Women's Representation Among Members and Leaders of National Medical Specialty Societies.

PURPOSE: National medical specialty societies speak for their respective fields in policy debates, influence research, affect trainees' specialization decisions, provide career development opportunities, and confer awards and recognitions. This study provides a comprehensive overview of the gender demographics of society members and leaders. METHOD: In 2016, the Group on Women in Medicine and Science (of the Association of American Medical Colleges) sought to characterize the gender of members and leaders of specialty societies from 2000 to 2015. This report provides descriptive data, including how many of the responding societies (representing each of 30 major medical specialties) had substantial (> 10%) increases in women's representation among leadership between the first and second halves of the study period. RESULTS: The average proportion of full members who were female in responding societies was 25.4% in 2005 and 29.3% in 2015. The proportion of women among those serving as the highest-ranking elected leader between 2000 and 2015 in each specialty ranged from 0% to 37.5% (mean, 15.8%). The mean proportion of women on governing boards ranged from 0% to 37.3% (mean of means, 18.8%) in 2000-2007 and from 0% to 47.6% (mean of means, 25.2%) in 2008-2015. In 9 specialties, the mean percentage of women serving on governing boards increased by over 10% from the first to the second half of the study period. CONCLUSIONS: Although many women are full members of specialty societies, women still constitute a minority of leaders. This report establishes a baseline from which to evaluate the effect of societies' efforts to improve diversity, equity, and inclusion.

Implementing Chief Resident Immersion Training (CRIT) in the Care of Older Adults: Overcoming Barriers and Promoting Facilitators.

The Chief Resident Immersion Training (CRIT) in the Care of Older Adults curriculum was developed at Boston University School of Medicine to improve the care of older adults through an educational intervention. The curriculum targeted chief residents (CRs) because their role as mediators between learners and faculty provides the greatest potential impact for transmitting knowledge. The goals of CRIT are to: (1) provide education on geriatric principles and on teaching/leadership skills, (2) foster interdisciplinary collaboration, and (3) complete an action project. This study demonstrates successful implementation of CRIT at a different academic institution in a rural state. The CRs indicated that their confidence in their ability to apply and teach geriatrics improved after CRIT. In addition, the CRs indicated that CRIT improved their confidence in their overall skills as CRs. The barriers and facilitators to implementation are addressed in order to promote successful adoption of CRIT at other institutions, including those in rural states.

Developing and mature human granulocytes express ELP 6 in the cytoplasm.

BACKGROUND: c3orf75 is a conserved open reading frame within the human genome and has recently been identified as the Elongator subunit, ELP6 [1]. The Elongator enzyme complex has diverse roles, including translational control, neuronal development, cell migration and tumorigenicity [2]. OBJECTIVE: To identify genes expressed early in human eosinophil development. METHODS: Eosinophilopoiesis was investigated by gene profiling of IL-5 stimulated CD34+ cells; ELP6 mRNA is upregulated. A monoclonal antibody was raised to the recombinant protein predicted by the open reading frame. RESULTS: ELP6 transcripts are upregulated in a human tissue culture model of eosinophil development during gene profiling experiments. Transcripts are expressed in most tissue types, as shown by reverse-transcriptase PCR. Western blot experiments show that human ELP6 is a 30 kDa protein expressed in the bone marrow, as well as in many other tissues. Flow cytometry experiments of human bone marrow mononuclear cells show that ELP6 is expressed intracellularly, in developing and mature human neutrophils, eosinophils and monocytes. CONCLUSIONS: ELP6 is expressed intracellularly in developing and mature granulocytes and monocytes but not in lymphocytes and erythrocytes.

Identification and validation of shrimp-tropomyosin specific CD4 T cell epitopes.

BACKGROUND: Shellfish allergy is an immune-mediated adverse reaction to allergenic shellfish and is responsible for significant morbidity and mortality. CD4 T cell responses play an important role in the pathophysiological mechanisms of sensitization and in production of IgE. OBJECTIVE: We sought to identify and validate CD4 T cell shrimp tropomyosin-derived epitopes and characterize CD4 T cell responses in subjects with a clinical history of shellfish allergy. METHOD: Using an in vitro MHC-peptide binding assay, we screened 91 overlapping peptides and identified 28 epitopes with moderate and strong binding capacities; 3 additional peptides were included based on MHC binding prediction score. These peptides were then examined in proliferation and cytokine release assays with T cells from allergic subjects. RESULT: 17 epitopes restricted to DRB(∗)01:01, DRB1(∗)03:01, DRB1(∗)04:01, DRB1(∗)09:01, DQB1(∗)02:01, DQB1(∗)03:02 and DQB1(∗)05:01 alleles were identified and validated by both the MHC binding and the functional assays. Two peptides showed specificities to more than one MHC class II allele. We demonstrated that these peptides exert functional responses in an epitope specific manner, eliciting predominantly IL-6 and IL-13. CONCLUSION: The identified epitopes are specific to common MHC class II alleles in the general population. Our study provides important data for the design of peptide-based immunotherapy of shrimp-allergic patients.

Penaeus monodon tropomyosin induces CD4 T-cell proliferation in shrimp-allergic patients.

Shellfish allergy affects approximately 2% of the population and can cause immediate hypersensitivity reactions such as urticaria, swelling, difficulty breathing, and, in some cases, anaphylaxis. Tropomyosin is the major shrimp allergen and binds IgE in two-thirds of patients. A total of 38 shrimp-allergic patients and 20 negative control subjects were recruited and evaluated on the basis of history, skin prick testing, specific immunoglobulin E (IgE) levels, and peripheral blood mononuclear cell proliferation in response to shrimp tropomyosin or shrimp tropomyosin-derived peptides. Of the classically allergic patients by history, 59% tested positive for serum shrimp IgE antibodies. Of patients with shrimp-specific IgE in sera, 70% also had significant IgE levels specific for shrimp tropomyosin. Peripheral blood mononuclear cells from classically shrimp-allergic patients proliferated in a dose-dependent manner in response to to tropomyosin. In addition, a T-cell line derived from a shrimp-allergic patient proliferated specifically in response to tropomyosin-derived peptides. These studies suggest a strategy for immunotherapy using a tropomyosin-derived T-cell epitope vaccination.

Mepolizumab as a corticosteroid-sparing agent in lymphocytic variant hypereosinophilic syndrome.

BACKGROUND: Mepolizumab, a monoclonal anti-IL-5 antibody, is an effective corticosteroid-sparing agent for patients with Fip1-like 1/platelet-derived growth factor receptor α fusion (F/P)-negative hypereosinophilic syndrome (HES). Lymphocytic variant hypereosinophilic syndrome (L-HES) is characterized by marked overproduction of IL-5 by dysregulated T cells. OBJECTIVE: To determine whether patients with L-HES respond to mepolizumab in terms of corticosteroid tapering and eosinophil depletion to the same extent as corticosteroid-responsive F/P-negative patients with HES and a normal T-cell profile. METHODS: Patients enrolled in the mepolizumab trial were evaluated for L-HES on the basis of T-cell phenotyping and T-cell receptor gene rearrangement patterns, and their serum thymus-and-activation-regulated chemokine (TARC) levels were measured. Response to treatment was compared in patient subgroups based on results of these analyses. RESULTS: Lymphocytic variant HES was diagnosed in 13 of 63 patients with HES with complete T-cell assessments. The ability to taper corticosteroids on mepolizumab was similar in patients with L-HES and those with a normal T-cell profile, although a lower proportion of patients with L-HES maintained eosinophil levels below 600/µL. Increased serum TARC levels (>1000 pg/mL) had no significant impact on the ability to reduce corticosteroid doses, but a lower proportion of patients with elevated TARC achieved eosinophil control on mepolizumab. CONCLUSION: Mepolizumab is an effective corticosteroid-sparing agent for patients with L-HES. In some cases however, eosinophil levels remain above 600/µL, suggesting incomplete neutralization of overproduced IL-5 or involvement of other eosinophilopoietic factors.

EGO, a novel, noncoding RNA gene, regulates eosinophil granule protein transcript expression.

Gene expression profiling of early eosinophil development shows increased transcript levels of proinflammatory cytokines, chemokines, transcription factors, and a novel gene, EGO (eosinophil granule ontogeny). EGO is nested within an intron of the inositol triphosphate receptor type 1 (ITPR1) gene and is conserved at the nucleotide level; however, the largest open reading frame (ORF) is 86 amino acids. Sucrose density gradients show that EGO is not associated with ribosomes and therefore is a noncoding RNA (ncRNA). EGO transcript levels rapidly increase following interleukin-5 (IL-5) stimulation of CD34(+) hematopoietic progenitors. EGO RNA also is highly expressed in human bone marrow and in mature eosinophils. RNA silencing of EGO results in decreased major basic protein (MBP) and eosinophil derived neurotoxin (EDN) mRNA expression in developing CD34(+) hematopoietic progenitors in vitro and in a CD34(+) cell line model. Therefore, EGO is a novel ncRNA gene expressed during eosinophil development and is necessary for normal MBP and EDN transcript expression.

Human eosinophil major basic protein 2: location of disulfide bonds and free sulfhydryl groups.

Eosinophil granule major basic protein 2 (MBP2 or major basic protein homolog) is a paralog of major basic protein (MBP1) and, similar to MBP1, is cytotoxic and cytostimulatory in vitro. MBP2, a small protein of 13,433 Da molecular weight, contains 10 cysteine residues. Mass spectrometry shows two cystine disulfide linkages (Cys20-Cys115 and Cys92-Cys107) and 6 cysteine residues with free sulfhydryl groups (Cys2, Cys23, Cys42, Cys43, Cys68, and Cys96). MBP2, similar to MBP1, has conserved motifs in common with C-type lectins. The disulfide bond locations are conserved among human MBP1, MBP2 and C-type lectins.

Eosinophil-derived cationic proteins activate the synthesis of remodeling factors by airway epithelial cells.

Eosinophil cationic proteins influence several biological functions of the respiratory epithelium, yet their direct contribution to airway remodeling has not been established. We show that incubation of the human bronchial epithelial cell line, BEAS-2B, or primary cultured human bronchial epithelial cells, normal human bronchial epithelial cells, with subcytotoxic concentrations (0.1, 0.3, and 1 microM) of major basic protein (MBP), or eosinophil peroxidase (EPO), augmented the transcripts of endothelin-1, TGF-alpha, TGF-beta1, platelet-derived growth factor (PDGF)-beta, epidermal growth factor receptor, metalloproteinase (MMP)-9, fibronectin, and tenascin. A down-regulation of MMP-1 gene expression was observed exclusively in BEAS-2B cells. Cationic protein-induced transcriptional effects were followed by the release of endothelin-1, PDGF-AB in the supernatants by ELISA, and by a down- and up-regulation, respectively, in the levels of MMP-1 and MMP-9 in cell lysates, by Western blot. Cell stimulation with the synthetic polycation, poly-L-arginine, reproduced some but not all effects of MBP and EPO. Finally, simultaneous cell incubation with the polyanion molecules, poly-L-glutamic acid or heparin, restored MMP-1 gene expression but incompletely inhibited MBP- and EPO-induced transcriptional effects as well as endothelin-1 and PDGF-AB release, suggesting that cationic proteins act partially through their cationic charge. We conclude that eosinophil-derived cationic proteins are able to stimulate bronchial epithelium to synthesize factors that influence the number and behavior of structural cells and modify extracellular matrix composition and turnover.

Differential extraction of eosinophil granule proteins.

Eosinophil granules contain several toxic cationic proteins that contribute to the pathophysiology of allergic diseases. These include eosinophil peroxidase, two ribonucleases, and two forms of the major basic protein (MBP). Extraction of eosinophil granules by exposure to acid solution and fractionation on Sephadex G-50 characteristically yields a distinctive profile of three discrete peaks, and these proteins are usually recovered in good quantities, except for the eosinophil major basic protein homolog (MBP2). We investigated the effect of multiple granule extractions by dilute HCl on the recovery of granule proteins. Isolated granules were repetitively extracted, up to 31 times, in 0.01 M HCl, and the extracts fractionated on Sephadex G-50. Whereas initial extracts yielded the characteristic three-peak fractionation pattern, later extracts yielded four discrete peaks. Characterization of the novel fourth peak showed that it contained MBP2. These results indicate that repetitive extraction of eosinophil granules yields an increased amount of all granule proteins, and that MBP2 can now be recovered in good quantities and in a relatively pure form.