriostatic against replicating bacteria, consistent with a mode of action against QcrB. The series had a narrow inhibitory spectrum, with no activity against other bacterial species. No synergy or antagonism was seen with other anti-tuberculosis drugs under development. In conclusion, our data support the hypothesis that the imidazopyridine series functions by reducing ATP generation via inhibition of QcrB.

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High levels of intrinsic tetracycline resistance in Mycobacterium abscessus is conferred by a tetracycline- modifying monooxygenase [PublishAheadOfPrint]

Tetracyclines have been one of the most successful class of antibiotics. However, its extensive use has led to the emergence of wide-spread drug resistance resulting in discontinuation of use against several bacterial infections. Prominent resistance mechanisms include drug efflux and the use of ribosome protection proteins. Infrequently, tetracyclines can be inactivated by the TetX class of enzymes, also referred to as tetracycline destructases. Low levels of tolerance to tetracycline in M. smegmatis and M. tuberculosis has been previously attributed to the WhiB7- dependent TetV/Tap efflux pump. However, M. abscessus is ~500 fold more resistant to tetracycline as compared to M. smegmatis and M. tuberculosis. In the present study, we show that this high level of resistance to tetracycline and doxycycline in M. abscessus is conferred by a WhiB7 independent tetracycline inactivating monooxygenase, MabTetX (MAB_1496c). Presence of sublethal doses of tetracycline and doxycycline results in >200-fold induction of MabTetX and an isogenic deletion strain is highly sensitive to both antibiotics. Further, purified MabTetX can rapidly monooxygenate both antibiotics. We also demonstrate that expression of MabTetX is repressed by MabTetR_x, by binding to an inverted repeat sequence upstream of MabTetR_x; presence of either antibiotic relieves this repression. Moreover, anhydrotetracycline (ATc) can effectively inhibit MabTetX activity in vitro and decreases the MIC of both tetracycline and doxycycline in vivo. Finally, we show that tigecycline, a third-generation tetracycline, is not only a poor substrate of MabTetX, but is also incapable of inducing the expression of MabTetX. This is the first demonstration of a tetracycline inactivating enzyme in mycobacteria. It a) elucidates the mechanism of tetracycline resistance in M. abscessus, 2) demonstrates the use of an inhibitor that can potentially reclaim the use of tetracycline and doxycycline and 3) identifies two sequential bottlenecks — MabTetX and MabTetR_x — for acquiring resistance to tigecycline thereby reiterating its use against M. abscessus.

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Polymyxin B in Combination with Enrofloxacin Exerts Synergistic Killing against Extensive Drug-resistant Pseudomonas aeruginosa [PublishAheadOfPrint]

Polymyxins are increasingly used as a last-resort class of antibiotics against extensive drug-resistant (XDR) Gram-negative bacteria. However, resistance to polymyxins can emerge with monotherapy. As nephrotoxicity is the major dose-limiting factor for polymyxin monotherapy, dose escalation to suppress the emergence of polymyxin resistance is not a viable option. Therefore, novel approaches are needed to preserve this last-line class of antibiotics. This study aimed to investigate the antimicrobial synergy of polymyxin B combined with enrofloxacin against Pseudomonas aeruginosa. Static time-kill studies were conducted over 24 h with polymyxin B (1-4 mg/L) and enrofloxacin (1-4 mg/L) alone or in combination. Additionally, a one-compartment in vitro model (IVM) and hollow-fiber infection model (HFIM) was performed against P. aeruginosa 12196. Polymyxin B and enrofloxacin in monotherapy were ineffective against all of the P. aeruginosa isolates examined. Whereas, polymyxin B-enrofloxacin in combination was synergistic against P. aeruginosa with ≥ 2-4 log₁₀ kill at 24 h in the static time-kill studies. In both IVM and HFIM, the combination was synergistic and the bacterial counting values were below the limit of quantification on day 5 in the HFIM. A population analysis profile indicated that the combination inhibited the emergence of polymyxin resistance in P. aeruginosa 12196. The mechanism-based modeling suggests that the synergistic killing is a result of the combination of mechanistic and subpopulation synergy. Overall, this is the first preclinical study to demonstrate that the polymyxins-enrofloxacin combination is of considerable utility for the treatment of XDR P. aeruginosa infections and warrants future clinical evaluations.

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Alterations of metabolic and lipid profiles in polymyxin-resistant Pseudomonas aeruginosa [PublishAheadOfPrint]

Multidrug-resistant Pseudomonas aeruginosa presents a global medical challenge and polymyxins are a key last-resort therapeutic option. Unfortunately, polymyxin resistance in P. aeruginosa has been increasingly reported. The present study was designed to define metabolic differences between paired polymyxin-susceptible and -resistant P. aeruginosa strains using untargeted metabolomics and lipidomics analyses. The metabolomes of wild-type PAK (polymyxin B MIC 1 mg/L) and its paired pmrB mutant strains, PAKpmrB6 and PAKpmrB12 (polymyxin B MICs 16 mg/L and 64 mg/L, respectively) were characterized using liquid chromatography-mass spectrometry, and metabolic differences were identified through multivariate and univariate statistics. PAKpmrB6 and PAKpmrB12 which displayed lipid A modification with 4-amino-4-deoxy-L-arabinose showed significant perturbations in amino acid and carbohydrate metabolism, particularly intermediate metabolites from 4-amino-4-deoxy-L-arabinose synthesis and the methionine salvage cycle pathways. Genomics result showed a premature termination (Y275stop) in speE (encoding spermidine synthase) in PAKpmrB6 and metabolomics data revealed a decreased intracellular level of spermidine in PAKpmrB6 compared to PAKpmrB12. Our results indicate that spermidine may play an important role in high-level polymyxin resistance in P. aeruginosa. Interestingly, both pmrB mutants had decreased levels of phospholipids, fatty acids and acyl-coenzyme A compared to the wild-type PAK strain. Moreover, the more resistant PAKpmrB12 mutant exhibited much lower levels of phospholipids than the PAKpmrB6 mutant, suggesting the decreased phospholipid level was associated with polymyxin resistance. In summary, this study provides novel mechanistic information on polymyxin resistance in P. aeruginosa and highlights its impacts on bacterial metabolism.

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Decay of the Stress-Induced Ligand MICA Is Controlled by the Expression of an Alternative 3' Untranslated Region [INNATE IMMUNITY AND INFLAMMATION]

Recognition of the human stress-induced ligand MHC class I polypeptide-related sequence A (MICA) by the receptor NKG2D expressed on NK cells leads to NK cell–mediated killing of the target cells. Hence, the expression of MICA must be tightly regulated, and its cell surface expression needs to be quickly downregulated to avoid inappropriate activation of immune cells. In this article, we describe a transcript variant of human MICA that has not yet been studied, which contains a 3' untranslated region of 119 nt instead of 174. We identify its polyadenylation signal and demonstrate that, upon stresses, such as heat shock, butyrate treatment, and some oxidative and DNA-damaging treatments, the balance between the two MICA variants changes in favor of the less stable, longer variant. Mechanistically, we showed that this change is linked to microRNA activity and that poly-ADP ribose polymerase 1 is involved in the induction of the longer variant following stress. Thus, to our knowledge, we identify the first regulatory mechanism of a stress ligand's decay and also provide one of the first physiological examples for the biological function of a longer 3' untranslated region of a particular gene.

https://ift.tt/2qk24Gj

IL-15 Promotes Polyfunctional NK Cell Responses to Influenza by Boosting IL-12 Production [INNATE IMMUNITY AND INFLAMMATION]

IL-15 is a key regulator of NK cell maintenance and proliferation and synergizes with other myeloid cell–derived cytokines to enhance NK cell effector function. At low concentrations, trans-presentation of IL-15 by dendritic cells can activate NK cells, whereas at higher concentrations it can act directly on NK cells, independently of accessory cells. In this study, we investigate the potential for IL-15 to boost responses to influenza virus by promoting accessory cell function. We find that coculture of human PBMCs with inactivated whole influenza virus (A/Victoria/361/2011) in the presence of very low concentrations of IL-15 results in increased production of myeloid cell–derived cytokines, including IL-12, IFN-α2, GM-CSF, and IL-1β, and an increased frequency of polyfunctional NK cells (defined by the expression of two or more of CD107a, IFN-, and CD25). Neutralization experiments demonstrate that IL-15–mediated enhancement of NK cell responses is primarily dependent on IL-12 and partially dependent on IFN-αβR1 signaling. Critically, IL-15 boosted the production of IL-12 in influenza-stimulated blood myeloid dendritic cells. IL-15 costimulation also restored the ability of less-differentiated NK cells from human CMV-seropositive individuals to respond to influenza virus. These data suggest that very low concentrations of IL-15 play an important role in boosting accessory cell function to support NK cell effector functions.

https://ift.tt/2qk2e0n

Fucosyltransferase Induction during Influenza Virus Infection Is Required for the Generation of Functional Memory CD4+ T Cells [INFECTIOUS DISEASE AND HOST RESPONSE]

T cells mediating influenza viral control are instructed in lymphoid and nonlymphoid tissues to differentiate into memory T cells that confer protective immunity. The mechanisms by which influenza virus–specific memory CD4⁺ T cells arise have been attributed to changes in transcription factors, cytokines and cytokine receptors, and metabolic programming. The molecules involved in these biosynthetic pathways, including proteins and lipids, are modified to varying degrees of glycosylation, fucosylation, sialation, and sulfation, which can alter their function. It is currently unknown how the glycome enzymatic machinery regulates CD4⁺ T cell effector and memory differentiation. In a murine model of influenza virus infection, we found that fucosyltransferase enzymatic activity was induced in effector and memory CD4⁺ T cells. Using CD4⁺ T cells deficient in the Fut4/7 enzymes that are expressed only in hematopoietic cells, we found decreased frequencies of effector cells with reduced expression of T-bet and NKG2A/C/E in the lungs during primary infection. Furthermore, Fut4/7^–/– effector CD4⁺ T cells had reduced survival with no difference in proliferation or capacity for effector function. Although Fut4/7^–/– CD4⁺ T cells seeded the memory pool after primary infection, they failed to form tissue-resident cells, were dysfunctional, and were unable to re-expand after secondary infection. Our findings highlight an important regulatory axis mediated by cell-intrinsic fucosyltransferase activity in CD4⁺ T cell effectors that ensure the development of functional memory CD4⁺ T cells.

https://ift.tt/2qm4Uun

RGC32 Promotes Bleomycin-Induced Systemic Sclerosis in a Murine Disease Model by Modulating Classically Activated Macrophage Function [INNATE IMMUNITY AND INFLAMMATION]

Systemic sclerosis (SSc) is a multisystem autoimmune disorder that is characterized by inflammation and fibrosis in the skin and internal organs. Previous studies indicate that inflammatory cells and cytokines play essential roles in the pathogenesis of SSc; however, the mechanisms that underlie the inflammation-driven development of SSc are not fully understood. In this study, we show that response gene to complement 32 (RGC32) is abundantly expressed in mouse macrophages in the early stage of bleomycin-induced SSc. Importantly, RGC32 is required to induce the inflammatory response during the onset of SSc, because RGC32 deficiency in mice significantly ameliorates skin and lung sclerosis and inhibits the expression of inflammatory mediators inducible NO synthase (iNOS) and IL-1β in macrophages. RGC32 appears to be a novel regulator for the differentiation of classically activated macrophages (M1 macrophages). IFN- and LPS stimulation induces RGC32 expression in primary peritoneal macrophages and bone marrow–derived macrophages. RGC32 deficiency impairs the polarization of M1 macrophages and attenuates iNOS and IL-1β production. Mechanistically, RGC32 interacts with NF-B proteins and promotes iNOS and IL-1β expression by binding to their promoters. Collectively, our data reveal that RGC32 promotes the onset of SSc by regulating the inflammatory response of M1 macrophages, and it may serve as a promising therapeutic target for treating SSc.

https://ift.tt/2qm4O5Z

The Immunogenicity of a Proline-Substituted Altered Peptide Ligand toward the Cancer-Associated TEIPP Neoepitope Trh4 Is Unrelated to Complex Stability [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Human cancers frequently display defects in Ag processing and presentation allowing for immune evasion, and they therefore constitute a significant challenge for T cell–based immunotherapy. We have previously demonstrated that the antigenicity of tumor-associated Ags can be significantly enhanced through unconventional residue modifications as a novel tool for MHC class I (MHC-I)–based immunotherapy approaches. We have also previously identified a novel category of cancer neo-epitopes, that is, T cell epitopes associated with impaired peptide processing (TEIPP), that are selectively presented by MHC-I on cells lacking the peptide transporter TAP. In this study, we demonstrate that substitution of the nonanchoring position 3 into a proline residue of the first identified TEIPP peptide, the murine Trh4, results in significantly enhanced recognition by antitumor CTLs toward the wild-type epitope. Although higher immunogenicity has in most cases been associated with increased MHC/peptide complex stability, our results demonstrate that the overall stability of H-2D^b in complex with the highly immunogenic altered peptide ligand Trh4-p3P is significantly reduced compared with wild-type H-2D^b/Trh4. Comparison of the crystal structures of the H-2D^b/Trh4-p3P and H-2D^b/Trh4 complexes revealed that the conformation of the nonconventional methionine anchor residue p5M is altered, deleting its capacity to form adequate sulfur– interactions with H-2D^b residues, thus reducing the overall longevity of the complex. Collectively, our results indicate that vaccination with Thr4-p3P significantly enhances T cell recognition of targets presenting the wild-type TEIPP epitope and that higher immunogenicity is not necessarily directly related to MHC/peptide complex stability, opening for the possibility to design novel peptide vaccines with reduced MHC/peptide complex stability.

https://ift.tt/2qk21KD

Associations of Simian Immunodeficiency Virus (SIV)-Specific Follicular CD8+ T Cells with Other Follicular T Cells Suggest Complex Contributions to SIV Viremia Control [INFECTIOUS DISEASE AND HOST RESPONSE]

Follicular CD8⁺ T (fCD8) cells reside within B cell follicles and are thought to be immune-privileged sites of HIV/SIV infection. We have observed comparable levels of fCD8 cells between chronically SIV-infected rhesus macaques with low viral loads (LVL) and high viral loads (HVL), raising the question concerning their contribution to viremia control. In this study, we sought to clarify the role of SIV-specific fCD8 cells in lymph nodes during the course of SIV infection in rhesus macaques. We observed that fCD8 cells, T follicular helper (Tfh) cells, and T follicular regulatory cells (Tfreg) were all elevated in chronic SIV infection. fCD8 cells of LVL animals tended to express more Gag-specific granzyme B and exhibited significantly greater killing than did HVL animals, and their cell frequencies were negatively correlated with viremia, suggesting a role in viremia control. Env- and Gag-specific IL-21⁺ Tfh of LVL but not HVL macaques negatively correlated with viral load, suggesting better provision of T cell help to fCD8 cells. Tfreg positively correlated with fCD8 cells in LVL animals and negatively correlated with viremia, suggesting a potential benefit of Tfreg via suppression of chronic inflammation. In contrast, in HVL macaques, Tfreg and fCD8 cell frequencies tended to be negatively correlated, and a positive correlation was seen between Tfreg number and viremia, suggesting possible dysfunction and suppression of an effective fCD8 cell immune response. Our data suggest that control of virus-infected cells in B cell follicles not only depends on fCD8 cell cytotoxicity but also on complex fCD8 cell associations with Tfh cells and Tfreg.

https://ift.tt/2qk2gFx

15-epi-Lipoxin A4, Resolvin D2, and Resolvin D3 Induce NF-{kappa}B Regulators in Bacterial Pneumonia [INNATE IMMUNITY AND INFLAMMATION]

Specialized proresolving mediators (SPMs) decrease NF-B activity to prevent excessive tissue damage and promote the resolution of acute inflammation. Mechanisms for NF-B regulation by SPMs remain to be determined. In this study, after LPS challenge, the SPMs 15-epi-lipoxin A₄ (15-epi-LXA₄), resolvin D1, resolvin D2, resolvin D3, and 17-epi-resolvin D1 were produced in vivo in murine lungs. In LPS-activated human bronchial epithelial cells, select SPMs increased expression of the NF-B regulators A20 and single Ig IL-1R–related molecule (SIGIRR). Of interest, 15-epi-LXA₄ induced A20 and SIGIRR in an lipoxin A₄ receptor/formyl peptide receptor 2 (ALX/FPR2) receptor–dependent manner in epithelial cells and in murine pneumonia. This SPM regulated NF-B–induced cytokines to decrease pathogen-mediated inflammation. In addition to dampening lung inflammation, surprisingly, 15-epi-LXA₄ also enhanced pathogen clearance with increased antimicrobial peptide expression. Taken together, to our knowledge these results are the first to identify endogenous agonists for A20 and SIGIRR expression to regulate NF-B activity and to establish mechanisms for NF-B regulation by SPMs for pneumonia resolution.

https://ift.tt/2qk2bBJ

Intravesicular Acidification Regulates Lipopolysaccharide Inflammation and Tolerance through TLR4 Trafficking [INNATE IMMUNITY AND INFLAMMATION]

TLRs recognize pathogen components and drive innate immune responses. They localize at either the plasma membrane or intracellular vesicles such as endosomes and lysosomes, and proper cellular localization is important for their ligand recognition and initiation of signaling. In this study, we disrupted ATP6V0D2, a component of vacuolar-type H⁺ adenosine triphosphatase (V-ATPase) that plays a central role in acidification of intracellular vesicles, in a macrophage cell line. ATP6V0D2-deficient cells exhibited reduced cytokine production in response to endosome-localized, nucleic acid-sensing TLR3, TLR7, and TLR9, but enhanced inflammatory cytokine production and NF-B activation following stimulation with LPS, a TLR4 agonist. Moreover, they had defects in internalization of cell surface TLR4 and exhibited enhanced inflammatory cytokine production after repeated LPS stimulation, thereby failing to induce LPS tolerance. A component of the V-ATPase complex interacted with ARF6, the small GTPase known to regulate TLR4 internalization, and ARF6 deficiency resulted in prolonged TLR4 expression on the cell surface. Taken together, these findings suggest that ATP6V0D2-dependent intravesicular acidification is required for TLR4 internalization, which is associated with prevention from excessive LPS-triggered inflammation and induction of tolerance.

https://ift.tt/2qk260T

Curcumin Suppresses IL-1{beta} Secretion and Prevents Inflammation through Inhibition of the NLRP3 Inflammasome [INNATE IMMUNITY AND INFLAMMATION]

Turmeric is traditionally used as a spice and coloring in foods. Curcumin is the primary active ingredient in the turmeric, and compelling evidence has shown that it has the ability to inhibit inflammation. However, the mechanism mediating its anti-inflammatory effects are not fully understood. We report that curcumin inhibited caspase-1 activation and IL-1β secretion through suppressing LPS priming and the inflammasome activation pathway in mouse bone marrow–derived macrophages. The inhibitory effect of curcumin on inflammasome activation was specific to the NLRP3, not to the NLRC4 or the AIM2 inflammasomes. Curcumin inhibited the NLRP3 inflammasome by preventing K⁺ efflux and disturbing the downstream events, including the efficient spatial arrangement of mitochondria, ASC oligomerization, and speckle formation. Reactive oxygen species, autophagy, sirtuin-2, or acetylated α-tubulin was ruled out as the mechanism by which curcumin inhibits the inflammasome. Importantly, in vivo data show that curcumin attenuated IL-1β secretion and prevented high-fat diet–induced insulin resistance in wide-type C57BL/6 mice but not in Nlrp3-deficient mice. Curcumin also repressed monosodium urate crystal–induced peritoneal inflammation in vivo. Taken together, we identified curcumin as a common NLRP3 inflammasome activation inhibitor. Our findings reveal a mechanism through which curcumin represses inflammation and suggest the potential clinical use of curcumin in NLRP3-driven diseases.

https://ift.tt/2qm4Jzd

Bach2 Promotes B Cell Receptor-Induced Proliferation of B Lymphocytes and Represses Cyclin-Dependent Kinase Inhibitors [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

BTB and CNC homology 2 (Bach2) is a transcriptional repressor that is required for the formation of the germinal center (GC) and reactions, including class switch recombination and somatic hypermutation of Ig genes in B cells, within the GC. Although BCR-induced proliferation is essential for GC reactions, the function of Bach2 in regulating B cell proliferation has not been elucidated. In this study, we demonstrate that Bach2 is required to sustain high levels of B cell proliferation in response to BCR signaling. Following BCR engagement in vitro, B cells from Bach2-deficient (Bach2^–/–) mice showed lower incorporation of BrdU and reduced cell cycle progression compared with wild-type cells. Bach2^–/– B cells also underwent increased apoptosis, as evidenced by an elevated frequency of sub-G₁ cells and early apoptotic cells. Transcriptome analysis of BCR-engaged B cells from Bach2^–/– mice revealed reduced expression of the antiapoptotic gene Bcl2l1 encoding Bcl-x_L and elevated expression of cyclin-dependent kinase inhibitor (CKI) family genes, including Cdkn1a, Cdkn2a, and Cdkn2b. Reconstitution of Bcl-x_L expression partially rescued the proliferation defect of Bach2^–/– B cells. Chromatin immunoprecipitation experiments showed that Bach2 bound to the CKI family genes, indicating that these genes are direct repression targets of Bach2. These findings identify Bach2 as a requisite factor for sustaining high levels of BCR-induced proliferation, survival, and cell cycle progression, and it promotes expression of Bcl-x_L and repression of CKI genes. BCR-induced proliferation defects may contribute to the impaired GC formation observed in Bach2^–/– mice.

https://ift.tt/2qk2zAb

Loss of the Immune Checkpoint CD85j/LILRB1 on Malignant Plasma Cells Contributes to Immune Escape in Multiple Myeloma [CLINICAL AND HUMAN IMMUNOLOGY]

Mechanisms of immune regulation may control proliferation of aberrant plasma cells (PCs) in patients with monoclonal gammopathy of undetermined significance (MGUS) preventing progression to active multiple myeloma (MM). We hypothesized that CD85j (LILRB1), an inhibitory immune checkpoint for B cell function, may play a role in MM pathogenesis. In this study, we report that patients with active MM had significantly lower levels of CD85j and its ligand S100A9. Decreased CD85j expression could also be detected in the premalignant condition MGUS, suggesting that loss of CD85j may be an early event promoting tumor immune escape. To gain insight into the molecular mechanisms underlying CD85j functions, we next enforced expression of CD85j in human myeloma cell lines by lentiviral transduction. Interestingly, gene expression profiling of CD85j-overexpressing cells revealed a set of downregulated genes with crucial functions in MM pathogenesis. Furthermore, in vitro functional assays demonstrated that CD85j overexpression increased susceptibility to T cell– and NK-mediated killing. Consistently, ligation of CD85j decreased the number of PCs from individuals with MGUS but not from patients with MM. In conclusion, downregulation of inhibitory immune checkpoints on malignant PCs may provide a novel mechanism of immune escape associated with myeloma pathogenesis.

https://ift.tt/2GObJQI

Constitutively Bound EGFR-Mediated Tyrosine Phosphorylation of TLR9 Is Required for Its Ability To Signal [INNATE IMMUNITY AND INFLAMMATION]

Mammalian TLRs recognize microbial infection or cell death–associated danger signals and trigger the appropriate cellular response. These responses determine the strength and the outcome of the host–microbe interaction. TLRs are transmembrane proteins located on the plasma or the endosomal membrane. Their ectodomains recognize specific microbial or endogenous ligands, and the cytoplasmic domains interact with specific proteins to activate intracellular signaling pathways. TLR9, an endosomal TLR, is activated by endocytosed DNA. Activated TLR9 recruits the cytoplasmic adapter MyD88 and other signaling proteins to induce the synthesis of inflammatory cytokines and IFN. Uncontrolled activation of TLR9 leads to the undesired overproduction of inflammatory cytokines and consequent pathogenesis. Therefore, appropriate activation and the regulation of TLR9 signaling are critical. Tyrosine (Tyr) phosphorylation of TLR9 is essential for its activation; however, the role of specific Tyr kinases is not clear. In this article, we report that epidermal growth factor receptor (EGFR), a membrane-bound protein Tyr kinase, is essential for TLR9 signaling. Genetic ablation of EGFR or pharmacological inhibition of its kinase activity attenuates TLR9-mediated induction of genes in myeloid and nonmyeloid cell types. EGFR is constitutively bound to TLR9; upon ligand stimulation, it mediates TLR9 Tyr phosphorylation, which leads to the recruitment of MyD88, activation of the signaling kinases and transcription factors, and gene induction. In mice, TLR9-mediated liver injury and death are blocked by an EGFR inhibitor or deletion of the EGFR gene from myeloid cells, which are the major producers of inflammatory cytokines.

https://ift.tt/2GJzqt6

Oncolytic Reovirus Inhibits Immunosuppressive Activity of Myeloid-Derived Suppressor Cells in a TLR3-Dependent Manner [TUMOR IMMUNOLOGY]

Oncolytic reovirus, which possesses 10 segments of dsRNA genome, mediates antitumor effects via not only virus replication in a tumor cell–specific manner, but also activation of antitumor immunity; however, the mechanism(s) of reovirus-induced activation of antitumor immunity have not been fully elucidated. Recent studies have demonstrated that overcoming an immunosuppressive environment in tumor-bearing hosts is important to achieve efficient activation of antitumor immunity. Among the various types of cells involved in immunosuppression, it has been revealed that myeloid-derived suppressor cells (MDSCs) are significantly increased in tumor-bearing hosts and play crucial roles in the immunosuppression in tumor-bearing hosts. In this study, we examined whether reovirus inhibits the immunosuppressive activity of MDSCs, resulting in efficient activation of immune cells after in vivo administration. The results showed that splenic MDSCs recovered from PBS-treated tumor-bearing mice significantly suppressed the Ag-specific proliferation of CD8⁺ T cells. In contrast, the suppressive activity of MDSCs on T cell proliferation was significantly reduced after reovirus administration. Reovirus also inhibited the immunosuppressive activity of MDSCs in IFN-β promoter stimulator-1 knockout (KO) mice and in wild-type mice. In contrast, the immunosuppressive activity of MDSCs in TLR-3 KO mice was not significantly altered by reovirus treatment. The activation levels of CD4⁺ and CD8⁺ T cells were significantly lower in TLR3 KO mice than in wild-type mice after reovirus administration. These results indicate that reovirus inhibits the immunosuppressive activity of MDSCs in a TLR3, but not IFN-β promoter stimulator-1, signaling-dependent manner.

https://ift.tt/2GJoiN3

Comment on "Type I CD20 Antibodies Recruit the B Cell Receptor for Complement-Dependent Lysis of Malignant B Cells" [LETTERS TO THE EDITOR]

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The TNF Superfamily Molecule LIGHT Promotes the Generation of Circulating and Lung-Resident Memory CD8 T Cells following an Acute Respiratory Virus Infection [MUCOSAL IMMUNOLOGY]

The transition of effector T cells or memory precursors into distinct long-lived memory T cell subsets is not well understood. Although many molecules made by APCs can contribute to clonal expansion and effector cell differentiation, it is not clear if clonal contraction and memory development is passive or active. Using respiratory virus infection, we found that CD8 T cells that cannot express the TNF family molecule lymphotoxin-like, exhibits inducible expression, competes with HSV glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes (LIGHT) are unimpaired in their initial response and clonally expand to form effector cell pools. Thereafter, LIGHT-deficient CD8 T cells undergo strikingly enhanced clonal contraction with resultant compromised accumulation of both circulating and tissue-resident memory cells. LIGHT expression at the peak of the effector response regulates the balance of several pro- and antiapoptotic genes, including Akt, and has a preferential impact on the development of the peripheral memory population. These results underscore the importance of LIGHT activity in programming memory CD8 T cell development, and suggest that CD8 effector T cells can dictate their own fate into becoming memory cells by expressing LIGHT.

https://ift.tt/2GObIME

Response to Comment on "Type I CD20 Antibodies Recruit the B Cell Receptor for Complement-Dependent Lysis of Malignant B Cells" [LETTERS TO THE EDITOR]

https://ift.tt/2GKNuCN

Teleost Basophils Have IgM-Dependent and Dual Ig-Independent Degranulation Systems [INNATE IMMUNITY AND INFLAMMATION]

Recently, mammalian basophils have been highlighted as having roles in allergy and antiparasitic immunity; however, there is little information about the functions and evolutionary origin of basophils, because they are the least abundant leukocyte in most vertebrates. In this study, we characterized the teleost basophils that are abundant in the peripheral blood of fugu (Takifugu rubripes). Fugu basophils have two distinct granules: reddish-purple and dark violet ones. Teleost fish do not have IgG and IgE, but we found that fugu IgM bound on the surface of the basophils, and the cross-linked IgM induced degranulation of both types of granules. This indicates that teleost basophils can be activated in an Ab-dependent manner. Furthermore, papain induced the degranulation of the reddish-purple granules, which contain histamine, and the released granules stimulated the migration of various leukocytes. In contrast, chitin elicited the degranulation of the dark violet granules, which resulted in CD4⁺ T cell–specific migration. Thus, fugu basophils control immune responses via two distinct Ab-independent mechanisms. In addition, fugu basophils endocytosed soluble Ag and expressed MHC class II and B7-H1/DC. These findings suggested that fugu basophils can interact with T cells as APCs. Thus, the Ab-dependent basophil activation predates the emergence of IgG and IgE, and fish basophils exhibit different dynamics and features of degranulation to distinct stimuli compared with mammalian basophils. Some features of teleost basophils are more similar to those of mammalian mast cells than to those of mammalian basophils.

https://ift.tt/2GJzp8w

The Impact of Maternal Microbes and Microbial Colonization in Early Life on Hematopoiesis [BRIEF REVIEWS]

All body surfaces are colonized by microbes, which occurs through a dynamic process over the first few years of life. Initial colonizing microbes are transferred from the maternal microbiota to the newborn through vertical transmission. Postnatal maturation of the immune system is heavily influenced by these microbes, particularly during early life. Although microbial-mediated education of the immune system is better understood at mucosal sites, recent data indicate that the systemic immune system is also shaped by the microbiota. Bacterial products and metabolites produced through microbial metabolism can reach distal sites, and metabolites derived from the maternal microbiota can cross the placenta and are present in milk. Recent studies show that the microbiota can even influence immune development in primary lymphoid organs like the bone marrow. This review outlines our current knowledge of how the microbiota can impact hematopoiesis, with a focus on the effects of maternal and early-life microbiota.

https://ift.tt/2qiflzh

Identification of MHC Class Ib Ligands for Stimulatory and Inhibitory Ly49 Receptors and Induction of Potent NK Cell Alloresponses in Rats [INNATE IMMUNITY AND INFLAMMATION]

Early studies indicate that rats may have a repertoire of MHC class Ib–reactive Ly49 stimulatory receptors capable of mounting memory-like NK cell alloresponses. In this article, we provide molecular and functional evidence for this assumption. Pairs of Ly49 receptors with sequence similarities in the lectin-like domains, but with opposing signaling functions, showed specificity for ligands with class Ia–like structural features encoded from the first telomeric MHC class Ib gene cluster, RT1-CE, which is syntenic with the H2-D/H2-L/H2-Q cluster in mice. The activating Ly49s4 receptor and its inhibitory counterparts, Ly49i4 and Ly49i3, reacted with all allelic variants of RT1-U, whereas Ly49s5 and Ly49i5 were specific for RT1-E^u. NK cell cytolytic responses were predictably activated and inhibited, and potent in vivo NK alloresponses were induced by repeated MHC class Ib alloimmunizations. Additional Ly49–class Ib interactions, including RT1-C^l with the Ly49s4/Ly49i4/Ly49i3 group of receptors, were characterized using overexpressed receptor/ligand pairs, in vitro functional assays, and limited mutational analyses. Obvious, as well as subtle, Ly49–class Ib interactions led to ligand-induced receptor calibration and NK subset expansions in vivo. Together, these studies suggest that in vivo NK alloresponses are controlled by pleomorphic Ly49–class Ib interactions, some of which may not be easily detectable in vitro.

https://ift.tt/2GIjhnM

Cutting Edge: Imbalanced Cation Homeostasis in MAGT1-Deficient B Cells Dysregulates B Cell Development and Signaling in Mice [CUTTING EDGE]

Cation homeostasis, in relation to various immune-suppressive diseases, is a novel field of investigation. Recently, patients with a loss-of-function mutation in magnesium transporter 1 (MAGT1) were reported to present a dysregulated Mg²⁺ homeostasis in T lymphocytes. Using Magt1-knockout mice (Magt1^–/y), we show that Mg²⁺ homeostasis was impaired in Magt1^–/y B cells and Ca²⁺ influx was increased after BCR stimulation, whereas T and NK cell function was unaffected. Consequently, mutant B cells displayed an increased phosphorylation of BCR-related proteins differentially affecting protein kinase C activation. These in vitro findings translated into increased frequencies of CD19⁺ B cells and marginal zone B cells and decreased frequencies of plasma cells among CD45⁺ splenocytes in vivo. Altogether, our study demonstrates for the first time, to our knowledge, that abolished MAGT1 function causes imbalanced cation homeostasis and developmental responses in B cells. Therefore, this study might contribute to a further understanding of B cell–related pathologies.

https://ift.tt/2GK0AjQ

Discovery of Blood Transcriptional Endotypes in Women with Pelvic Inflammatory Disease [SYSTEMS IMMUNOLOGY]

Sexually transmitted infections with Chlamydia trachomatis and/or Neisseria gonorrhoeae and rates of pelvic inflammatory disease (PID) in women continue to rise, with reinfection being common because of poor adaptive immunity. Diagnosis remains imprecise, and pathogenesis data are derived primarily from monoinfection of mice with C. trachomatis or N. gonorrhoeae. By comparing blood mRNA responses of women with C. trachomatis– and/or N. gonorrhoeae–induced PID and histologic endometritis with those from women with C. trachomatis and/or N. gonorrhoeae infection limited to their cervix and asymptomatic uninfected women determined via microarray, we discovered important pathogenic mechanisms in PID and response differences that provide a pathway to biomarker discovery. Women with N. gonorrhoeae– and/or C. trachomatis–induced PID exhibit overexpression of myeloid cell genes and suppression of protein synthesis, mitochondrial oxidative phosphorylation, and T cell–specific genes. Coinfected women exhibited the greatest activation of cell death pathways and suppression of responses essential for adaptive immunity. Women solely infected with C. trachomatis expressed elevated levels of type I and type II IFN genes, and enhanced type I IFN–induced chemokines in cervical secretions were associated with ascension of C. trachomatis to the endometrium. Blood microarrays reveal discrete pathobiological endotypes in women with PID that are driven by pathogen invasion of the upper genital tract.

https://ift.tt/2GIjh7g

Circulating Exosomes with Distinct Properties during Chronic Lung Allograft Rejection [AUTOIMMUNITY]

Circulating exosomes containing donor HLA and lung-associated self-antigens (SAg) are thought to play an important role in allograft rejection after human lung transplantation. We characterized exosomes isolated from serum of 10 lung transplant recipients (LTxR) diagnosed with bronchiolitis obliterans syndrome (BOS) and compared them with exosomes isolated from serum of 10 stable LTxR. Lung-associated SAg (K-α-1-tubulin [Kα1T] and collagen V [Col-V]), MHC class II molecules, costimulatory molecules CD40, CD80, and CD86, and transcription factors class II MHC trans-activator, NF-B, hypoxia-inducible factor 1-α, IL-1R–associated kinase 1, MyD88, and 20S proteasome were detected in exosomes from BOS, but not stable LTxR. In contrast, adhesion molecules were present in both groups. C57BL/6 mice immunized with exosomes from BOS but not stable LTxR demonstrated Ab to SAg (Col-V, 33.5 ± 15.7 versus 10.4 ± 6.4, p = 0.021; Kα1T, 925 ± 403 versus 317 ± 285, p = 0.044) and HLA (mean fluorescence intensity: BOS, 8450; stable, 632; p < 0.05). Furthermore, splenic lymphocytes demonstrated increased frequency of lung SAg-specific IL-17 (Col-V, 128 ± 46 versus 31 ± 21, p = 0.013; Kα1T, 194 ± 47 versus 67 ± 43, p = 0.014) and IFN- (Col-V, 165 ± 79 versus 38 ± 40, p = 0.042; Kα1T, 232 ± 64 versus 118 ± 39, p = 0.012). Reduced levels of IL-10–producing cells were seen in BOS exosome immunized mice compared with mice immunized with stable exosomes (Col-V, 59 ± 23 versus 211 ± 85, p = 0.016; Kα1T, 78 ± 49 versus 295 ± 104, p = 0.017). Owing to the unique immune-stimulating properties of exosomes induced during rejection, we propose that they play an important role in eliciting both alloantigen- and SAg-specific immunity, leading to chronic rejection after lung transplantation.

https://ift.tt/2qm570D

In This Issue [IN THIS ISSUE]

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rIgG1 Fc Hexamer Inhibits Antibody-Mediated Autoimmune Disease via Effects on Complement and Fc{gamma}Rs [AUTOIMMUNITY]

Activation of Fc receptors and complement by immune complexes is a common important pathogenic trigger in many autoimmune diseases and so blockade of these innate immune pathways may be an attractive target for treatment of immune complex-mediated pathomechanisms. High-dose IVIG is used to treat autoimmune and inflammatory diseases, and several studies demonstrate that the therapeutic effects of IVIG can be recapitulated with the Fc portion. Further, recent data indicate that recombinant multimerized Fc molecules exhibit potent anti-inflammatory properties. In this study, we investigated the biochemical and biological properties of an rFc hexamer (termed Fc-μTP-L309C) generated by fusion of the IgM μ-tailpiece to the C terminus of human IgG1 Fc. Fc-μTP-L309C bound FcRs with high avidity and inhibited FcR-mediated effector functions (Ab-dependent cell-mediated cytotoxicity, phagocytosis, respiratory burst) in vitro. In addition, Fc-μTP-L309C prevented full activation of the classical complement pathway by blocking C2 cleavage, avoiding generation of inflammatory downstream products (C5a or sC5b-9). In vivo, Fc-μTP-L309C suppressed inflammatory arthritis in mice when given therapeutically at approximately a 10-fold lower dose than IVIG, which was associated with reduced inflammatory cytokine production and complement activation. Likewise, administration of Fc-μTP-L309C restored platelet counts in a mouse model of immune thrombocytopenia. Our data demonstrate a potent anti-inflammatory effect of Fc-μTP-L309C in vitro and in vivo, likely mediated by blockade of FcRs and its unique inhibition of complement activation.

https://ift.tt/2GOzloc

Contribution of Adipose-Derived Factor D/Adipsin to Complement Alternative Pathway Activation: Lessons from Lipodystrophy [INNATE IMMUNITY AND INFLAMMATION]

Factor D (FD) is an essential component of the complement alternative pathway (AP). It is an attractive pharmaceutical target because it is an AP-specific protease circulating in blood. Most components of the complement activation pathways are produced by the liver, but FD is highly expressed by adipose tissue. Two critical questions are: 1) to what degree does adipose tissue contribute to circulating FD levels and 2) what quantity of FD is sufficient to maintain a functional AP? To address these issues, we studied a novel mouse strain with complete lipodystrophy (LD), the fld mouse with partial LD, an FD-deficient mouse, and samples from lipodystrophic patients. FD was undetectable in the serum of LD mice, which also showed minimal AP function. Reconstitution with purified FD, serum mixing experiments, and studies of partial LD mice all demonstrated that a low level of serum FD is sufficient for normal AP activity in the mouse system. This conclusion was further supported by experiments in which wild-type adipose precursors were transplanted into LD mice. Our results indicate that almost all FD in mouse serum is derived from adipose tissue. In contrast, FD levels were reduced ~50% in the sera of patients with congenital generalized LD. Our studies further demonstrate that a relatively small amount of serum FD is sufficient to facilitate significant time-dependent AP activity in humans and in mice. Furthermore, this observation highlights the potential importance of obtaining nearly complete inhibition of FD in treating alternative complement activation in various autoimmune and inflammatory human diseases.

https://ift.tt/2GLkURT

CCR7 on CD4+ T Cells Plays a Crucial Role in the Induction of Experimental Autoimmune Encephalomyelitis [AUTOIMMUNITY]

Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the CNS. Myelin-specific CD4⁺ Th lymphocytes are known to play a major role in both MS and its animal model experimental autoimmune encephalomyelitis (EAE). CCR7 is a critical element for immune cell trafficking and recirculation, that is, lymph node homing, under homeostatic conditions; blocking CCR7⁺ central memory cells from egress of lymph nodes is a therapeutic approach in MS. To define the effect of CD4⁺ T cell–specific constitutive deletion of CCR7 in the priming and effector phase in EAE, we used an active EAE approach in T cell reconstituted Rag1^–/– mice, as well as adoptive transfer EAE, in which mice received in vitro–primed CCR7^–/– or CCR7^+/+ myelin Ag TCR-transgenic 2d2 Th17 cells. Two-photon laser scanning microscopy was applied in living anesthetized mice to monitor the trafficking of CCR7-deficient and wild-type CD4⁺ T cells in inflammatory lesions within the CNS. We demonstrate that CD4⁺ T cell–specific constitutive deletion of CCR7 led to impaired induction of active EAE. In adoptive transfer EAE, mice receiving in vitro–primed CCR7^–/– 2d2 Th17 cells showed similar disease onset as mice adoptively transferred with CCR7^+/+ 2d2 Th17 cells. Using two-photon laser scanning microscopy CCR7^–/– and CCR7^+/+ CD4⁺ T cells did not reveal differences in motility in either animal model of MS. These findings indicate a crucial role of CCR7 in neuroinflammation during the priming of autoimmune CD4⁺ T cells but not in the CNS.

https://ift.tt/2qjpFqM

MTOR Suppresses Environmental Particle-Induced Inflammatory Response in Macrophages [INNATE IMMUNITY AND INFLAMMATION]

Increasing toxicological and epidemiological studies have demonstrated that ambient particulate matter (PM) could cause adverse health effects including inflammation in the lung. Alveolar macrophages represent a major type of innate immune responses to foreign substances. However, the detailed mechanisms of inflammatory responses induced by PM exposure in macrophages are still unclear. We observed that coarse PM treatment rapidly activated mechanistic target of rapamycin (MTOR) in mouse alveolar macrophages in vivo, and in cultured mouse bone marrow–derived macrophages, mouse peritoneal macrophages, and RAW264.7 cells. Pharmacological inhibition or genetic knockdown of MTOR in bone marrow–derived macrophages leads to an amplified cytokine production upon PM exposure, and mice with specific knockdown of MTOR or ras homolog enriched in brain in myeloid cells exhibit significantly aggregated airway inflammation. Mechanistically, PM activated MTOR through modulation of ERK, AKT serine/threonine kinase 1, and tuberous sclerosis complex signals, whereas MTOR deficiency further enhanced the PM-induced necroptosis and activation of subsequent NF light-chain–enhancer of activated B cells (NFKB) signaling. Inhibition of necroptosis or NFKB pathways significantly ameliorated PM-induced inflammatory response in MTOR-deficient macrophages. The present study thus demonstrates that MTOR serves as an early adaptive signal that suppresses the PM-induced necroptosis, NFKB activation, and inflammatory response in lung macrophages, and suggests that activation of MTOR or inhibition of necroptosis in macrophages may represent novel therapeutic strategies for PM-related airway disorders.

https://ift.tt/2GMdvSp

Biotin Deficiency Induces Th1- and Th17-Mediated Proinflammatory Responses in Human CD4+ T Lymphocytes via Activation of the mTOR Signaling Pathway [CLINICAL AND HUMAN IMMUNOLOGY]

Biotin (vitamin B7) is essential for human health because of its involvement, as a cofactor, in a variety of critical cellular metabolic reactions. Previous studies have shown that biotin deficiency enhances inflammation, and certain chronic inflammatory diseases are associated with biotin deficiency; however, the mechanisms that mediate the association between biotin status and inflammation are not well understood. In this study, we examined the effect of biotin deficiency on human CD4⁺ T cell responses to determine their role in biotin deficiency–associated inflammation. Our investigations revealed that anti-CD3/CD28–stimulated CD4⁺ T cells cultured in biotin-deficient medium secreted significantly enhanced levels of the proinflammatory cytokines IFN-, TNF, and IL-17. Expression of the transcription factors T-bet and RORt was increased, whereas Foxp3 expression was decreased, in biotin-deficient CD4⁺ T cells. The percentage of T regulatory cells was also decreased under biotin-deficient condition. A similar increase in T-bet, RORt, and proinflammatory cytokine levels, as well as a decrease in Foxp3, was observed in inguinal lymph nodes of mice fed a biotin-deficient diet relative to pair-fed controls. Furthermore, differentiation of CD4⁺ T cells toward Th1 and Th17 cells was also enhanced. In vitro and in vivo investigations indicated that the increased inflammatory response was due to enhanced activation of the mammalian target of rapamycin signaling pathway in biotin-deficient CD4⁺ T cells. In summary, these results demonstrate that biotin deficiency enhances the inflammatory responses in CD4⁺ T cells, which may contribute to inflammation associated with biotin deficiency.

https://ift.tt/2GKXkET

Discovery and Analysis of Invertebrate IgVJ-C2 Structure from Amphioxus Provides Insight into the Evolution of the Ig Superfamily [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

The emergence of adaptive immunity in jawed vertebrates depended on the appearance of variable immune receptors, BCRs and TCRs, which exhibit variable-J–constant (V_J-C)–type Ig superfamily folds. Hitherto, however, the structures of IgV-J-IgC–type molecules had never been characterized in invertebrates, leaving the origin of BCR/TCR-type molecules unknown. Using x-ray crystallography, the structure of a V_J-C2 molecule, named AmpIgV_J-C2, was determined in amphioxus (Branchiostoma floridae). The first domain shows typical V folding, including the hydrophobic core, CDR analogs, and eight conserved residues. The second domain is a C2-type Ig superfamily domain, as defined by its short length and the absence of β-strand D- and C1-typical motifs. AmpIgV_J-C2 molecules form homodimers, using "three-layer packing dimerization," as described for TCRs and BCRs. The AmpIgV_J-C2 V domain harbors a diglycine motif in β-strand G and forms a β-bulge structure participating in V–V intermolecular interaction. By immunohistochemistry, AmpIgV_J-C2 molecules were primarily found in mucosal tissues, whereas PCR and sequence analysis indicated considerable genetic variation at the single-gene level; these findings would be consistent with an immune function and a basic ability to adapt to binding different immune targets. Our results show a BCR/TCR-ancestral like molecule in amphioxus and help us to understand the evolution of the adaptive immune system.

https://ift.tt/2GKf7vD

MTOR Suppresses Cigarette Smoke-Induced Epithelial Cell Death and Airway Inflammation in Chronic Obstructive Pulmonary Disease [CLINICAL AND HUMAN IMMUNOLOGY]

Airway epithelial cell death and inflammation are pathological features of chronic obstructive pulmonary disease (COPD). Mechanistic target of rapamycin (MTOR) is involved in inflammation and multiple cellular processes, e.g., autophagy and apoptosis, but little is known about its function in COPD pathogenesis. In this article, we illustrate how MTOR regulates cigarette smoke (CS)–induced cell death, airway inflammation, and emphysema. Expression of MTOR was significantly decreased and its suppressive signaling protein, tuberous sclerosis 2 (TSC2), was increased in the airway epithelium of human COPD and in mouse lungs with chronic CS exposure. In human bronchial epithelial cells, CS extract (CSE) activated TSC2, inhibited MTOR, and induced autophagy. The TSC2–MTOR axis orchestrated CSE-induced autophagy, apoptosis, and necroptosis in human bronchial epithelial cells; all of which cooperatively regulated CSE-induced inflammatory cytokines IL-6 and IL-8 through the NF-B pathway. Mice with a specific knockdown of Mtor in bronchial or alveolar epithelial cells exhibited significantly augmented airway inflammation and airspace enlargement in response to CS exposure, accompanied with enhanced levels of autophagy, apoptosis, and necroptosis in the lungs. Taken together, these data demonstrate that MTOR suppresses CS-induced inflammation and emphysema—likely through modulation of autophagy, apoptosis, and necroptosis—and thus suggest that activation of MTOR may represent a novel therapeutic strategy for COPD.

https://ift.tt/2qm53Or

CXCL17 Chemokine-Dependent Mobilization of CXCR8+CD8+ Effector Memory and Tissue-Resident Memory T Cells in the Vaginal Mucosa Is Associated with Protection against Genital Herpes [MUCOSAL IMMUNOLOGY]

Circulating conventional memory CD8⁺ T cells (i.e., the CD8⁺ effector memory T [T_EM] cell and CD8⁺ central memory T [T_CM] cell subsets) and the noncirculating CD8⁺ tissue-resident memory T (T_RM) cell subset play a critical role in mucosal immunity. Mucosal chemokines, including the recently discovered CXCL17, are also important in mucosal immunity because they are homeostatically expressed in mucosal tissues. However, whether the CXCL17 chemokine contributes to the mobilization of memory CD8⁺ T cell subsets to access infected mucosal tissues remains to be elucidated. In this study, we report that after intravaginal HSV type 1 infection of B6 mice, we detected high expression levels of CXCL17 and increased numbers of CD44^highCD62L^lowCD8⁺ T_EM and CD103^highCD8⁺ T_RM cells expressing CXCR8, the cognate receptor of CXCL17, in the vaginal mucosa (VM) of mice with reduced genital herpes infection and disease. In contrast to wild-type B6 mice, the CXCL17^–/– mice developed 1) fewer CXCR8⁺CD8⁺ T_EM and T_RM cells associated with more virus replication in the VM and more latency established in dorsal root ganglia, and 2) reduced numbers and frequencies of functional CD8⁺ T cells in the VM. These findings suggest that the CXCL17/CXCR8 chemokine pathway plays a crucial role in mucosal vaginal immunity by promoting the mobilization of functional protective CD8⁺ T_EM and CD8⁺ T_RM cells, within this site of acute and recurrent herpes infection.

https://ift.tt/2GK1P2k

NIH completes in-depth genomic analysis of 33 cancer types

The Cancer Genome Atlas (TCGA), supported by NIH's NHGRI and NCI, concludes with an in-depth genomic analysis of 33 cancer types called the PanCancer Atlas. Findings are being published as a collection of 27 papers across multiple Cell journals.

https://ift.tt/2qgpVrc

Cortical Processing Related to Intensity of a Modulated Noise Stimulus—a Functional Near-Infrared Study

Abstract

Sound intensity is a key feature of auditory signals. A profound understanding of cortical processing of this feature is therefore highly desirable. This study investigates whether cortical functional near-infrared spectroscopy (fNIRS) signals reflect sound intensity changes and where on the brain cortex maximal intensity-dependent activations are located. The fNIRS technique is particularly suitable for this kind of hearing study, as it runs silently. Twenty-three normal hearing subjects were included and actively participated in a counterbalanced block design task. Four intensity levels of a modulated noise stimulus with long-term spectrum and modulation characteristics similar to speech were applied, evenly spaced from 15 to 90 dB SPL. Signals from auditory processing cortical fields were derived from a montage of 16 optodes on each side of the head. Results showed that fNIRS responses originating from auditory processing areas are highly dependent on sound intensity level: higher stimulation levels led to higher concentration changes. Caudal and rostral channels showed different waveform morphologies, reflecting specific cortical signal processing of the stimulus. Channels overlying the supramarginal and caudal superior temporal gyrus evoked a phasic response, whereas channels over Broca's area showed a broad tonic pattern. This data set can serve as a foundation for future auditory fNIRS research to develop the technique as a hearing assessment tool in the normal hearing and hearing-impaired populations.

https://ift.tt/2GJruYR

High Thyroid Cancer Mortality Rate in Japan: A Result of Nonaggressive Treatment Strategy, or Just an Aging Population?

Thyroid, Ahead of Print.


https://ift.tt/2Jze3bN

Comparison of the Reynell Developmental Language Scale II and the Galker test of word-recognition-in-noise in Danish day-care children

Publication date: June 2018
Source:International Journal of Pediatric Otorhinolaryngology, Volume 109
Author(s): Jørgen Lous, Maj-Britt Glenn Lauritsen
ObjectiveTo search for predictive factors for language development measured by two receptive language tests for children, the Galker test (a word-recognition-in-noise test) testing hearing and vocabulary, and the Danish version of Reynell Developmental Language Scale (2nd revision, RDLS II) test, a language comprehension test. The study analysed if information about background variables and parents and pre-school teachers was predictive for test scores; if earlier middle ear disease, actual hearing loss and tympanometry was important for language development; and if the two receptive tests differed in terms of the degree to which variables were able to predict test scores at the age of three to five years.MethodsAll children aged three and five years attending 20 day-care centres for children without cognitive development issues from the Municipality of Hillerød, Denmark, were invited to participate. We used questionnaires to the parents and day-care teachers and examined the children using tympanometry, hearing test and the two receptive language tests. We performed unadjusted and adjusted analyses of raw and grouped scores and background variables, as well as stepwise regression analysis with group scores as outcome.ResultsThe results of the two tests were surprisingly similar in relation to background variables. The same variables were predictive for scores in the two receptive language tests. The predictive variables were: age group (22–31%), having no sibling (2–3%), being a boy (1%), information from the parents about the child's vocabulary (3%), phonology (0–2%). information from the pre-school teachers on the child's vocabulary (4–6%), and hearing beyond 25 dB in best ear (mean of four frequencies) (1%).ConclusionWe found that nearly the same variables were predictive for the test score and the grouped score in pre-school children in the RDLS II and the Galker test. Information from the pre-school teachers was more predictive of the test score than information from the parents. In the adjusted analysis, beside age group, information about the child's vocabulary was the most predictive information explaining 4–6% of the variation.



https://ift.tt/2IFgwjA

To Track Environmental Impact on Genome, Don’t Forget the “Epi” in Genetics Research, Johns Hopkins Scientist Says

In a review article published April 5 in the New England Journal of Medicine, scientist Andrew Feinberg, M.D., calls for more integration between two fields of DNA-based research: genetics and epigenetics.

https://ift.tt/2Elolsp

Hammans crunch: a forgotten clue to the diagnosis of spontaneous pneumomediastinum

Description

A 23-year-old Caucasian woman with a thin and tall body habitus presented to the emergency department with dizziness and chest pain. The pain had begun 12 hours before presentation without relation to exertion or trauma, radiating continuously to the neck and dorsum and being exacerbated by coughing or taking deep breaths.

The patient was previously healthy except for an episode of flu-like illness 2 weeks before presentation. She was not taking any medication and was a non-smoker. She had no relevant family history.

On clinical examination, she was conscious and reactive, afebrile and haemodynamically stable. She was eupnoeic and her oxygen saturation on pulse oximetry was 100%. Her breath sounds were normal on pulmonary auscultation, but the presence of a crunching sound synchronous with the heart beat was noted on cardiac auscultation (Hamman's sign—video 1). A discrete subcutaneous emphysema was found on palpation of the left supraclavicular...

https://ift.tt/2JxGve3

A new family of periplasmic-binding proteins that sense arsenic oxyanions

Badilla, C; Osborne, TH; Cole, A; Watson, C; Djordjevic, S; Santini, JM; (2018) A new family of periplasmic-binding proteins that sense arsenic oxyanions. Scientific Reports (In press).

https://ift.tt/2EwBcaY

Scientific data compression for the Solar Wind Analyser onboard Solar Orbiter

Amoruso, L; Abbattista, C; Fortunato, V; Owen, CJ; Bruno, R; Salatti, M; (2015) Scientific data compression for the Solar Wind Analyser onboard Solar Orbiter. In: (Proceedings) The 4th International Workshop on On-Board Payload Data Compression. European Space Agency Green open access

https://ift.tt/2JxDL0f

Can somatic GATA2 mutation mimic germline GATA2 mutation?

Sekhar, M; Pocock, R; Lowe, D; Mitchell, C; Marafioti, T; Dickinson, R; Collin, M; Sekhar, M; Pocock, R; Lowe, D; Mitchell, C; Marafioti, T; Dickinson, R; Collin, M; Lipman, M; - view fewer (2018) Can somatic GATA2 mutation mimic germline GATA2 mutation? Blood Advances (In press).

https://ift.tt/2EwUsoX

Emotion regulation and well-being in primary classrooms situated in low-socioeconomic communities

Somerville, MP; Whitebread, D; (2018) Emotion regulation and well-being in primary classrooms situated in low-socioeconomic communities. British Journal of Educational Psychology (In press).

https://ift.tt/2JywkpS

Performance of the inFLUenza Patient-Reported Outcome (FLU-PRO) diary in patients with influenza-like illness (ILI)

Powers, JH; Bacci, ED; Leidy, NK; Poon, J-L; Stringer, S; Memoli, MJ; Han, A; ... Guerrero, ML; + view all Powers, JH; Bacci, ED; Leidy, NK; Poon, J-L; Stringer, S; Memoli, MJ; Han, A; Fairchok, MP; Coles, C; Owens, J; Chen, W-J; Arnold, JC; Danaher, PJ; Lalani, T; Burgess, TH; Millar, EV; Ridore, M; Hernández, A; Rodríguez-Zulueta, P; Ortega-Gallegos, H; Galindo-Fraga, A; Ruiz-Palacios, GM; Pett, S; Fischer, W; Gillor, D; Moreno Macias, L; DuVal, A; Rothman, R; Dugas, A; Guerrero, ML; - view fewer (2018) Performance of the inFLUenza Patient-Reported Outcome (FLU-PRO) diary in patients with influenza-like illness (ILI). PLoS One , 13 (3) , Article e0194180. 10.1371/journal.pone.0194180 . Green open access

https://ift.tt/2Euho8d

Reduction of Tribocorrosion Products When using the Platform-Switching Concept

Alrabeah, GO; Knowles, JC; Petridis, H; (2018) Reduction of Tribocorrosion Products When using the Platform-Switching Concept. Journal of Dental Researh 10.1177/0022034518765751 . (In press). Green open access

https://ift.tt/2Jyw3mQ

Developing student-driven learning: the patterns, the context, and the process

Watkins, Chris; (2016) Developing student-driven learning: the patterns, the context, and the process. In: Alias, N. A. and Luaran, J. E., (eds.) Student-Driven Learning Strategies for the 21st Century Classroom. (pp. 1-9). IGI Global

https://ift.tt/2IAHYPB

Clarity, Surprises, and Further Questions in the Article 29 Working Party Draft Guidance on Automated Decision-Making and Profiling

Veale, M; Edwards, L; (2018) Clarity, Surprises, and Further Questions in the Article 29 Working Party Draft Guidance on Automated Decision-Making and Profiling. Computer Law and Security Review , 34 (2) pp. 398-404. 10.1016/j.clsr.2017.12.002 . Green open access

https://ift.tt/2Jxu8yX

Measurement of the Higgs boson coupling properties in the H → ZZ∗ → 4ℓ decay channel at s√=13s=13 TeV with the ATLAS detector

Aaboud, M; Aad, G; Abbott, B; Abdinov, O; Abeloos, B; Abidi, SH; AbouZeid, OS; ... Antrim, DJ; + view all Aaboud, M; Aad, G; Abbott, B; Abdinov, O; Abeloos, B; Abidi, SH; AbouZeid, OS; Abraham, NL; Abramowicz, H; Abreu, H; Abreu, R; Abulaiti, Y; Acharya, BS; Adachi, S; Adamczyk, L; Adelman, J; Adersberger, M; Adye, T; Affolder, AA; Afik, Y; Agatonovic-Jovin, T; Agheorghiesei, C; Aguilar-Saavedra, JA; Ahlen, SP; Ahmadov, F; Aielli, G; Akatsuka, S; Akerstedt, H; Åkesson, TPA; Akilli, E; Akimov, AV; Alberghi, GL; Albert, J; Albicocco, P; Alconada Verzini, MJ; Alderweireldt, SC; Aleksa, M; Aleksandrov, IN; Alexa, C; Alexander, G; Alexopoulos, T; Alhroob, M; Ali, B; Aliev, M; Alimonti, G; Alison, J; Alkire, SP; Allbrooke, BMM; Allen, BW; Allport, PP; Aloisio, A; Alonso, A; Alonso, F; Alpigiani, C; Alshehri, AA; Alstaty, MI; Alvarez Gonzalez, B; Álvarez Piqueras, D; Alviggi, MG; Amadio, BT; Amaral Coutinho, Y; Amelung, C; Amidei, D; Amor Dos Santos, SP; Amoroso, S; Amundsen, G; Anastopoulos, C; Ancu, LS; Andari, N; Andeen, T; Anders, CF; Anders, JK; Anderson, KJ; Andreazza, A; Andrei, V; Angelidakis, S; Angelozzi, I; Angerami, A; Anisenkov, AV; Anjos, N; Annovi, A; Antel, C; Antonelli, M; Antonov, A; Antrim, DJ; - view fewer (2018) Measurement of the Higgs boson coupling properties in the H → ZZ∗ → 4ℓ decay channel at s√=13s=13 TeV with the ATLAS detector. Journal of High Energy Physics , 2018 (3) , Article 95. 10.1007/JHEP03(2018)095 . Green open access

https://ift.tt/2Exft2L

A survey of pharmacists' perception of foundation level competencies in African countries

Udoh, A; Bruno, A; Bates, I; (2018) A survey of pharmacists' perception of foundation level competencies in African countries. Human Resources for Health , 16 (1) , Article 16. 10.1186/s12960-018-0280-1 . Green open access

https://ift.tt/2JygtHw

Plasma Evolution within an Erupting Coronal Cavity

Long, DM; Harra, LK; Matthews, SA; Warren, HP; Lee, KS; Doschek, GA; Hara, H; Long, DM; Harra, LK; Matthews, SA; Warren, HP; Lee, KS; Doschek, GA; Hara, H; Jenkins, JM; - view fewer (2018) Plasma Evolution within an Erupting Coronal Cavity. The Astrophysical Journal , 855 (2) , Article 74. 10.3847/1538-4357/aaad68 . Green open access

https://ift.tt/2EuXutW

Information-based cues at point of choice to change selection and consumption of food, alcohol and tobacco products: a systematic review

Carter, P; Bignardi, G; Hollands, GJ; Marteau, TM; (2018) Information-based cues at point of choice to change selection and consumption of food, alcohol and tobacco products: a systematic review. BMC Public Health , 18 , Article 418. 10.1186/s12889-018-5280-5 . Green open access

https://ift.tt/2Jx9dvU

Sedimented governance in the English NHS

Jones, LA; (2017) Sedimented governance in the English NHS. In: Bevir, M and Waring, J, (eds.) Decentring Health Policy: Learning from British Experiences in Healthcare Governance. (pp. 17-33). Routledge: London.

https://ift.tt/2IGpYDh

Estimating the Comparative Effectiveness of Feeding Interventions in the Pediatric Intensive Care Unit: A Demonstration of Longitudinal Targeted Maximum Likelihood Estimation

Kreif, N; Tran, L; Grieve, R; De Stavola, B; Tasker, RC; Petersen, M; (2017) Estimating the Comparative Effectiveness of Feeding Interventions in the Pediatric Intensive Care Unit: A Demonstration of Longitudinal Targeted Maximum Likelihood Estimation. American Journal of Epidemiology , 186 (12) pp. 1370-1379. 10.1093/aje/kwx213 . Green open access

https://ift.tt/2JxDDhh

xGASS: Total cold gas scaling relations and molecular-to-atomic gas ratios of galaxies in the local Universe

Catinella, B; Saintonge, A; Janowiecki, S; Cortese, L; Davé, R; Lemonias, JJ; Cooper, AP; ... Wang, J; + view all Catinella, B; Saintonge, A; Janowiecki, S; Cortese, L; Davé, R; Lemonias, JJ; Cooper, AP; Schiminovich, D; Hummels, CB; Fabello, S; Geŕeb, K; Kilborn, V; Wang, J; - view fewer (2018) xGASS: Total cold gas scaling relations and molecular-to-atomic gas ratios of galaxies in the local Universe. Monthly Notices of the Royal Astronomical Society , 476 (1) pp. 875-895. 10.1093/mnras/sty089 . Green open access

https://ift.tt/2IASEhd

Do primary care placements influence career choice: What is the evidence?

Amin, M; Chande, S; Park, S; Rosenthal, J; Jones, M; (2018) Do primary care placements influence career choice: What is the evidence? Education for Primary Care , 29 (2) pp. 64-67. 10.1080/14739879.2018.1427003 .

https://ift.tt/2JxE9Mb

IL1RN Variation Influences both Disease Susceptibility and Response to Human Recombinant IL-1RA Therapy in Systemic Juvenile Idiopathic Arthritis

Arthur, VL; Shuldiner, E; Remmers, EF; Hinks, A; Grom, AA; Foell, D; Martini, A; ... Ombrello, MJ; + view all Arthur, VL; Shuldiner, E; Remmers, EF; Hinks, A; Grom, AA; Foell, D; Martini, A; Gattorno, M; Özen, S; Prahalad, S; Zeft, AS; Bohnsack, JF; Ilowite, NT; Mellins, ED; Russo, R; Len, C; Oliveira, S; Yeung, RSM; Rosenberg, AM; Wedderburn, LR; Anton, J; Haas, J-P; Rösen-Wolff, A; Minden, K; Szymanski, AM; Thomson, W; Kastner, DL; Woo, P; Ombrello, MJ; - view fewer (2018) IL1RN Variation Influences both Disease Susceptibility and Response to Human Recombinant IL-1RA Therapy in Systemic Juvenile Idiopathic Arthritis. Arthritis & Rheumatology 10.1002/art.40498 . (In press).

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Sustaining tuberculosis decline in the UK

Adam, BU; Cosford, P; Anderson, SR; Abubakar, I; (2017) Sustaining tuberculosis decline in the UK. The Lancet , 389 (10075) pp. 1176-1177. 10.1016/S0140-6736(17)30755-9 . Green open access

https://ift.tt/2JtQbX4

Acute Respiratory Distress Syndrome: Response

Thompson, BT; Chambers, RC; Liu, KD; (2017) Acute Respiratory Distress Syndrome: Response. [Letter]. The New England Journal of Medicine , 377 (19) pp. 1904-1905. 10.1056/NEJMc1711824 .

https://ift.tt/2IELWqs

Technologies for Migration and Population Analysis: Spatial Interaction Data Applications

Stillwell, J; Dennett, AR; Duke-Williams, O; (2010) Technologies for Migration and Population Analysis: Spatial Interaction Data Applications. In: Stillwell, J and Duke-Williams, O and Dennett, A, (eds.) Technologies for Migration and Population Analysis: Spatial Interaction Data Applications. (p. 1). IGI Global: Hershey.

https://ift.tt/2JxDlqH

Magnetic Resonance (MR) Imaging & Blood Biomarkers for Head and Neck Cancer

Condition:   Head and Neck Cancer
Interventions:   Procedure: MRI;   Procedure: Blood Draw;   Behavioral: Questionnaires
Sponsors:   M.D. Anderson Cancer Center;   Radiological Society of North America;   The Royal Australian and New Zealand College of Radiologists
Recruiting

https://ift.tt/2uUnkry

Feasibility of PET/CT to Detect the Oral/Pulmonary Distribution of Nicotine Following E-cigarette Use

Condition:   E-cigarette Use
Interventions:   Drug: C-11 labeled nicotine;   Radiation: PET/CT imaging
Sponsor:   Ohio State University
Recruiting

https://ift.tt/2HkkS0c

Fibroblast Growth Factor-23 and Risks of Cardiovascular and Non-cardiovascular Diseases: a Meta-analysis

Marthi, A; Donovan, K; Haynes, R; Wheeler, DC; Baignent, C; Rooney, CM; Landray, MJ; ... Herrington, W; + view all Marthi, A; Donovan, K; Haynes, R; Wheeler, DC; Baignent, C; Rooney, CM; Landray, MJ; Moe, SM; Yang, J; Holland, L; Giuseppe, RD; Bouma-deKrijger, A; Mihaylova, B; Herrington, W; - view fewer (2018) Fibroblast Growth Factor-23 and Risks of Cardiovascular and Non-cardiovascular Diseases: a Meta-analysis. Journal of the American Society of Nephrology (In press).

https://ift.tt/2qgNCPm

Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy

Finkel, RS; Mercuri, E; Darras, BT; Connolly, AM; Kuntz, NL; Kirschner, J; Chiriboga, CA; ... De Vivo, DC; + view all Finkel, RS; Mercuri, E; Darras, BT; Connolly, AM; Kuntz, NL; Kirschner, J; Chiriboga, CA; Saito, K; Servais, L; Tizzano, E; Topaloglu, H; Tulinius, M; Montes, J; Glanzman, AM; Bishop, K; Zhong, ZJ; Gheuens, S; Bennett, CF; Schneider, E; Farwell, W; De Vivo, DC; - view fewer (2017) Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. New England Journal of Medicine , 377 (18) pp. 1723-1732. 10.1056/NEJMoa1702752 . Green open access

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