Publications by authors named "Susan M MacDonald"

29 Publications

  • Page 1 of 1

Women in Academic Urology: A Qualitative Analysis of the Relationship Between Pregnancy, Parenting and Delayed Promotion.

Urology 2022 Apr 22. Epub 2022 Apr 22.

University of Maryland School of Medicine, Department of Surgery, Division of Urology, Baltimore, MD, USA.

Objective: To determine the role that the burden of childbearing, including pregnancy and maternity leave, play in academic promotion for women in urology, which has been shown to be delayed as compared to their male counterparts.

Method: Female academic urologists of varying academic rank who have children were invited to participate in a semi-structured interview. A representative sample from multiple subspecialties and geographic locations were targeted. Topics addressed included pregnancy, maternity leave, parenting, and promotion in academic urology. Transcripts of the interview were analyzed using grounded theory methodology.

Results: Eleven participants were interviewed, including 3 assistant, 5 associate, and 3 full professors. The majority of participants chose to time pregnancy with training either during less strenuous portions or avoiding residency altogether. Nearly half endorsed self-inflicted hardships during pregnancy or early postpartum to prevent inconveniencing colleagues or to "pull their weight" in accordance with surgical culture. Outsourcing of childcare and household duties, along with spousal support, were discussed as contributing to success. Lack of transparency for promotional criteria was identified as a significant obstacle to promotion. Sponsorship and self-motivated information gathering were identified as critical components to success in promotion.

Conclusion: A culture of support created by administration and colleagues is critical for a positive experience with childbearing, and return to clinical practice or training postpartum. Explicit promotional criteria that are accessible in early career development and sponsorship from members of the academic department or subspecialty community are crucial for all urologists, but for women in particular.
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http://dx.doi.org/10.1016/j.urology.2022.02.030DOI Listing
April 2022

Physiology of Erection and Pathophysiology of Erectile Dysfunction.

Urol Clin North Am 2021 Nov;48(4):513-525

James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, 600 North Wolfe Street, Marburg 407, Baltimore, MD 21287, USA.

The science of penile erection, including recent advances in its molecular physiology and neuroanatomic pathways, is described. The pathophysiology of erectile dysfunction is presented, acknowledging associated disease states, and accordingly follows a practical classification scheme: vasculogenic, neurogenic, endocrine, and psychogenic.
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http://dx.doi.org/10.1016/j.ucl.2021.06.009DOI Listing
November 2021

Pyoderma gangrenosum of the penis.

Can J Urol 2021 02;28(1):10560-10564

Department of Urology, Montefiore Medical Center, Bronx, New York, USA.

Pyoderma gangrenosum (PG) is a cutaneous inflammatory disorder that results in painful ulcers. Isolated penile PG is an exceedingly rare entity that has only been reported in a handful of cases. This case highlights the course of a 71-year old man with a locally destructive, nonhealing penile ulceration who was ultimately diagnosed with PG. He underwent extensive work up to reach the diagnosis. His disease progression was halted with systemic steroids and Methotrexate. We present his clinical course and a review of the literature to highlight the need for early recognition of this potentially devastating condition and to outline management options.
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February 2021

Widely Variable Parental Leave Practices for Urology Residency Programs in the United States.

Urology 2021 07 13;153:81-86. Epub 2021 Feb 13.

Department of Surgery, Division of Urology, The Pennsylvania State University, College of Medicine, Hershey, PA.

Objective: To query a cohort of program directors to better understand the contemporary landscape of parental leave for urology trainees. The American Board of Urology mandates that a resident must work 46 weeks annually in order to not extend residency. We hypothesize that formal parental leave policies may vary by institution and may not be easily accessible.

Methods And Materials: A 22 question survey designed to assess parental leave policies was distributed to 144 American College of Graduate Medical Education accredited Urology residency program directors in the United States via e-mail. Results were collected anonymously.

Results: A total of 65 program directors completed the survey for a response rate of 43%. The median age of program directors was 49 and 78% were male. Only 12% reported no formal maternity leave policy, while 21% reported no formal paternity leave policy. Maternity leave duration varied greatly with 6 (49%) and 12 weeks (27%) as the most common duration, while paternity leave was most commonly reported as 2 (39%), 6 (18%) and 12 weeks (19%) in length. Most parental leave policies were available via an institutional website (81%), with only 39% available on a public website. While most leave policies covered compensation, few addressed call expectations or procedural safety precautions.

Conclusion: Parental leave policies across Urology training programs in the United States are variable, and may not cover critical components of pregnancy or leave. An opportunity exists to create a comprehensive, standardized parental leave policy.
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http://dx.doi.org/10.1016/j.urology.2020.12.049DOI Listing
July 2021

Urinary tract foreign body: A case of panurethral and intravesical spray foam insulation.

Urol Case Rep 2020 Nov 29;33:101363. Epub 2020 Jul 29.

Division of Urology, Penn State Health Milton S. Hershey Medical Center, 500 University Drive, P.O. Box 850, Hershey, PA, USA.

Foreign bodies are inserted into the genitourinary tract for various reasons, and may present a challenge to remove. We report a case of foam insulation injected into the urethra almost entirely occluding the urethra and filling the bladder. Ultimately both a cystotomy and perineal urethrotomy were required for removal.
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http://dx.doi.org/10.1016/j.eucr.2020.101363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573941PMC
November 2020

Management of common iatrogenic iris defects induced by cataract surgery.

J Cataract Refract Surg 2021 Apr;47(4):522-532

From The Eye Center of Northern Colorado, PC (Foster), Fort Collins, Colorado, Ophthalmic Partners of PA (Ayres), Bala Cynwyd, Pennsylvania, Advanced Eye Care (Fram), Los Angeles, California, Baylor College of Medicine (Khandelwal), Houston, Texas, Eye Corps (MacDonald), Dallas, Texas, Tufts University School of Medicine (MacDonald), Boston, Massachusetts, Stein Eye Institute (Miller), University of California, Los Angeles, Los Angeles, California, Eye Associates of New Mexico, University of New Mexico (Ogawa), Albuquerque, New Mexico, Cincinnati Eye Institute (Snyder), Cincinnati, Ohio, USA; Iladevi Cataract & IOL Research Center (Vasavada) Ahmedabad, India.

The proximity of the iris to the instruments and currents of cataract surgery makes iatrogenic damage to the iris a common complication of cataract surgery. This article discusses techniques to prevent or minimize this damage. When damage does occur, the surgeon must decide if, when, and how to repair the damage. Principles governing these decisions and techniques for repair are discussed. Figures and videos, included as online Supplemental Data files, illustrate cases of iatrogenic damage and repair techniques.
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http://dx.doi.org/10.1097/j.jcrs.0000000000000411DOI Listing
April 2021

Phacoemulsification of posterior polar cataracts.

J Cataract Refract Surg 2019 02;45(2):228-235

Iladevi Cataract & IOL Research Centre, Ahmedabad, India.

Posterior polar cataracts present a unique challenge for the cataract surgeon. This review describes the steps a surgeon can take to overcome these challenges for the successful phacoemulsification of the posterior polar cataract. Proper preoperative examination and diagnostics will allow appropriate preoperative counseling and surgical planning to increase the likelihood of success. Specific techniques for each stage of the procedure are described, all with the aim of protecting the posterior capsule and preserving intraocular lens (IOL) fixation options. Posterior polar cataracts present dilemmas in preoperative evaluation, surgical management, and IOL fixation.
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http://dx.doi.org/10.1016/j.jcrs.2018.09.029DOI Listing
February 2019

Sexual Harassment in Ophthalmology: A Survey Study.

Ophthalmology 2019 01 16;126(1):172-174. Epub 2018 Oct 16.

Department of Ophthalmology, Tufts University, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.ophtha.2018.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629426PMC
January 2019

History of Histamine-Releasing Factor (HRF)/Translationally Controlled Tumor Protein (TCTP) Including a Potential Therapeutic Target in Asthma and Allergy.

Results Probl Cell Differ 2017;64:291-308

The Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Room 3B.69, Baltimore, MD, 21224, USA.

Histamine-releasing factor (HRF) also known as translationally controlled tumor protein (TCTP) is a highly conserved, ubiquitous protein that has both intracellular and extracellular functions. Here we will highlight the subcloning of the molecule, its clinical implications, as well as an inducible-transgenic mouse. Particular attention will be paid to its extracellular functioning and its potential role as a therapeutic target in asthma and allergy. The cells and the cytokines that are produced when stimulated or primed by HRF/TCTP will be detailed as well as the downstream signaling pathway that HRF/TCTP elicits. While it was originally thought that HRF/TCTP interacted with IgE, the finding that cells not binding IgE also respond to HRF/TCTP called this interaction into question. HRF/TCTP or at least its mouse counterpart appears to interact with some, but not all IgE and IgG molecules. HRF/TCTP has been shown to activate multiple human cells including basophils, eosinophils, T cells, and B cells. Since many of the cells that are activated by HRF/TCTP participate in the allergic response, the extracellular functions of HRF/TCTP could exacerbate the allergic, inflammatory cascade. Particularly exciting is that small molecule agonists of the phosphatase SHIP-1 have been shown to modulate the P13 kinase/AKT pathway and may control inflammatory disorders. This review discusses this possibility in light of HRF/TCTP.
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http://dx.doi.org/10.1007/978-3-319-67591-6_16DOI Listing
July 2019

Nationwide Procedural Trends for Renal Trauma Management.

Ann Surg 2019 02;269(2):367-369

Wake Forest School of Medicine, Department of Urology, Winston-Salem, NC.

Objective: To characterize national trends in procedural management of renal trauma.

Background: Management of renal trauma has evolved to favor a more conservative approach. For patients requiring intervention, there is a paucity of information to characterize the nature of procedural therapy administered.

Methods: A retrospective cross-sectional analysis was performed using data contained within the National Trauma Data Bank. The National Trauma Data Bank is a voluntary data repository managed by the American College of Surgeons, containing data regarding trauma admissions at 747 level I to V trauma centers throughout the United States and Canada. Participants included any patient with renal trauma requiring intervention from 2002 to 2012. They were identified according to International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes, with codes 866.00 through 866.03 for blunt renal trauma, and codes 866.10 through 866.13 for penetrating trauma. Cases were separated into those requiring nephrectomy, renorrhaphy, or endovascular repair based on ICD-9 procedure code. The number of cases performed each year and yearly trends as measured by linear regression.

Results: A total of 4296 cases were reported during the study period. Of these cases, 2635 involved blunt trauma and 1661 involved penetrating injury. There was a significant increase in the percentage of cases managed by endovascular means for both blunt and penetrating trauma (R = 0.92, P < 0.01; and R = 0.86, P < 0.01, respectively). This was primarily at the expense of nephrectomy, with cases showing significant decline in both groups.

Conclusions: National trends for procedural management of renal trauma are toward less invasive interventions. These trends suggest favorable change towards renal preservation and decreased morbidity, potentially facilitated, in part, by improved radiographic staging and endovascular techniques, and also increased provider awareness of the safety and value of conservative management.
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http://dx.doi.org/10.1097/SLA.0000000000002475DOI Listing
February 2019

Periurethral Gland Calculus Discovered on Workup for Dyspareunia.

Curr Urol 2017 Apr 30;10(1):55-56. Epub 2017 Mar 30.

Wake Forest Baptist Health, Department of Urology, Winston Salem, N.C., USA.

A 55-year-old woman with a history of chronic dysuria in the absence of infection was found to have an unusual lesion below the urethral meatus. This was subsequently determined to be a periurethral gland containing a sizeable calculus. Pathologic analysis found the composition to be car bonate apatite (dahllite). Only one prior report of a female periurethral calculus has been noted in the English peer-reviewed literature.
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http://dx.doi.org/10.1159/000447152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436006PMC
April 2017

February consultation #4.

J Cataract Refract Surg 2016 Feb;42(2):341

Peabody, Massachusetts, USA.

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http://dx.doi.org/10.1016/j.jcrs.2016.01.005DOI Listing
February 2016

Sex Differences Among Career Development Awardees in the Attainment of Independent Research Funding in a Department of Medicine.

J Womens Health (Larchmt) 2015 Nov 20;24(11):933-9. Epub 2015 Aug 20.

1 Department of Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland.

Background: National data suggest that women are overall less likely than men to attain independent research funding. However, it remains unclear whether such sex differences are also observed in academic institutions that have integrated diversity in the workplace as a priority.

Methods: During 1999-2008, all National Institutes of Health (NIH) Career Development (K01, K08, or K23) awardees in the Department of Medicine at Johns Hopkins University School of Medicine were identified to investigate differences in the attainment of independent funding by sex, including NIH Research Project Grant (R01) or equivalent awards, (U01, P01, P50), and any R award (also R03, R21, R34) through 2012.

Results: A similar number of men (n = 49) and women (n = 43) received a K award. There were no significant sex differences in attaining an R01/equivalent award or any R award. The median time to attaining the first R01/equivalent award was similar for men and women (5.6 vs. 5.3 years, p = 0.93). The actuarial rate of R01/equivalent award attainment at 10 years was 64% overall (56% among men vs. 74% among women; log-rank p = 0.41). For any R award, the rate was 72% overall (70% among men vs. 76% among women; log-rank p = 0.63). In Cox proportional hazards models, adjusting for race/ethnicity, age, Doctor of Medicine (MD) degree, and funding period, sex was not an independent predictor of R01/equivalent or any R award attainment. Interestingly, black race and/or Hispanic ethnicity significantly predicted any R award attainment (adjusted hazard ratio [HR] = 2.34, 95% confidence interval [CI] 1.02-5.37).

Conclusions: No sex differences were found in the attainment of independent funding by K awardees in our study. Future studies to investigate the impact of specific diversity initiatives on subsequent success in attaining independent research funding are needed.
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http://dx.doi.org/10.1089/jwh.2015.5331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4649769PMC
November 2015

Through a Gender Lens: A View of Gender and Leadership Positions in a Department of Medicine.

J Womens Health (Larchmt) 2015 Oct 22;24(10):837-42. Epub 2015 Jul 22.

4 Division of Hematology, Departments of Medicine, Oncology, and Institute for Cellular Engineering, Johns Hopkins University School of Medicine , Baltimore, Maryland.

Background: Despite increasing numbers in academic medicine, women remain underrepresented in top leadership positions. The objectives of this study were to characterize leadership positions held by department of medicine (DOM) faculty at all ranks at one Academic Health Center and to compare leadership positions held by male and female faculty.

Methods: This was a cross-sectional survey to collect information on all leadership positions from 16 divisions in the DOM at the Johns Hopkins University School of Medicine in early 2012, including type of position, method used to fill the position, and financial compensation. Chi-square testing was used to compare leadership position characteristics by rank and gender.

Results: The study included 474 DOM faculty at the rank of instructor or higher; 38% were women. Of the 258 leadership positions identified, 35% were held by women. More leadership positions among assistant professors were held by women compared with men (56% of positions vs. 44%), with women assistant professors more likely to hold a leadership position than men (p=0.03). Numbers of women faculty declined at higher ranks, with leadership positions remaining proportionate to faculty representation. Most division director positions (88%) were held by men, and most leadership positions were compensated (89%) and appointed by the DOM chair or a division director (80%).

Conclusions: Leadership positions held by women and men were proportionate to faculty representation, although the top leadership positions were held almost exclusively by men. While female assistant professors were more likely to hold leadership positions than male assistant professors, these positions appear to be low status positions and it is not clear that they contribute to professional advancement, as few women hold the rank of full professor. Effective interventions are needed to address the gender disparity in top leadership positions.
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http://dx.doi.org/10.1089/jwh.2014.5054DOI Listing
October 2015

Potential role of histamine releasing factor (HRF) as a therapeutic target for treating asthma and allergy.

J Asthma Allergy 2012 17;5:51-9. Epub 2012 Sep 17.

The Johns Hopkins Asthma and Allergy Center, Baltimore MD, USA.

Histamine releasing factor (HRF), also known as translationally controlled tumor protein (TCTP), is a highly conserved, ubiquitous protein that has both intracellular and extracellular functions. Here, we will highlight the history of the molecule, its clinical implications with a focus on its extracellular functioning, and its potential role as a therapeutic target in asthma and allergy. The cells and cytokines produced when stimulated or primed by HRF/TCTP are detailed as well as the downstream signaling pathway that HRF/TCTP elicits. While it was originally thought that HRF/TCTP interacted with IgE, the finding that cells not binding IgE also respond to HRF/TCTP called this interaction into question. HRF/TCTP, or at least its mouse counterpart, appears to interact with some, but not all IgE and IgG molecules. HRF/TCTP has been shown to activate multiple human cells including basophils, eosinophils, T cells, and B cells. Since many of the cells activated by HRF/TCTP participate in the allergic response, extracellular functions of HRF/TCTP may exacerbate the allergic, inflammatory cascade. Particularly exciting is that small molecule agonists of Src homology 2-containing inositol phosphatase-1 have been shown to modulate the phosphoinositide 3-kinase/AKT pathway and may control inflammatory disorders. This review discusses this possibility in light of HRF/TCTP.
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http://dx.doi.org/10.2147/JAA.S28868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461606PMC
October 2012

Histamine-releasing factor has a proinflammatory role in mouse models of asthma and allergy.

J Clin Invest 2012 Jan 1;122(1):218-28. Epub 2011 Dec 1.

Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.

IgE-mediated activation of mast cells and basophils underlies allergic diseases such as asthma. Histamine-releasing factor (HRF; also known as translationally controlled tumor protein [TCTP] and fortilin) has been implicated in late-phase allergic reactions (LPRs) and chronic allergic inflammation, but its functions during asthma are not well understood. Here, we identified a subset of IgE and IgG antibodies as HRF-interacting molecules in vitro. HRF was able to dimerize and bind to Igs via interactions of its N-terminal and internal regions with the Fab region of Igs. Therefore, HRF together with HRF-reactive IgE was able to activate mast cells in vitro. In mouse models of asthma and allergy, Ig-interacting HRF peptides that were shown to block HRF/Ig interactions in vitro inhibited IgE/HRF-induced mast cell activation and in vivo cutaneous anaphylaxis and airway inflammation. Intranasally administered HRF recruited inflammatory immune cells to the lung in naive mice in a mast cell- and Fc receptor-dependent manner. These results indicate that HRF has a proinflammatory role in asthma and skin immediate hypersensitivity, leading us to suggest HRF as a potential therapeutic target.
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http://dx.doi.org/10.1172/JCI59072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248297PMC
January 2012

The effects of overexpression of histamine releasing factor (HRF) in a transgenic mouse model.

PLoS One 2010 Jun 11;5(6):e11077. Epub 2010 Jun 11.

Graduate Institute of Natural Healing Sciences, Nanhua University, Chiayi, Taiwan.

Background: Asthma is a disease that affects all ages, races and ethnic groups. Its incidence is increasing both in Westernized countries and underdeveloped countries. It involves inflammation, genetics and environment and therefore, proteins that exacerbate the asthmatic, allergic phenotype are important. Our laboratory purified and cloned a histamine releasing factor (HRF) that was a complete stimulus for histamine and IL-4 secretion from a subpopulation of allergic donors' basophils. Throughout the course of studying HRF, it was uncovered that HRF enhances or primes histamine release and IL-13 production from all anti-IgE antibody stimulated basophils. In order to further delineate the biology of HRF, we generated a mouse model.

Methodology/principal Findings: We constructed an inducible transgenic mouse model with HRF targeted to lung epithelial cells, via the Clara cells. In antigen naïve mice, overproduction of HRF yielded increases in BAL macrophages and statistical increases in mRNA levels for MCP-1 in the HRF transgenic mice compared to littermate controls. In addition to demonstrating intracellular HRF in the lung epithelial cells, we have also been able to document HRF's presence extracellularly in the BAL fluid of these transgenic mice. Furthermore, in the OVA challenged model, we show that HRF exacerbates the allergic, asthmatic responses. We found statistically significant increases in serum and BAL IgE, IL-4 protein and eosinophils in transgenic mice compared to controls.

Conclusions/significance: This mouse model demonstrates that HRF expression enhances allergic, asthmatic inflammation and can now be used as a tool to further dissect the biology of HRF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011077PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2884026PMC
June 2010

Histamine-releasing factor/translationally controlled tumor protein (HRF/TCTP)-induced histamine release is enhanced with SHIP-1 knockdown in cultured human mast cell and basophil models.

J Leukoc Biol 2008 Oct 14;84(4):1151-8. Epub 2008 Jul 14.

The John Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA.

Previously, we demonstrated a negative correlation between histamine release to histamine-releasing factor/translationally controlled tumor protein (HRF/TCTP) and protein levels of SHIP-1 in human basophils. The present study was conducted to investigate whether suppressing SHIP-1 using small interfering (si)RNA technology would alter the releasability of culture-derived mast cells and basophils, as determined by HRF/TCTP histamine release. Frozen CD34+ cells were obtained from the Fred Hutchinson Cancer Research Center (Seattle, WA, USA). Cells were grown in StemPro-34 medium containing cytokines: mast cells with IL-6 and stem cell factor (100 ng/ml each) for 6-8 weeks and basophils with IL-3 (6.7 ng/ml) for 2-3 weeks. siRNA transfections were performed during Week 6 for mast cells and Week 2 for basophils with siRNA for SHIP-1 or a negative control siRNA. Changes in SHIP-1 expression were determined by Western blot. The functional knockdown was measured by HRF/TCTP-induced histamine release. siRNA knockdown of SHIP-1 in mast cells ranged from 31% to 82%, mean 65 +/- 12%, compared with control (n=4). Histamine release to HRF/TCTP was increased only slightly in two experiments. SHIP-1 knockdown in basophils ranged from 34% to 69%, mean 51.8 +/- 7% (n=4). Histamine release to HRF/TCTP in these basophils was dependent on the amount of SHIP knockdown. Mast cells and basophils derived from CD34+ precursor cells represent suitable models for transfection studies. Reducing SHIP-1 protein in cultured mast cells and in cultured basophils increases releasability of the cells.
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http://dx.doi.org/10.1189/jlb.0308172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2538601PMC
October 2008

Induced loss of Syk in human basophils by non-IgE-dependent stimuli.

J Immunol 2008 Mar;180(6):4208-17

Asthma and Allergy Center, Johns Hopkins University, Baltimore, MD 21224, USA.

In the general population, Syk expression in human basophils is highly variable and correlates well with the IgE-mediated responsiveness of these cells. Previous studies established that IgE-mediated stimulation results in loss of Syk expression. The current studies investigated whether stimulation through other receptors results in loss of Syk. Two classes of stimulation were examined, those that operate through the kinase Syk and those that operate through a GTP-binding protein. These studies demonstrated that aggregation of leukocyte Ig-like receptor LILRA-2 resulted in phosphorylation of Syk and c-Cbl, was inhibited by a third generation Syk inhibitor with an expected IC(50), and induced histamine release in strict proportion to release induced by anti-IgE Ab. Stimulation of LILRA-2 for 18 h resulted in modest loss of Syk that correlated with the more profound loss of Syk induced by anti-IgE Ab. Human recombinant histamine-releasing factor has also recently been shown to induce Syk phosphorylation and in the current studies has also been shown to induce loss of Syk in 18-h cultures. fMLP stimulation for 18 h was also found to induce modest loss of Syk. fMLP induced phosphorylation of c-Cbl that was sustained for at least 45 min. Phosphorylation of c-Cbl was inhibited by a Syk kinase inhibitor but with an IC(50) that was not consistent with Syk activity, suggesting another kinase was responsible for Cbl phosphorylation following fMLP. These studies demonstrate that it is possible to induce the loss of Syk expression in human basophils by a non-IgE-dependent mechanism and even by a mechanism that does directly involve Syk in the reaction complex.
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http://dx.doi.org/10.4049/jimmunol.180.6.4208DOI Listing
March 2008

Human IgE+ and IgE- are not equivalent to mouse highly cytokinergic IgE.

J Allergy Clin Immunol 2008 Apr 30;121(4):1027-33. Epub 2008 Jan 30.

Johns Hopkins Asthma and Allergy Center at Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: We have previously defined IgE+ as the IgE on basophils from a subset of highly allergic asthmatic subjects that release histamine after stimulation with histamine-releasing factor (HRF). The mechanism of IgE+ remains an enigma. Recently, there have been reports of monomeric highly cytokinergic IgEs causing mediator release, cytokine release, and phosphorylation events in cultured rodent and human mast cells in the absence of antigen.

Objective: We investigated whether human IgE+ might exist as highly cytokinergic IgE in the human system.

Methods: IgE+ was defined as causing greater than 10% histamine release by using HRF as a stimulus of human basophils. By definition, IgE- did not support histamine release to HRF. Once defined, serum and various purified human IgEs were used to stimulate purified human basophils or cultured human mast cells. The cells were examined for histamine release, extracellular signal-regulated kinase (ERK) phosphorylation, and IL-13 secretion.

Results: We found that neither IgE+ nor IgE- induced ERK phosphorylation, histamine release, and IL-13 release from freshly isolated basophils in the absence of a specific antigen. However, human IgE alone did stimulate ERK phosphorylation in cultured human mast cells and IL-3-primed human basophils.

Conclusion: Human IgE+ is not an equivalent of the mouse highly cytokinergic IgE. However, human IgE did have effects on cultured mast cells and basophils. The effect of highly cytokinergic IgE on ERK phosphorylation and cytokine secretion might be due to the priming effect of human basophils and mast cells.
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http://dx.doi.org/10.1016/j.jaci.2007.12.1157DOI Listing
April 2008

Distinct characteristics of signal transduction events by histamine-releasing factor/translationally controlled tumor protein (HRF/TCTP)-induced priming and activation of human basophils.

Blood 2008 Feb 27;111(4):1789-96. Epub 2007 Nov 27.

The Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA.

We previously identified a negative correlation between histamine release to histamine releasing factor/translationally controlled tumor protein (HRF/TCTP) and protein levels of the Src homology 2 domain-containing inositol 5' phosphatase (SHIP) in basophils. We have also demonstrated that HRF/TCTP primes basophils to release mediators. The purpose of this study was to begin characterization of signal transduction events directly induced by HRF/TCTP and to investigate these events when HRF/TCTP is used as a priming agent for human basophil histamine release. Highly purified human basophils were examined for surface expression of bound HRF/TCTP, changes in calcium, and phosphorylation of Akt, mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase (ERK), Syk, and FcepsilonRIgamma. Results showed that basophils from all donors bound HRF/TCTP. There was a biphasic calcium response to HRF/TCTP, which corresponded to the magnitude of histamine release. Furthermore, those donors who have direct histamine release when exposed to HRF/TCTP (HRF/TCTP responder [HRF/TCTP-R] donors) have phosphorylation of Syk, Akt, MEK, and ERK. Remarkably, basophils from HRF/TCTP-nonresponder (HRF/TCTP-NR) donors do not show phosphorylation of these molecules. This finding is different from IL-3, which also primes basophils for histamine release, but does show phosphorylation of these events. We conclude that priming induced by HRF/TCTP is distinct from that induced by IL-3.
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http://dx.doi.org/10.1182/blood-2007-07-104364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2234039PMC
February 2008

A phase III randomized, double-blind, placebo-controlled study evaluating dextromethorphan plus slow-release morphine for chronic cancer pain relief in terminally ill patients.

J Pain Symptom Manage 2007 Apr;33(4):365-71

Palliative Care Medicine, Queen's University, Kingston, Ontario, Canada.

This multicenter trial examined the efficacy and safety of dextromethorphan (DM) as an enhancer of analgesia and modulator of opioid tolerance in cancer patients with pain. Eligible patients were randomized to slow-release morphine plus DM or slow-release morphine plus placebo. The initial DM dose was 60 mg four times daily for seven days, with an increase to 120 mg four times daily, if tolerated, for another seven days. During the study, patients recorded medications and scores for pain, nausea, drowsiness, and insomnia. Sixty-five patients were randomized. Although average pain scores (12.6 vs. 15.8), number of breakthrough doses (9 vs. 11.3), and change in total morphine consumption (550.9 mg vs. 597.1mg) were less in the DM group than placebo group, the differences were not statistically significant (P=0.31-0.33). Side-effect scores were not statistically significantly different. Dizziness was greater in the DM (58%) than placebo (36%) group. This study showed a statistically nonsignificant enhancement of analgesia or modulation of opioid tolerance in cancer patients with pain when DM was added to morphine. Participants receiving the DM also had more toxicity, particularly dizziness. This toxicity and the limited evidence of effect do not support the use of DM to enhance opioid analgesia or to modulate opioid tolerance in cancer patients.
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http://dx.doi.org/10.1016/j.jpainsymman.2006.09.017DOI Listing
April 2007

Regulation of rat basophilic leukemia-2H3 mast cell secretion by a constitutive Lyn kinase interaction with the high affinity IgE receptor (Fc epsilon RI).

J Immunol 2005 Oct;175(7):4543-54

Johns Hopkins University Asthma and Allergy Center, Baltimore, MD 21224, USA.

Signaling through the high affinity IgE receptor is initiated by noncovalently associated Lyn kinase, resulting in the secretion of inflammatory mediators from mast cells. A fraction of the total cellular Lyn is associated via its N-terminal unique domain with the cytoplasmic domain of the Fc epsilonRI beta subunit before receptor aggregation. In the current study, we stably transfected the unique domain of Lyn into rat basophilic leukemia-2H3 mast cells and examined the consequences on Fc epsilonRI-induced signal transduction and mediator secretion to further define the role of the unique domain of Lyn in mast cell secretion. Tyrosine phosphorylation of Fc epsilonRI beta and gamma subunits was partially inhibited in the Lyn unique domain transfectants after Ag stimulation. Ag stimulation of Lyn unique domain transfectants was accompanied by enhanced phosphorylation of MEK and ERK-2, which are required for leukotriene C4 (LTC4) release, and production of LTC4 was increased 3- to 5-fold, compared with cells transfected with vector alone. Conversely, tyrosine phosphorylation of the adaptor protein Gab2, which is essential for mast cell degranulation, was inhibited after Ag stimulation of Lyn unique domain transfectants, and Ag-induced release of histamine was inhibited up to 48%. In rat basophilic leukemia-2H3 cells, Lyn thus plays a dual role by positively regulating Fc epsilonRI phosphorylation and degranulation while negatively regulating LTC4 production. This study provides further evidence that the constitutive interaction between the unique domain of Lyn and the Fc epsilonRI beta subunit is a crucial step in the initiation of Fc epsilonRI signaling and that Lyn is limiting for Fc epsilonRI-induced secretion of inflammatory mediators.
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http://dx.doi.org/10.4049/jimmunol.175.7.4543DOI Listing
October 2005

Assays for histamine-releasing factors: from identification and cloning to discovery of binding partners.

Methods Mol Biol 2006 ;315:231-43

The Johns Hopkins Asthma and Allergy Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

When using a model to study disease, it may be advantageous to identify molecules responsible for biologic functions observed in the model to better understand the disease process being studied. The late phase reaction is used as a model for chronic inflammation, and the histamine releasing activity observed from late phase fluids was thought to be an important factor in the propagation of symptoms that remain in both the late-phase reaction and in chronic inflammation, when the offending antigen is no longer present. Purification from biologic fluids and identification may be helpful in understanding the role of the histamine-releasing factors in inflammation. Once the specific molecule is identified and cloned, techniques such as yeast two-hybrid screens and co-immunoprecipitation experiments can be used to identify binding partners and further elucidate the role of the cloned molecule. The purification and cloning of human recombinant histamine-releasing factor and the subsequent yeast two-hybrid screen and co-immunoprecipitation will be described to illustrate how any functionally defined molecule can be investigated.
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http://dx.doi.org/10.1385/1-59259-967-2:231DOI Listing
December 2005

Identification of the interaction between the human recombinant histamine releasing factor/translationally controlled tumor protein and elongation factor-1 delta (also known as eElongation factor-1B beta).

Biochim Biophys Acta 2004 Apr;1688(3):232-6

The Division of Allergy and Clinical Immunology, Asthma and Allergy Center, The Johns Hopkins School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA.

The human recombinant histamine releasing factor (HrHRF), also known as translationally controlled tumor protein (TCTP), p23 and fortilin, has been described to have both extra- and intracellular functions. To elucidate an extra- or intracellular role for HrHRF, we used the yeast two-hybrid system with HrHRF as the bait and a Jurkat T cell library. We isolated a partial cDNA clone of the human elongation factor-1 delta (EF-1delta) encoding for amino acids 12 to 281. This interaction was confirmed by co-immunoprecipitation experiments. Previously, both HrHRF and EF-1delta have been isolated and identified in association with malignancy in numerous studies. EF-1delta is part of the EF-1 complex responsible for kinetic proofreading in protein synthesis. Additionally, DNA microarray data classifies TCTP (HrHRF) as co-regulated with ribosomal proteins and recent structural analysis of TCTP (HrHRF) relates it to a guanine nucleotide-free chaperone. Our findings of an interaction between HrHRF and EF-1delta taken with some of the recently published information concerning the TCTP (HrHRF) mentioned above suggest a possible intracellular role for TCTP/HrHRF.
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http://dx.doi.org/10.1016/j.bbadis.2003.12.007DOI Listing
April 2004

Inhibition of cytokine gene transcription by the human recombinant histamine-releasing factor in human T lymphocytes.

J Immunol 2003 Oct;171(7):3742-50

The Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA.

Human recombinant histamine-releasing factor (HrHRF) preincubation enhances the secretion of histamine, IL-4, and IL-13 from FcepsilonRI-stimulated human basophils. In GM-CSF-primed human eosinophils, HrHRF increases IL-8 production. Our recent experiments were designed to evaluate the effects of HrHRF on human T cell cytokine production. Purified T cells were preincubated with GST-tagged HrHRF, followed by stimulation with PMA and A23187 overnight. A partial inhibition of IL-2 and IL-13 production (30 and 75%, respectively) was detected compared with that in cells treated with PMA/A23187 alone. However, the production of IFN-gamma was similar in PMA/A23187 stimulated cells with or without HrHRF. The inhibition of cytokine protein production was dose dependent and specific to the HrHRF portion of GST-HrHRF. The inhibition was not due to endotoxin, since preincubation with polymyxin B and HrHRF gave similar results to that with HrHRF alone. The same pattern and specificity of cytokine regulation were replicated in the Jurkat T cell line as for primary T cells. The PMA/A23187-stimulated activity of a proximal promoter IL-13, IL-4, or IL-2 luciferase construct transfected into Jurkat cells was partially inhibited (60, 32, or 70%, respectively) upon GST-HrHRF preincubation, suggesting that HrHRF functions to inhibit cytokine production in Jurkat cells by preventing gene transcription. The inhibition of IL-2 promoter activation was specific to the HrHRF portion of GST-HrHRF. We conclude that HrHRF, in addition to functioning as a histamine-releasing factor, can differentially modulate the secretion of cytokines from human basophils, eosinophils, T cells, and murine B cells, suggesting that it may induce a complex array of responses at sites of allergic inflammation.
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http://dx.doi.org/10.4049/jimmunol.171.7.3742DOI Listing
October 2003

Lack of correlation between bronchial late allergic reaction to Dermatophagoides pteronyssinus and in vitro immunoglobulin E reactivity to histamine-releasing factor derived from mononuclear cells.

Ann Allergy Asthma Immunol 2002 Dec;89(6):606-12

Department of Immunopathology, Sanquin Research at CLB, Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, The Netherlands.

Background: Activity of immunoglobulin (Ig)E-dependent histamine-releasing factor (HRF) is dependent on the IgE molecules bound to the surface of basophils. Sera capable of passively sensitizing basophils to release histamine to HRF were designated IgE+ sera. IgE+ and HRF have been suggested to play a role in late allergic reaction (LAR).

Objective: The working hypothesis was tested that IgE+ induces a LAR. Further, activity of HRF produced by mononuclear cells (HRF(mn)) was compared with that of recombinant HRF p23.

Methods: Atopic patients (n = 82) were bronchially provoked with Dermatophagoides pteronyssinus extract and the change in forced expiratory volume in 1 second was monitored. A LAR was defined as forced expiratory volume in 1 second as percentage of baseline < 80% 4 to 10 hours after allergen challenge. The presence of HRF-responsive IgE in serum was determined using basophils sensitized in vitro by serum.

Results: The presence of HRF(mn)-responsive IgE (IgE(mn+)) in serum was shown not be essential for a LAR: 63% of the patients with a LAR had no IgE(mn+) in their serum. Further, 71% of patients with IgE(mn+) did not have a LAR. HRF(mn) and recombinant HRF p23 were not equivalent in the bioassay: serum of 38 of 82 atopic patients sensitized basophils to release histamine to HRF(mn), whereas this was found with serum of 1 of 82 patients to HRF p23.

Conclusions: The results do not support the hypothesis that IgE(mn+) induces a LAR, but do not exclude the alternative hypothesis that HRFs are released during a LAR and contribute to asthma severity.
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http://dx.doi.org/10.1016/S1081-1206(10)62109-6DOI Listing
December 2002

Association of the Src homology 2 domain-containing inositol 5' phosphatase (SHIP) to releasability in human basophils.

Mol Immunol 2002 Sep;38(16-18):1323-7

The Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA.

During the study of the biology of the Human recombinant Histamine Releasing Factor (HrHRF), we uncovered a hyperreleasable phenotype of basophils from HrHRF-responder donors. Basophils from these donors released histamne to HrHRF, IL-3 and D(2)O. While there has been a significant amount of work elucidating signal transduction events in human basophils, the reason for this hyperreleasable phenotype remained illusive. A clue to the releasability of these highly allergic, asthmatic HrHRF-responder donor basophils was demonstrated in studies using SHIP knockout mice. Bone marrow-derived mast cells from the SHIP knockout mice demonstrated hyperreleasability to stimuli through the IgE receptor and alteration of subsequent signal transduction events. We have demonstrated a highly significant negative correlation between the amount of SHIP protein per cell equivalent and maximum histamine release to HrHRF. These results provide a clue to the hyperreleasable phenotype and implicate SHIP as an additional regulator of secretion in human basophils.
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http://dx.doi.org/10.1016/s0161-5890(02)00082-2DOI Listing
September 2002

IgE-Dependent Histamine-Releasing Factor: A Unique Cytokine.

Int Arch Allergy Immunol 1992 2;99(2-4):316-318. Epub 2009 Sep 2.

Numerous cytokines have been reported to influence basophil histamine release. The IgE-dependent histamine-releasing factor (HRF), interleukin-3 and mononuclear cell chemotactic activating factor (MCAF) are among the direct agonists of basophil histamine release. Kinetic experiments distinguish these three agonists with only HRF paralleling AlgE-induced release. Furthermore, HRF differs from enhancers of release such as IL-3, IL-1 and stem cell factor. Agents which do not cause release include IL-2, IL-4, IL-5, IL-6, G-CSF and ε-binding-protein. Thus, the IgE-dependent HRF appears to be a novel releasing cytokine.
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http://dx.doi.org/10.1159/000236272DOI Listing
September 2009
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