Esther M Sternberg

Interests

Research

Integrative Health, Integrative Medicine, Design and Health

Teaching

Integrative Health, Integrative Medicine, Design and Health

Courses

Scholarly Contributions

Books

• Sternberg, E. M. (2009). Healing Spaces: The Science of Place and Well-being. Harvard University Press, Cambridge, MA.
• Sternberg, E. M. (2000). The Balance Within: The Science Connecting Health and Emotions. W.H. Freeman Publishers, New York.

Chapters

• Butts, C. L., & Sternberg, E. M. (2011).

  Neuroendocrine Immune Interactions: Principles and Relevance to Systemic Lupus Erythematosus in: 

  . In Dubois' Lupus Erythematosus. doi:10.1016/B978-1-4377-1893-5.00013-3
• Michelson, D., Pw, G., & Sternberg, E. M. (1994).

  The stress response in critical illness.

  . In New Horiz. New Horiz.
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  : Under normal, unstressed conditions, the body maintains a dynamic equilibrium known as homeostasis--a complex interplay balancing the conflicting demands presented by many internal and external forces. In the face of threatened or actual disruptions (i.e., stress), molecular, cellular, physiologic, and behavioral responses act to restore homeostasis. These responses can be specific to a particular stressor and relatively circumscribed (e.g., secretion of insulin in response to an increase in blood glucose), or can be generalized and relatively nonspecific (e.g., behavioral manifestations of severe anxiety). Typically, more nonspecific and generalized responses occur in the setting of severe and threatening disruptions in homeostasis, and taken together, these responses are known as the "general adaptation or stress syndrome". We will describe the elements and organization of the generalized stress response with particular attention to the hypothalamic-pituitary-adrenal axis as it interacts with the immune system, and we will review what is known about this interactive network in the setting of critical illness.

Journals/Publications

• Sternberg, E. M. (2018). Heart Rate Variability and Inflammation: A Meta-Analysis of Human Studies. Brain Behavior and Immunity.
• Sternberg, E. M. (2021). An Integrative Health Framework for Wellbeing in the Built Environment. Building and Environment. doi:https://doi.org/10.1016/j.buildenv.2021.108253
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  Engineer A, Gualano RJ, Crocker RL, Smith JL, Maizes V, Weil A, Sternberg E. An Integrative Health Framework for Wellbeing in the Built Environment. Building and Environment 2021 August; https://doi.org/10.1016/j.buildenv.2021.108253
• Sternberg, E. M. (2021). Personality and Workstation Type Predict Task Focus and Happiness in the Workplace. PsyArXiv. doi:DOI: https://doi.org/10.31234/osf.io/nqbh9
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  Lindberg C, Baranski E, Gilligan B, Fisher J, Canada K, Heerwagen J, Kampschroer K, Sternberg EM, Mehl M. Personality and Workstation Type Predict Task Focus and Happiness in the Workplace. PsyArXiv 2021 January DOI: https://doi.org/10.31234/osf.io/nqbh9.
• Sternberg, E. M., & Sternberg, E. M. (2021). Effect of workstation type on the relationship between fatigue, physical activity, stress, and sleep. Journal of Occupational and Environmental Medicine. doi:DOI:10.1097/0000000000002108.
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  Goel R, Pham A, Nguyen H, Lindberg C, Gilligan B, Mehl M, Heerwagen J, Kampschroer K, Sternberg EM, Najafi B, and The Wellbuilt for Wellbeing Team: Effect of workstation type on the relationship between fatigue, physical activity, stress, and sleep. Journal of Occupational and Environmental Medicine. 2021 Mar;63(3):e103-e110. DOI:10.1097/0000000000002108.
• Alschuler, L. N., Weil, A. T., Maizes, V., Horwitz, R. J., Chiasson, A. M., Crocker, R. L., & Sternberg, E. M. (2020). Integrative medicine considerations for convalescence from mild-to- moderate COVID-19 disease. Explore, 1-9. doi:doi.org/10.1016/j.explore.2020.12.005
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  The majority of individuals infected with SARS-CoV-2 have mild-to-moderate COVID-19 disease. Convalescence from mild-to-moderate (MtoM) COVID-19 disease may be supported by integrative medicine strategies. Integrative Medicine (IM) is defined as healing-oriented medicine that takes account of the whole person, including all aspects of lifestyle. Integrative medicine strategies that may support recovery from MtoM COVID-19 are proposed given their clinically studied effects in related conditions. Adoption of an anti-inflammatory diet, supplementation with vitamin D, glutathione, melatonin, Cordyceps, Astragalus and garlic have potential utility. Osteopathic manipulation, Qigong, breathing exercises and aerobic exercise may support pulmonary recovery. Stress reduction, environmental optimization, creative expression and aromatherapy can provide healing support and minimize enduring trauma. These modalities would benefit from clinical trials in people recovering from COVID-19 infection.
• Alschuler, L. N., Weil, A. T., Maizes, V., Horwitz, R. J., Chiasson, A. M., Crocker, R. L., & Sternberg, E. M. (2022). Integrative medicine considerations for convalescence from mild-to- moderate COVID-19 disease. Explore (NY), 18(2), 140-148.
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  The majority of individuals infected with SARS-CoV-2 have mild-to-moderate COVID-19 disease. Convalescence from mild-to-moderate (MtoM) COVID-19 disease may be supported by integrative medicine strategies. Integrative Medicine (IM) is defined as healing-oriented medicine that takes account of the whole person, including all aspects of lifestyle. Integrative medicine strategies that may support recovery from MtoM COVID-19 are proposed given their clinically studied effects in related conditions. Adoption of an anti-inflammatory diet, supplementation with vitamin D, glutathione, melatonin, Cordyceps, Astragalus and garlic have potential utility. Osteopathic manipulation, Qigong, breathing exercises and aerobic exercise may support pulmonary recovery. Stress reduction, environmental optimization, creative expression and aromatherapy can provide healing support and minimize enduring trauma. These modalities would benefit from clinical trials in people recovering from COVID-19 infection.
• Engineer, A. A., Ida, A., & Sternberg, E. M. (2020). Healing Spaces: Designing Physical Environments to Optimize Health, Wellbeing and Performance.. International Journal of Environmental Research and Public Health (IJERPH), 17(115), 1-4.
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  Editorial, IJERPH journal special issue on Healing Spaces.
• Oberman, H., Engineer, A., Sternberg, E. M., & Oberman, H. (2019).

  Trauma, place, and transformation:

  . Archive for the Psychology of Religion, 41(1), 26-32. doi:10.1177/0084672418824067
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  This commentary comprises three different responses to Counted and Zock’s article: “Place Spirituality: An Attachment Perspective.” The first response is from Esther Sternberg, MD, who gives a psyc...
• Sternberg, E. M., Mehl, M. R., Ram, S., Currim, F., Srinivasan, K., Burton, A., Razjouyan, J., Lee, H., Gilligan, B., Lindberg, C., Nguyen, H., Canada, K., Sharafkhaneh, A., Goebel, N., Lunden, M., Bhangar, S., Heerwagen, J., Kampschroer, K., & Najafi, B. (2019).

  Wellbuilt for wellbeing: Controlling relative humidity in the workplace matters for our health

  . Indoor Air, 30(1), 167-179. doi:10.1111/ina.12618
• Sternberg, E. M., Foote, F. O., Benson, H., Berger, A., Berman, B., DeLeo, J., Deuster, P. A., Lary, D. J., & Silverman, M. N. (2018).

  Advanced Metrics for Assessing Holistic Care: The “Epidaurus 2” Project

  . Global Advances in Health and Medicine, 7, 2164957X18755981. doi:10.1177/2164957x18755981
• Sternberg, E. M., Skeath, P., Jia, M., Chew, W. M., & Feinstein, Y. (2016).

  Quantification of cortisol in human eccrine sweat by liquid chromatography – tandem mass spectrometry

  . The Analyst, 141(6), 2053-2060. doi:10.1039/c5an02387d
• Sternberg, E., Crist, J. D., Coats, H., Berger, A., & Rosenfeld, A. G. (2016).

  African American Elders’ Serious Illness Experiences: Narratives of “God Did,” “God Will,” and “Life Is Better”

  . Qualitative Health Research, 27(5), 634-648. doi:10.1177/1049732315620153
• K, B., Sternberg, E., J, P., E, S., A, B., White, J., Sternberg, E. M., Skeath, P., S, N., Pollack, J., Phillips, J., P, S., Norris, S., Katheria, V., Katheria, K., J, W., J, P., Handel, D., Groninger, H., , D, H., et al. (2013).

  The nature of life-transforming changes among cancer survivors.

  . Qualitative health research, 23(9), 1155-67. doi:10.1177/1049732313499074
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  Some cancer survivors report positive subjective changes they describe as "life transforming." We used a grounded theory approach to identify the content, underlying process, and identifying characteristics of self-defined "life-transforming" changes (LTCs) reported by 9 cancer survivors. To actualize their hopes for improvement, participants used a self-guided process centered on pragmatic action: researching options, gaining experience, and frankly evaluating results. Many participants discovered unanticipated personal abilities and resources, and those became highly useful in coping with other challenges apart from cancer. This made the increased personal abilities and resources "life transforming" rather than being substantially limited to reducing cancer-related problems. The action-oriented features and processes of LTCs seemed to be more fully described by experiential learning theory than by posttraumatic growth and coping. Supportive intervention to facilitate positive change processes could decrease suffering and enhance positive psychosocial and spiritual outcomes for cancer survivors.
• Sternberg, E. M., & Bevans, M. (2012).

  Caregiving burden, stress, and health effects among family caregivers of adult cancer patients.

  . JAMA, 307(4), 398-403. doi:10.1001/jama.2012.29
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  Unlike professional caregivers such as physicians and nurses, informal caregivers, typically family members or friends, provide care to individuals with a variety of conditions including advanced age, dementia, and cancer. This experience is commonly perceived as a chronic stressor, and caregivers often experience negative psychological, behavioral, and physiological effects on their daily lives and health. In this report, we describe the experience of a 53-year-old woman who is the sole caregiver for her husband, who has acute myelogenous leukemia and was undergoing allogeneic hematopoietic stem cell transplantation. During his intense and unpredictable course, the caregiver's burden is complex and complicated by multiple competing priorities. Because caregivers are often faced with multiple concurrent stressful events and extended, unrelenting stress, they may experience negative health effects, mediated in part by immune and autonomic dysregulation. Physicians and their interdisciplinary teams are presented daily with individuals providing such care and have opportunity to intervene. This report describes a case that exemplifies caregiving burden and discusses the importance of identifying caregivers at risk of negative health outcomes and intervening to attenuate the stress associated with the caregiving experience.
• Sternberg, E. M., Raman, V. V., Gallagher, S., & Critchley, S. (2011).

  A self-fulfilling prophecy: linking belief to behavior.

  . Annals of the New York Academy of Sciences, 1234(1), 98-9. doi:10.1111/j.1749-6632.2011.06184.x
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  Moderated by Esther Sternberg (author of Healing Spaces: The Science of Place and Well-being), philosopher Simon Critchley (the New School for Social Research), cognitive scientist Shaun Gallagher (University of Central Florida), and physicist V.V. Raman (Rochester Institute of Technology) survey how the self is shaped by interactions with the environment; how free will, responsibility, and other traits emerge; and how character and virtue become targets for constructing the self. The following is an edited transcript of the discussion that occurred April 28, 2011, 7:00-8:15 PM, at the New York Academy of Sciences in New York City.
• Sternberg, E. M., Salter, C. E., Lim, J. K., Jones, Y. L., Butts, C. L., & Belyavskaya, E. (2011).

  Tissue expression of steroid hormone receptors is associated with differential immune responsiveness.

  . Brain, behavior, and immunity, 25(5), 1000-7. doi:10.1016/j.bbi.2010.11.003
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  Glucocorticoids have been used as treatments against a number of diseases, especially autoimmune/inflammatory conditions in which the immune system is overactive. These treatments have varying degrees of responsiveness among individuals and in different tissues (including brain); therefore, it is important to determine what could account for these differences. In this study, we evaluated expression of stress hormone receptors in immune cells from lymphoid and non-lymphoid tissues (including brain) as a possible explanation. We analyzed leukocytes (CD45(+)) in kidney, liver, spleen, and thymus tissues from healthy mice for expression of the receptor for stress hormone (glucocorticoid-GR) as well as other steroid hormones (androgen-AR, progesterone-PR) and found that all tissues expressed these steroid hormone receptors but with varying patterns. To determine whether tissue-specific differences were related to immune cell composition, we examined steroid hormone receptor expression in T lymphocytes from each of these tissues and found similar patterns of expression in these cells regardless of tissue source. Because glucocorticoids can also impact brain function, we further examined expression of the stress hormone receptor in brain tissue and found GR expressed in immune cells at this site. In order to investigate the potential impact in an area of neuropathology, we utilized a mouse model of West Nile Virus (WNV). We observed pathological changes in brains of WNV-infected animals and T lymphocytes in the areas of inflammation; however, these cells did not express GR. These data indicate that tissue-specific differences in steroid hormone receptor expression by immune cells could determine responsiveness to steroid hormone treatment.
• Butts, C. L., Warfel, J. M., Sternberg, E. M., D'agnillo, F., Candando, K. M., Butts, C. L., & Belyavskaya, E. (2010).

  Progesterone effects on regulating uterine dendritic cell function vary depending on stage of rodent estrus cycle.

  . Mucosal immunology, 3(5), 496-505. doi:10.1038/mi.2010.28
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  Steroid hormones, such as progesterone, are able to modify immunity and influence disease outcome. Dendritic cells (DCs) drive potent immune responses, express receptors for steroid hormones, and may be a primary target of steroid hormone actions during infection of the genital tract, including uterine tissue. Here, we report that progesterone limited DC-associated activation marker expression and inhibited cytokine secretion by uterine DCs, which was associated with changes in signal transducer and activator of transcription 1 (STAT1) activity. We also found that DCs from mice at stages with higher progesterone concentrations (diestrus, metaestrus) were more sensitive to progesterone than those in stages with lower progesterone concentrations (proestrus, estrus), both in vitro and in vivo. This difference correlated with the levels of progesterone receptor expressed by DCs. These data suggest that progesterone regulates DC function and could contribute to the susceptibility of females to uterine and other genital tract infections at selected time periods throughout the life cycle.
• Sternberg, E. M., Silverman, M. N., & Marques, A. H. (2010).

  Evaluation of stress systems by applying noninvasive methodologies: measurements of neuroimmune biomarkers in the sweat, heart rate variability and salivary cortisol.

  . Neuroimmunomodulation, 17(3), 205-8. doi:10.1159/000258725
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  The two main arms of the stress system include the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis. These two neural stress systems coordinate the response of many other physiological systems to a stressor, including the immune and cardiovascular systems, bringing the body back to homeostasis. The nervous and immune systems communicate with each other in a bidirectional manner. In this review, we will discuss the use of noninvasive methods to evaluate the immune system, ANS and HPA axis. Collection of sweat and saliva, and measurement of heart rate variability are noninvasive methods that can be applied to evaluate neuroimmune interactions. Recently, we validated a new methodology to simultaneously evaluate a large array of neural and immune biomarkers in sweat, collected through cutaneous sweat patches and measured by recycling immunoaffinity chromatography. Noninvasive and ambulatory methodologies of biomarker collection can overcome several limitations intrinsic to invasive methods, such as reducing the stress triggered by collection itself and allowing a wider application to field and community-based settings. Ultimately, simultaneous evaluation of neural and immune systems with noninvasive techniques will help elucidate the underlying interactions of these systems and their role in disease susceptibility and progression of stress-related disorders.
• West, A., Thayer, J. F., Sternberg, E. M., Sterling, C., Sollers, J. J., Silverman, M. N., Phillips, T. M., Marques, A. H., Kampschroer, K., Heerwagen, J., Cizza, G., Christie, I. C., & Abernethy, D. R. (2010).

  The effects of the physical work environment on circadian variations in heart rate variability and the morning rise in cortisol.

  . Eur J Cardiovasc Prev Rehabil, 431-9. doi:10.1016/j.bbi.2008.04.080
• West, A., Verkuil, B., Thayer, J. F., Sternberg, E. M., Sterling, C., Sollers, J. J., Marques, A. H., Kevin, K., Kampschroer, K., Cizza, G., Christie, I. C., Brosschotj, J. F., Brosschot, J. F., & Abernethy, D. R. (2010).

  Effects of the physical work environment on physiological measures of stress.

  . European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology, 17(4), 431-9. doi:10.1097/hjr.0b013e328336923a
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  In this study we investigated the effects of the physical work environment on two physiological measures of the stress response..Circadian variations in vagally mediated heart rate variability (HRV) and the morning rise in cortisol were evaluated in 60 participants working in a government building either in a traditional (individual offices and old cubicles; n=40) or a modern workspace (individualized cubicles with improved views and lighting; n=20). Results revealed significant linear (B=-1.03; confidence interval: -1.05 to -1.01, P
• Sternberg, E. M., & Judd, L. L. (2009).

  Glucocorticoids and Mood 

  . Annals of the New York Academy of Sciences, 1179(1), 229-33. doi:10.1111/j.1749-6632.2009.05059.x
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  The discovery of glucocorticoids and their enormous therapeutic benefits led to the use of these compounds as valuable medications for a wide variety of diseases. In 1950 this effort was ushered in by a landmark event-the awarding of the 1950 Nobel Prize in Physiology and Medicine to Drs. Phillip Hench, Edward Kendall, and Tadeus Reichstein. It was Hench who described and researched the successful use of the glucocorticoid, cortisone, and pituitary adrenocorticotrophic hormones to treat rheumatoid arthritis. Significant scientific discovery preceded Hench and colleagues' efforts, but the revolutionary accumulation of discovery in glucocorticoids since then is one of the unique scientific stories in the history of medicine. The scientific conference upon which this volume is based represents an attempt to convene a state-of-the-science meeting on the current understanding and scientific status of this fascinating, far-reaching, and fast-moving field. This last chapter will summarize the exciting presentations of this 2-day conference.
• Sternberg, E. M., Marketon, J. I., Kang, Z., & Johnson, A. (2009).

  Bacillus anthracis lethal toxin represses MMTV promoter activity through transcription factors.

  . Journal of molecular biology, 389(3), 595-605. doi:10.1016/j.jmb.2009.04.030
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  We have recently shown that the anthrax lethal toxin (LeTx) selectively represses nuclear hormone receptors. In this study, we found that LeTx repressed the activation of the mouse mammary tumor virus promoter related to overexpression of the transcription factors hepatocyte nuclear factor 3, octamer-binding protein 1, and c-Jun. LeTx transcriptional repression was associated with a decrease in the protein levels of these transcription factors in a lethal factor protease activity-dependent manner. Early administration of LeTx antagonists partially or completely abolished the repressive effects of LeTx. In contrast to the rapid cleavage of mitogen-activated protein kinase kinases by LeTx, the degradation of these transcription factors occurred at a relatively late stage after LeTx treatment. In addition, LeTx repressed phorbol-12-myristate-13-acetate-induced mouse mammary tumor virus promoter activity and phorbol 12-myristate 13-acetate induction of endogenous c-Jun protein. Collectively, these findings suggest that transcription factors are intracellular targets of LeTx and expand our understanding of the molecular action of LeTx at a later stage of low-dose exposure.
• Sternberg, E. M., & Marketon, J. I. (2008).

  Neuroendocrinology of Inflammatory Disorders

  . NeuroImmune Biology, 7, 319-348. doi:10.1016/s1567-7443(07)00217-7
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  Abstract The central nervous system (CNS) and immune systems regulate each other; the immune system is regulated by the CNS through hormonal signals and neuronal pathways and conversely the CNS is regulated by the immune system through cellular pathways and molecular signals including cytokines, chemokines, and interleukins (ILs). The CNS regulates the immune system through several routes: the hypothalamic–pituitary–adrenal (HPA) axis, the autonomic nervous system, and the peripheral nervous system. This neuroendocrine regulation of immune function through resultant glucocorticoid release is essential for survival from stress, infection, or inflammatory diseases. Glucocorticoids function through the glucocorticoid receptor (GR) to elicit multiple effects on immune cells and molecules. This chapter will mainly focus on the regulation of the immune response by the neuroendocrine system and the implications for inflammatory disease. Interruptions of this regulatory loop at multiple levels predispose and enhance inflammatory diseases and cause glucocorticoid resistance in a number of diseases.
• Tait, A. S., Sternberg, E. M., & Butts, C. L. (2008).

  The role of glucocorticoids and progestins in inflammatory, autoimmune, and infectious disease.

  . Journal of leukocyte biology, 84(4), 924-31. doi:10.1189/jlb.0208104
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  A bidirectional communication exists between the CNS and the immune system. The autonomic nervous system, through neurotransmitters and neuropeptides, works in parallel with the hypothalamic-pituitary-adrenal axis through the actions of glucocorticoids to modulate inflammatory events. The immune system, through the action of cytokines and other factors, in turn, activates the CNS to orchestrate negative-feedback mechanisms that keep the immune response in check. Disruption of these interactions has been associated with a number of syndromes including inflammatory, autoimmune, and cardiovascular diseases, metabolic and psychiatric disorders, and the development of shock. The hypothalamic-pituitary-gonadal axis also plays an important part in regulating immunity through the secretion of sex hormones. Although numerous studies have established a role for immunomodulation by estrogen and testosterone, the role of progesterone is less well understood. Progesterone is crucial for reproductive organ development and maintenance of pregnancy, and more recent studies have clearly shown its role as an important immune regulator. The main focus of this review will be about the role of steroid hormones, specifically glucocorticoids and progesterone, in inflammatory responses and infectious diseases and how dysregulation of their actions may contribute to development of autoimmune and inflammatory disease.
• Torvik, S., Sternberg, E. M., Silverman, M. N., Phillips, T. M., Marques, A. H., Eskandari, F., Cizza, G., & Christie, I. C. (2008).

  Elevated neuroimmune biomarkers in sweat patches and plasma of premenopausal women with major depressive disorder in remission: the POWER study.

  . Biological psychiatry, 64(10), 907-11. doi:10.1016/j.biopsych.2008.05.035
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  Major depressive disorder (MDD) is inconsistently associated with elevations in proinflammatory cytokines and neuropeptides. We used a skin sweat patch, recently validated in healthy control subjects, and recycling immunoaffinity chromatography to measure neuroimmune biomarkers in patients with MDD mostly in remission..We collected blood at 8:00 am and applied skin sweat patches for 24 hours in 21- to 45-year-old premenopausal women (n = 19) with MDD (17/19 in remission) and age-matched healthy controls (n = 17) participating in the POWER (Premenopausal, Osteopenia/Osteoporosis, Women, Alendronate, Depression) Study..Proinflammatory cytokines, neuropeptide Y, substance P, and calcitonin-gene-related peptide were significantly higher and vasoactive intestinal peptide, a marker of parasympathetic activity, was significantly lower in patients compared to controls, and depressive symptomatology strongly correlated with biomarker levels. All analytes were strongly correlated in the skin sweat patch and plasma in patients (r = .73 to .99; p < .0004)..The skin sweat patch allows detection of disrupted patterns of proinflammatory cytokines and neuropeptides in women with MDD in clinical remission, which could predispose to medical consequences such as cardiovascular disease, osteoporosis, and diabetes. This method permits measurement of cytokines in ambulatory settings where blood collection is not feasible.
• Sternberg, E. M., Marques, A. H., & Cizza, G. (2007).

  [Brain-immune interactions and implications in psychiatric disorders].

  . Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999), 29 Suppl 1(suppl 1), S27-32. doi:10.1590/s1516-44462007000500006
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  This review will focus on the role of cytokines in the central nervous system and its implications to depressive disorder. We will then discuss the main findings of cytokine measurements in patients with major depressive disorder..We searched Pubmed for studies published from 1999-2007, using the keywords depression and cytokine; and depressive disorder and cytokine. We have focused on pro-inflammatory cytokine measurements in patients with depression syndrome using DSM-criteria..Several lines of evidence suggest that cytokines have effects on depression, such as the induction of sickness behavior; clinical conditions related to cytokines that also overlap depressive symptoms; and immunotherapy that can lead to depressive symptoms attenuated by antidepressant treatment. Finally, patients with depression exhibit increased levels of pro-inflammatory cytokines, although conflicting results have been described..Cytokines may play a role in the pathophysiology of some cases of depression, although a causal link has not been established yet. Further longitudinal studies are needed to determine patterns of cytokine in patients with major depressive disorder, taking into account confounding factors closely associated with the activation of pro-inflammatory cytokines. In addition, simultaneous measurements of multiple biomarkers could provide critical insights into mechanisms underlying major depressive disorder and a variety of common cytokine-related diseases.
• Sternberg, E. M., Shukair, S. A., Harris, C. W., Duncan, K. M., Butts, C. L., & Belyavskaya, E. (2007).

  Effects of dexamethasone on rat dendritic cell function.

  . Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 39(6), 404-12. doi:10.1055/s-2007-980195
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  Glucocorticoids have been reported to affect immunity at varying concentrations. While glucocorticoids have shown profound effects on innate immunity, their effects on rat dendritic cells have not been fully examined. In this study, we evaluated the effects of the synthetic glucocorticoid dexamethasone on cultured rat dendritic cells (DCs) from spleen and derived from bone marrow cells to determine whether responsiveness to dexamethasone varies between DCs from different organ sites. Cells were analyzed for expression of glucocorticoid receptor (GR), the primary receptor through which dexamethasone exerts its effects and was found to be primarily located in the cytoplasm of immature DCs. Bone marrow-derived DCs showed more sensitivity to dexamethasone treatment compared to splenic DCs. Dexamethasone treatment of LPS-matured DCs had profound dose-dependent effects on cytokine production. Dexamethasone treatment also led to a dose-dependent downregulation of expression of costimulatory molecules by mature DCs. Dexamethasone modified immature DC uptake of antigen (FITC-Dextran), with slightly higher numbers of splenic DCs taking up antigen compared to bone marrow-derived DCs. These data suggest that dexamethasone is able to similarly affect both bone marrow-derived and splenic DC function at the immature and mature DC states and could contribute to exacerbation of infection by hindering DC-mediated immune responses.
• Sternberg, E. M., Shukair, S. A., Harris, C. W., Duncan, K. M., Butts, C. L., & Belyavskaya, E. (2007).

  Evaluation of steroid hormone receptor protein expression in intact cells using flow cytometry.

  . Nuclear receptor signaling, 5(1), e007. doi:10.1621/nrs.05007
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  Several methods are currently employed to evaluate expression of steroid hormone receptors in tissues and cells, including real-time reverse-transcriptase polymerase chain reaction (real-time RT-PCR) and western blot assays. These methods require homogenization of cells, thereby preventing evaluation of individual cells or specific cell types in a given tissue sample. In addition, methods such as real-time RT-PCR assess mRNA levels, which may be subject to posttranslational modifications that prevent subsequent production of functional proteins. Flow cytometry is a fluorescence-based technique commonly used to evaluate expression of cell surface and intracellular proteins. This method is especially useful as it allows for single-cell analysis and can be utilized to determine the amount of receptor expressed by individual cells. Flow cytometry is commonly used to analyze immune cell activity and determine functionality based on changes in expression of cell surface molecules, as well as intracellular proteins (such as cytokines). Here, we describe a method to identify protein expression of steroid hormone receptors by rat leukocytes from different organs (spleen, liver and thymus) using flow cytometry. We examined expression of glucocorticoid receptor (GR), androgen receptor (AR) and progesterone receptor (PR) by cells at these sites and were able to demonstrate expression of receptors, as well as the intensity of expression of each receptor. This method is useful for rapid, high throughput measurement of steroid hormone receptors at the protein level in single, intact cells and would be valuable to determine which cells are more likely to respond to steroid hormone treatment.
• Sternberg, E. M., Silverman, M. N., & Cizza, G. (2007).

  The neuroendocrine system and rheumatoid arthritis: insights from anti-tumor necrosis factor-alpha therapy.

  . The Journal of rheumatology, 34(7), 1443-5.
• Tait, A. S., Sternberg, E. M., Popoff, M. R., Geny, B., Dalton, M., & D'agnillo, F. (2007).

  The large clostridial toxins from Clostridium sordellii and C. difficile repress glucocorticoid receptor activity.

  . Infection and immunity, 75(8), 3935-40. doi:10.1128/iai.00291-07
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  We have previously shown that Bacillus anthracis lethal toxin represses glucocorticoid receptor (GR) transactivation. We now report that repression of GR activity also occurs with the large clostridial toxins produced by Clostridium sordellii and C. difficile. This was demonstrated using a transient transfection assay system for GR transactivation. We also report that C. sordellii lethal toxin inhibited GR function in an ex vivo assay, where toxin reduced the dexamethasone suppression of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha). Furthermore, the glucocorticoid antagonist RU-486 in combination with C. sordellii lethal toxin additively prevented glucocorticoid suppression of TNF-alpha. These findings corroborate the fact that GR is a target for the toxin and suggest a physiological role for toxin-associated GR repression in inflammation. Finally, we show that this repression is associated with toxins that inactivate p38 mitogen-activated protein kinase (MAPK).
• Tonelli, L. H., Sternberg, E. M., Shukair, S. A., Horn, C., Duncan, K. M., Butts, C. L., Bowers, E., & Belyavskaya, E. (2007).

  Progesterone inhibits mature rat dendritic cells in a receptor-mediated fashion.

  . International immunology, 19(3), 287-96. doi:10.1093/intimm/dxl145
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  A variety of extraimmune system factors, including hormones, play a critical role in regulating immunity. Progesterone has been shown to affect immunity in rodents and humans, mainly at concentrations commensurate with pregnancy. These effects are primarily mediated via the progesterone receptor (PR), which acts as a transcription factor, although non-genomic effects of PR activation have been reported. In this study, we evaluated the effects of progesterone on rat dendritic cells (DCs) at ranges encompassing physiologic and pharmacologic concentrations to determine whether progesterone plays a role in modulating DC-mediated immune responses. DCs were derived by culturing rat bone marrow cells in granulocyte macrophage colony-stimulating factor and IL-4. Cells were analyzed for expression of PR using FACS analysis, real-time reverse transcriptase-PCR and fluorescent microscopy. Progesterone treatment of LPS-activated, mature bone marrow-derived dendritic cells (BMDCs) suppressed production of the pro-inflammatory response-promoting cytokines tumor necrosis factor-alpha and IL-1beta in a dose-dependent manner but did not affect production of the pro-inflammatory response-inhibiting cytokine IL-10. Treatment of cells with progesterone also resulted in down-regulation of co-stimulatory molecule CD80 and MHC class II molecule RT1B expression. In addition, progesterone inhibited DC-stimulated proliferation of T cells. Suppression of pro-inflammatory response-promoting cytokine production by progesterone was prevented using the PR antagonist RU486. There was no dose-dependent effect of progesterone treatment on immature DC capacity to take up antigenic peptide. These data indicate that progesterone directly inhibits mature rat BMDC capacity to drive pro-inflammatory responses. This mechanism could contribute to or account for some of the differential expression of autoimmune/inflammatory disease in females.
• Sternberg, E. M. (2006).

  A Compassionate Universe

  . Science, 311(5761), 611-612. doi:10.1126/science.1123276
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  The Universe in a Single Atom . The Convergence of Science and Spirituality. By the Dalai Lama . Morgan Road, New York, 2005. 224 pp. $24.95, C$32.95. ISBN: 0-7679-2066-X. The author offers a Buddhist perspective on the relation between science and religion through discussions of such contentious topics as the origin of the universe, human consciousness, evolution, and genetic engineering.
• Sternberg, E. M. (2006).

  Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens.

  . Nature reviews. Immunology, 6(4), 318-28. doi:10.1038/nri1810
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  The central nervous system (CNS) regulates innate immune responses through hormonal and neuronal routes. The neuroendocrine stress response and the sympathetic and parasympathetic nervous systems generally inhibit innate immune responses at systemic and regional levels, whereas the peripheral nervous system tends to amplify local innate immune responses. These systems work together to first activate and amplify local inflammatory responses that contain or eliminate invading pathogens, and subsequently to terminate inflammation and restore host homeostasis. Here, I review these regulatory mechanisms and discuss the evidence indicating that the CNS can be considered as integral to acute-phase inflammatory responses to pathogens as the innate immune system.
• Thayer, J. F., & Sternberg, E. M. (2006).

  Beyond heart rate variability: vagal regulation of allostatic systems.

  . Annals of the New York Academy of Sciences, 1088(1), 361-72. doi:10.1196/annals.1366.014
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  The autonomic nervous system (ANS) plays a role in a wide range of somatic and mental diseases. Whereas the role of the ANS in the regulation of the cardiovascular system seems evident, its role in the regulation of other systems associated with allostasis is less clear. Using a model of neurovisceral integration we describe how the ANS and parasympathetic tone in particular may be associated with the regulation of allostatic systems associated with glucose regulation, hypothalamic-pituitary-adrenal (HPA) axis function, and inflammatory processes. Decreased vagal function and heart rate variability (HRV) were shown to be associated with increased fasting glucose and hemoglobin A1c levels, increased overnight urinary cortisol, and increased proinflammatory cytokines and acute-phase proteins. All of these factors have been associated with increased allostatic load and poor health. Thus, vagal activity appears to play an inhibitory function in the regulation of allostatic systems. The prefrontal cortex and the amygdala are important central nervous system structures linked to the regulation of these allostatic systems via the vagus nerve. Finally, the identification of this neurovisceral regulatory system may help to illuminate the pathway via which psychosocial factors may influence health and disease.
• Wilson, M. A., & Sternberg, E. M. (2006).

  Neuroscience and architecture: seeking common ground.

  . Cell, 127(2), 239-42. doi:10.1016/j.cell.2006.10.012
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  As these paired Commentaries discuss, neuroscientists and architects are just beginning to collaborate, each bringing what they know about their respective fields to the task of improving the environment of research buildings and laboratories.
• Sternberg, E. M., Marques-deak, A., & Cizza, G. (2005).

  Brain-immune interactions and disease susceptibility.

  . Molecular psychiatry, 10(3), 239-50. doi:10.1038/sj.mp.4001643
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  Many studies have established the routes by which the immune and central nervous (CNS) systems communicate. This network of connections permits the CNS to regulate the immune system through both neuroendocrine and neuronal pathways. In turn, the immune system signals the CNS through neuronal and humoral routes, via immune mediators and cytokines. This regulatory system between the immune system and CNS plays an important role in susceptibility and resistance to autoimmune, inflammatory, infectious and allergic diseases. This review focuses on the regulation of the immune system via the neuroendocrine system, and underlines the link between neuroendocrine dysregulation and development of major depressive disorders, autoimmune diseases and osteoporosis.
• Sternberg, E. M., Mohr, D. C., Huitinga, I., Heesen, C., Gold, S. M., & Flachenecker, P. (2005).

  The role of stress-response systems for the pathogenesis and progression of MS.

  . Trends in immunology, 26(12), 644-52. doi:10.1016/j.it.2005.09.010
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  Disease progression in multiple sclerosis (MS)--an inflammatory demyelinating and neurodegenerative disease with a presumed T-cell driven autoimmune origin--has long been hypothesized to be associated with stress. However, this notion has only recently been supported by prospective clinical studies. Several clinical and molecular studies in MS and its animal models have recently shown disruptions in the communication between the immune system and the two major stress response systems, the hypothalamo-pituitary-adrenal (HPA) axis and the autonomic nervous system. Insensitivity to glucocorticoid and beta-adrenergic modulation might be involved in overshooting inflammation in MS, whereas hyperactivity of the HPA axis has been linked to neurodegeneration and increased disability. Here, we integrate findings from molecular, cellular, experimental, clinical and epidemiological research to describe the involvement of stress response systems in MS pathogenesis and progression.
• Sternberg, E. M., Sternberg, E. M., Marques-deak, A., Marques-deak, A., Cizza, G., & Cizza, G. (2005).

  Brain-immune interactions and disease susceptibility

  . Molecular Psychiatry, 10(10), 972-972. doi:10.1038/sj.mp.4001732
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  Correction to: Molecular Psychiatry (2005) 10, 239–250, doi:10.1038/sj.mp.4001643 Following publication of the above editorial, the author has identified the following error: In Figure 1, PNS means ‘peripheral nervous system’ and in lines 7 and 8 in the Figure 1 legend, the words ‘and peripheral nervous system’ following after ‘parasympathetic nervous system’ were missing.
• Webster, J. I., & Sternberg, E. M. (2005).

  Anthrax lethal toxin represses glucocorticoid receptor (GR) transactivation by inhibiting GR-DNA binding in vivo.

  . Molecular and cellular endocrinology, 241(1-2), 21-31. doi:10.1016/j.mce.2005.03.011
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  Anthrax lethal factor (LF) is a non-competitive repressor of glucocorticoid (GR) and progesterone receptor (PR) transactivation. This repression was shown to be specific and selective and was dependent on promoter context and receptor subtype. Anthrax lethal toxin (LeTx) selectively repressed GR-mediated transactivation but not transrepression. The DNA binding region of GR was required for repression by LeTx and LeTx prevented GR-DNA binding in vivo, which had downstream consequences on polymerase II binding and histone acetylation. In addition, LeTx also prevented the accessory protein C/EBP from binding to a GR-responsive promoter. We hypothesize that LeTx may remove/inactivate one of the many co-factors or accessory proteins that are required to stabilize the GR-DNA complex. These findings enhance the current knowledge of the molecular mechanism by which the anthrax lethal factor represses nuclear hormone receptors and could provide an approach to overcome some of LeTx's effects.
• Wiggins, J. F., Webster, J. I., Sternberg, E. M., Moayeri, M., & Leppla, S. H. (2005).

  Endocrine perturbation increases susceptibility of mice to anthrax lethal toxin.

  . Infection and immunity, 73(7), 4238-44. doi:10.1128/iai.73.7.4238-4244.2005
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  Bacillus anthracis lethal toxin (LT) causes vascular collapse and high lethality in BALB/cJ mice, intermediate lethality in C57BL/6J mice, and no lethality in DBA/2J mice. We found that adrenalectomized (ADX) mice of all three strains had increased susceptibility to LT. The increased susceptibility of ADX-DBA/2J mice was not accompanied by changes in their macrophage sensitivity or cytokine response to LT. DBA/2J mice showed no change in serum corticosteroid levels in response to LT injection, while BALB/cJ mice showed a fivefold increase in serum corticosterone. However, LT inhibited dexamethasone (DEX)-induced glucocorticoid receptor gene activation to similar extents in all three strains. DEX treatment did not rescue ADX mice from LT-mediated mortality. Surprisingly, oral DEX treatment also sensitized adrenally intact DBA/2J mice to LT lethality at all doses tested and also exacerbated LT-mediated pathogenesis and mortality in BALB/cJ mice. Aldosterone did not protect ADX mice from toxin challenge. These results indicate that susceptibility to anthrax LT in mice depends on a fine but easily perturbed balance of endocrine functions. Thus, the potentially detrimental consequences of steroid therapy for anthrax must be considered in treatment protocols for this disease.
• Sternberg, E. M., Eskandari, F., & Derijk, R. H. (2004).

  Corticosteroid resistance in a subpopulation of multiple sclerosis patients as measured by ex vivo dexamethasone inhibition of LPS induced IL-6 production.

  . Journal of neuroimmunology, 151(1-2), 180-8. doi:10.1016/j.jneuroim.2004.02.009
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  We assessed corticosteroid sensitivity in multiple sclerosis (MS) patients compared to control subjects, using an in vitro assay of dexamethasone (Dex) inhibition of lipopolysaccharide (LPS) stimulated-blood interleukin-6 production. Significantly higher concentrations of dexamethasone were needed to obtain 50%-inhibition (ID(50)) of in vitro LPS stimulated interleukin (IL)-6 production (28.4 x 10(-7) M) in relapsing-remitting MS (RRMS) patients compared to chronic progressive MS (CPMS) patients (6.2 x 10(-7) M) or compared to controls (3.0 x 10(-7) M). We also found a trend towards worsening of clinical status over time with increasing corticosteroid resistance. These data suggest that corticosteroid sensitivity may be a factor in the pathogenesis and could be used for prognosis of MS.
• Webster, J. I., & Sternberg, E. M. (2004).

  Role of the hypothalamic-pituitary-adrenal axis, glucocorticoids and glucocorticoid receptors in toxic sequelae of exposure to bacterial and viral products.

  . The Journal of endocrinology, 181(2), 207-21. doi:10.1677/joe.0.1810207
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  The hypothalamic-pituitary-adrenal (HPA) axis is activated during many bacterial and viral infections, resulting in an increase in circulating glucocorticoid levels. This HPA axis activation and glucocorticoid response are critical for the survival of the host, as demonstrated by the fact that removal of the HPA axis (by adrenalectomy or hypophysectomy) or glucocorticoid receptor (GR) blockade enhances the severity of the infection and in some cases enhances the mortality rate. Replacement with a synthetic glucocorticoid reverses these effects by reducing the severity of the infection and provides protection against lethal effects. In addition, some bacteria and viral infections have been shown to affect the GR directly. These have been described and the implications of such an effect discussed.
• Webster, J. I., Sternberg, E. M., & Moayeri, M. (2004).

  Novel repression of the glucocorticoid receptor by anthrax lethal toxin.

  . Annals of the New York Academy of Sciences, 1024(1), 9-23. doi:10.1196/annals.1321.003
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  Death from anthrax has been reported to occur from systemic shock. The lethal toxin (LeTx) is the major effector of anthrax mortality. Although the mechanism of entry of this toxin into cells is well understood, its actions once inside the cell are not as well understood. LeTx is known to cleave and inactivate MAPKKs. We have recently shown that LeTx represses the glucocorticoid receptor (GR) both in vitro and in vivo. This repression is partial and specific, repressing the glucocorticoid, progesterone, and estrogen receptor alpha, but not the mineralocorticoid or estrogen receptor beta. This toxin does not affect GR ligand or DNA binding, and we have suggested that it may function by removing/inactivating one or more of the many cofactors involved in nuclear hormone receptor signaling. Although the precise involvement of this nuclear hormone receptor repression in LeTx toxicity is unknown, examples of blunted HPA axis and glucocorticoid signaling in numerous autoimmune/inflammatory diseases suggest that such repression of critically important receptors could have deleterious effects on health.
• Webster, J. I., Tonelli, L. H., Sternberg, E. M., Simons, S. S., Moayeri, M., & Leppla, S. H. (2003).

  Anthrax lethal factor represses glucocorticoid and progesterone receptor activity.

  . Proceedings of the National Academy of Sciences of the United States of America, 100(10), 5706-11. doi:10.1073/pnas.1036973100
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  We report here that a bacterial toxin, anthrax lethal toxin (LeTx), at very low concentrations represses glucocorticoid receptor (GR) transactivation in a transient transfection system and the activity of an endogenous GR-regulated gene in both a cellular system and an animal model. This repression is noncompetitive and does not affect ligand binding or DNA binding, suggesting that anthrax lethal toxin (LeTx) probably exerts its effects through a cofactor(s) involved in the interaction between GR and the basal transcription machinery. LeTx-nuclear receptor repression is selective, repressing GR, progesterone receptor B (PR-B), and estrogen receptor alpha (ERalpha), but not the mineralocorticoid receptor (MR) or ERbeta. GR repression was also caused by selected p38 mitogen-activated protein (MAP) kinase inhibitors, suggesting that the LeTx action may result in part from its known inactivation of MAP kinases. Simultaneous loss of GR and other nuclear receptor activities could render an animal more susceptible to lethal or toxic effects of anthrax infection by removing the normally protective antiinflammatory effects of these hormones, similar to the increased mortality seen in animals exposed to both GR antagonists and infectious agents or bacterial products. These finding have implications for development of new treatments and prevention of the toxic effects of anthrax.
• Sternberg, E. M. (2002).

  Walter B. Cannon and " 'Voodoo' Death": a perspective from 60 years on.

  . American journal of public health, 92(10), 1564-6. doi:10.2105/ajph.92.10.1564
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  The remarkable accuracy of Walter B. Cannon’s 1942 article “ ‘Voodoo’ Death,” excerpted in this issue of the Journal,1 proposing a scientific basis for “voodoo” death is at once surprising and not surprising. Voodoo death, as defined by Cannon, is sudden, unexplained death resulthing from a voodoo curse. At first glance, it is surprising that scientific discoveries over the last 60 years have largely filled out the details of—but not overturned—most of Cannon’s proposed explanation of the physiological underpinnings of this phenomenon. On the other hand, it is not surprising when one considers the fact that Cannon’s research formed the basis for much of our modern understanding of the physiological response systems involved in linking emotions, such as fear, with illness. If submitted to a scientific journal today, this paper would not make it beyond the review process, as it would be described (probably with some disdain) as simply “anecdotal” and hypothetical. However, fortunately for our generation, our predecessors were apparently not averse to recording oral reports of inexplicable phenomena in detail—even down to the names of the individuals who experienced or perpetrated these events. Thus, Cannon starts his article with several anecdotal case reports, all of which share several important features that lead him to propose, first, that there may indeed be a physiological basis for the phenomenon of voodoo death and, second, what that physiological basis might be. The dramatic suddenness of the illness following the threat, coupled with a lack of any apparent injury, exposure to toxins, or infection suggested to Cannon that merely the fear of death could, through physiological response mechanisms initiated by fear, precipitate death itself. Cannon focused on the “sympathetic” and “sympathicoadrenal” divisions of the nervous system—terms still in use today (although “sympatho-adrenal” is now the more common term). He outlines all the aspects of bodily function over which this arm of the nervous system exerts control—blood vessel contraction, dilation of bronchioles, adrenaline release, release of sugar from the liver—all effects that together prepare the animal to attack or run—to “fight or flee.” Cannon thus elegantly lays out both the physiology and the evolutionary rationale for the “fight or flight response,” a term still in use today that he coined to describe this neurophysiological–behavioral response pattern. We could not have provided a better rationale for this aspect of the phenomenon today. This piece has stood the test of time. In the 60 years since Cannon first published his work, we have simply gained a clearer understanding of the brain regions that become activated when a fearful stimulus is experienced and a better road map of the pathways linking those brain centers involved in receiving sensory signals (in Cannon’s example, seeing a bone pointed at one) to the part of the brain that processes the emotional component of fear—the amygdala. In today’s terms, we would call this the “vision-to-fear pathway” or “auditory-to-fear pathway,” depending on the sense through which the threat is initially received. We have a deeper understanding of the neurotransmitters and neuropeptides involved in initiating these responses and perpetuating them through learning and memory. We know how such chemical signals are translated into electrical impulses and how quickly or slowly they are conveyed along nerve fibers. And we now know that such nerve chemicals and proteins are made by genes within the nucleus of nerve cells, that are switched on and off by all sorts of chemical and physical signals. We know that when we learn to fear something there are permanent changes in the shape and wiring of nerve cells that make it more likely that the next time we experience the fearful stimulus, those same pathways will be switched on all the more rapidly. Strikingly absent, however, from Cannon’s explanation is the hormonal stress response—the cascade of hormones released from the brain, pituitary gland, and adrenal gland within minutes of exposure to any sort of stressor. This is because in 1942, when the article was written, many of these hormones were yet to be discovered. Furthermore, the term “stress,” popularized by Cannon’s admirer Hans Selye and others in the postwar period, was not yet in general use. The structure of cortisol, the hormone released from the cortex of the adrenal glands during stress, was identified in 1936 by Edward Kendall and Tadeus Reichstein,2,3 who received the Nobel Prize for their discoveries in 1950 together with Philip Hench. However, the full cascade of hormones involved in the hormonal stress response was not fully elucidated until the identity of the brain’s hypothalamic stress hormone, corticotropin releasing hormone or CRH, was discovered by Wylie Vale in 1981.4 Thus, Cannon could not have included in his scenario of the possible causes of voodoo death the role of hypothalamic CRH released after signals from the amygdala, the brain’s fear center, reached the hypothalamus. Nor could he include how the cross-talk between the brain stem adrenaline centers involved in initiation of the sympathetic response could coordinate with hormones released from the brain’s hypothalamic stress center5 to cause a massive release of both adrenaline-like nerve chemicals and stress hormones. Together these might well cause illness,6–9 including loss of appetite, weakness, cardiac arrhythmias, and even vascular collapse that could result in death. Thus, Cannon’s rather simplistic explanation of how shock could ensue simply by removal of blood volume through sympathetic clamping of peripheral arterioles is in part correct, but he could not know of the complexity of hormones and nerve chemicals that, when all released together, might be more likely to produce the cardiac arrhythmias and vascular collapse than he predicted. Finally, he did not have the tools to go beyond hypothesis into the experimental stage in humans—to measure the responses he predicted and to prove through such measures which parts of his hypotheses were correct. He could not, as we can today, use neuroimaging technologies, electroencephalograms, and even single neuron recordings to measure nerve cell activation in different stress- and fear-related brain regions. He could not use telemetry devices and complex computer-generated mathematical analyses to noninvasively measure changes in heart rate variability, blood pressure, and cardiac blood flow in humans while they are going about their daily routines. Nor could he ask his subjects to respond to questions, programmed in their palm-pilots and synchronized with their heart rate monitors, about their moment-tomoment emotional states, to indicate within milliseconds whether a given threat caused a particular arrhythmia. He could not imagine that one could measure minute amounts of stress hormones and nerve chemicals released into the saliva during fear, simply by asking the subject to chew on a lemon-soaked cotton swab and spit into a cup. And he could not imagine how such hormones and nerve chemicals could possibly affect cells of the immune system to cause chronic wasting or disease. Cannon could not imagine how one could accomplish all this because the tools of neuroscience, molecular biology, computational mathematics, bioengineering, neuroimaging, endocrinology, and cellular immunology had not yet been invented or discovered. But, on the basis of observation, logic, and deduction, he did imagine that there could be a biological basis to the seemingly magical phenomenon of voodoo death. And, what’s more, he had the courage to predict and record in writing that there should be, some day, a way to get the answers. In this, Cannon was perhaps among the first physiologists to apply his scientific background to attempt to explain otherwise inexplicable illnesses and phenomena that seemed to link emotions and disease. This approach, combining open-mindedness and scientific rigor, is the essence of modern complementary and alternative medicine research.
• Sternberg, E. M., & Jafarian-tehrani, M. (2002).

  Neuroendocrine-immune modulation of autoimmune/inflammatory diseases.

  . Frontiers of hormone research, 29, 69-82. doi:10.1159/000061056
• Webster, E. L., Sternberg, E. M., Rice, K. C., Mccarthy, E. F., Ligier, S., Isaac, M. G., Gold, P. W., Gabry, K. E., Contoreggi, C., Chrousos, G. P., & Barrientos, R. M. (2002).

  Corticotropin releasing hormone (CRH) antagonist attenuates adjuvant induced arthritis: role of CRH in peripheral inflammation.

  . The Journal of rheumatology, 29(6), 1252-61.
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  To determine whether a corticotropin releasing hormone (CRH) type 1-specific receptor antagonist, antalarmin, would alter the progression of inflammation in adjuvant induced arthritis (AIA) susceptible LEW/N rats by blocking local CRH mediated inflammatory responses or render AIA resistant F344/N rats more susceptible to AIA by blocking central CRH, thus reducing secretion of endogenous glucocorticoids..F344/N and LEW/N rats were assigned to either drug or vehicle groups and treated with 20 mg/kg antalarmin or vehicle alone BID for 25 days by intraperitoneal injection. Arthritis was induced in both antalarmin and vehicle treated LEW/N and F344/N rats by subcutaneous injections at the base of the tail of incomplete Freund's adjuvant containing 10 mg/ml heat killed Mycobacterium tuberculosis. Control F344/N and LEW/N rats were maintained on either antalarmin or vehicle..Chronic blockade of CRH-R1 with systemic antalarmin significantly ameliorated AIA in LEW/N rats, reducing the severity of inflammation in peripheral joints, evidenced by clinical and histopathology scores, and weight loss associated with disease onset. Antalarmin neither induced nor exacerbated arthritis expression in F344/N or LEW/N rats, despite suppression of levels of adjuvant induced corticosterone, the major antiinflammatory glucocorticoid in rats..Systemic blockade of CRH-RI appeared to predominantly block peripheral proinflammatory effects of immune CRH, rather than the systemic glucocorticoid mediated antiinflammatory effects of hypothalamic CRH. Results indicate that chronic treatment with a CRH antagonist attenuates progressive inflammation induced degeneration of synovia, cartilage, and bone in arthritic joints, suggesting that antalarmin may have therapeutic potential in treatment of human autoimmune and inflammatory disorders.
• Webster, J. I., Tonelli, L. H., & Sternberg, E. M. (2002).

  Neuroendocrine regulation of immunity.

  . Annual review of immunology, 20(1), 125-63. doi:10.1146/annurev.immunol.20.082401.104914
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  A reciprocal regulation exists between the central nervous and immune systems through which the CNS signals the immune system via hormonal and neuronal pathways and the immune system signals the CNS through cytokines. The primary hormonal pathway by which the CNS regulates the immune system is the hypothalamic-pituitary-adrenal axis, through the hormones of the neuroendocrine stress response. The sympathetic nervous system regulates the function of the immune system primarily via adrenergic neurotransmitters released through neuronal routes. Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease. Glucocorticoids are the main effector end point of this neuroendocrine system and, through the glucocorticoid receptor, have multiple effects on immune cells and molecules. This review focuses on the regulation of the immune response via the neuroendocrine system. Particular details are presented on the effects of interruptions of this regulatory loop at multiple levels in predisposition and expression of immune diseases and on mechanisms of glucocorticoid effects on immune cells and molecules.
• Wei, R., Sternberg, E. M., & Phillips, T. M. (2002).

  Specific up-regulation of CRH or AVP secretion by acetylcholine or lipopolysaccharide in inflammatory susceptible Lewis rat fetal hypothalamic cells.

  . Journal of neuroimmunology, 131(1-2), 31-40. doi:10.1016/s0165-5728(02)00251-5
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  Lewis (LEW/N) rats, compared to Fischer (F344/N) rats, are susceptible to inflammatory/autoimmune diseases, in part, as a result of their blunted hypothalamic-pituitary-adrenal (HPA) axis responses. We examined regulation of LEW/N and F344/N fetal hypothalamic cell secretion of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), two major HPA axis mediators, by inflammatory and neurotransmitter stimuli. Interleukin-1beta (IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and protein kinase A (PKA) and protein kinase C (PKC) activators did not affect LEW/N basal secretion. Compared to F344/N, LEW/N cells were hyporesponsive to lipopolysaccharide (LPS), serotonin (5-HT), and acetylcholine chloride (ACh). However, LPS-induced AVP release and ACh-evoked CRH secretion in LEW/N were comparable with those of F344/N. Our findings suggest that the blunted LEW/N neuropeptide response was more likely related to components of second messenger systems, rather than to any one specific stimulus.
• Sternberg, E. M. (2001).

  Neuroendocrine regulation of autoimmune/inflammatory disease.

  . The Journal of endocrinology, 169(3), 429-35. doi:10.1677/joe.0.1690429
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  Interactions between the immune and nervous systems play an important role in modulating host susceptibility and resistance to inflammatory disease. Neuroendocrine regulation of inflammatory and immune responses and disease occurs at multiple levels: systemically, through the anti-inflammatory action of glucocorticoids released via hypothalamic-pituitary-adrenal axis stimulation; regionally, through production of glucocorticoids within and sympathetic innervation of immune organs such as the thymus; locally, at sites of inflammation. Estrogens also play an important role in immune modulation, and contribute to the approximately 2- to 10-fold higher incidence of autoimmune/inflammatory diseases seen in females of all mammalian species. During inflammation, cytokines from the periphery activate the central nervous system through multiple routes. This results in stimulation of the hypothalamic-pituitary-adrenal axis which, in turn through the immunosuppressive effects of the glucocorticoids, generally inhibits inflammation. Recent studies indicate that physiological levels of glucocorticoids are immunomodulatory rather than solely immunosuppressive, causing a shift in patterns of cytokine production from a TH1- to a TH2-type pattern. Interruptions of this loop at any level and through multiple mechanisms, whether genetic, or through surgical or pharmacological interventions, can render an inflammatory resistant host susceptible to inflammatory disease. Over-activation of this axis, as occurs during stress, can also affect severity of infectious disease through the immunosuppressive effects of the glucocorticoids. These interactions have been clearly demonstrated in many animal models, across species, strains and diseases, and are also relevant to human inflammatory, autoimmune and allergic illnesses, including rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, allergic asthma and atopic skin disease. While many genes and environmental factors contribute to susceptibility and resistance to autoimmune/inflammatory diseases, a full understanding of the molecular effects on immune responses of combinations of neuropeptides, neurohormones and neurotransmitters at all levels has opened up new therapeutic approaches and are essential for the design of future therapies based on such principles.
• Sternberg, E. M. (2001).

  Piecing Together a Puzzling World

  . Science, 292(5522), 1661-1662. doi:10.1126/science.1062103
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  Memento . Christopher Nolan, Director. Newmarket Film Group, 2001. See: [www.otnemem.com][1] This film noir, with a protagonist whose injury prevents him from processing short-term memories, offers an intriguing perspective on the neurobiology of memory. [1]: http://www.otnemem.com/
• Sternberg, E. M., & Moghaddam, M. (2001).

  Neuroendocrine stress and inflammatory disease:From animal model to human disease

  . NeuroImmune Biology, 1, 115-120. doi:10.1016/s1567-7443(01)80012-0
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  Abstract This review will outline scientific advances in understanding the communication networksbetween the nervous and immune systems: the scientific underpinning of the popular mindbody interaction. The idea that the mind and negative or positive states of mind, such as psychological stress or well-being, can influence health and disease has been in the popular culture for thousands of years. Recent scientific advances prove that there is a molecular, cellular, neuroanatomical and neurohormonal basis for communication between the brain and the immune system. Through such communications the nervous and immune systems interact and modify each other's functions. Interruptions of this interaction, on a genetic, drug-induced or surgical basis, lead to enhanced susceptibility to inflammatory disease. Over-activity of the neuroendocrine component of these interactions, such as occurs during stress, is associated with exacerbations of, or increased susceptibility to, infectious disease. The presence of cytokines in the brain, and their role in neuronal cell death and survival, help explain the role of immune molecules in degenerative brain diseases like dementia seen in Alzheimer's and AIDS. Cytokines expressed within the nervous system also play a role in nerve damage and recovery from nerve trauma. On the basis of such findings, new drug treatments are currently being developed, such as the use of anti-inflammatory drugs in Alzheimer's or neurotransmitter related drugs for improving immune responses associated with aging.
• Tonelli, L. H., Sternberg, E. M., Riley, A. L., Listwak, S. J., & Gomez-serrano, M. (2001).

  Effects of cross fostering on open-field behavior, acoustic startle, lipopolysaccharide-induced corticosterone release, and body weight in Lewis and Fischer rats.

  . Behavior genetics, 31(5), 427-36. doi:10.1023/a:1012742405141
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  Lewis (LEW/N) and Fischer (F344/N) rats differ on a myriad of behavioral and physiological endpoints, some of which have been reported to be affected by maternal experience in outbred rats and other strains. To assess whether epigenetic factors contribute to the differential behavioral responses to stress and pro-inflammatory challenges in these strains, the effects of cross fostering on open-field, acoustic startle, and glucocorticoid reactivity to lipopolysaccharide (LPS) were examined in the present experiment. In the open-field test, although in-fostered female LEW/N and F344/N strains did not differ, female LEW/N rats displayed significantly greater activity than female F344/N rats in the cross-fostered condition. Differences between males of the two strains were increased by cross fostering, with the LEW/N strain displaying greater total activity. In acoustic startle, there was little strain difference between in-fostered or cross-fostered female rats. On the other hand, in-fostered male LEW/N rats had a significantly greater startle response than in-fostered male F344/N rats, an effect that was dramatically reduced by cross fostering. In-fostered female LEW/N rats displayed a blunted corticosterone response relative to in-fostered female F344/N rats, an effect that was reduced by cross fostering. Conversely, although there was no strain difference between male in-fostered rats, cross-fostered male F344/N rats displayed a significantly greater corticosterone response to LPS than cross-fostered male LEW/N rats. Finally, body weight differences between in-fostered LEW/N and F344/N rats were reduced by cross fostering. Together, these data illustrate that maternal factors play a role in the behavioral and physiological responses to stress between the two strains.
• Vitkovic, L., Sternberg, E. M., & Maeda, S. (2001).

  Anti-inflammatory cytokines: expression and action in the brain.

  . Neuroimmunomodulation, 9(6), 295-301. doi:10.1159/000059387
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  Transforming growth factor-beta(1) (TGF-beta(1)) and interleukin (IL)-10 gene expression is equivocal in normal brain and upregulated in over a dozen central and peripheral diseases/disorders. The patterns of specific expression of cytokines differ in these diseases. Published data indicate that these cytokines are produced by and act on both neurons and glial cells. Although their actions are commonly viewed as 'anti-inflammatory', they protect neurons and downregulate the responses of glial cells to diseases/disorders in the absence of inflammation. Their actions counterbalance the actions of elevated IL-1 and/or tumor necrosis factor-alpha to maintain homeostasis. Their therapeutic potential will be realized by improving our understanding of their place in neural cytokine networks.
• Vreugdenhil, E., Turner, G., Sternberg, E. M., Schaaf, M. J., Kloet, E. R., Emery, P., Detera-wadleigh, S. D., Derijk, R. H., Datson, N. A., & Cidlowski, J. A. (2001).

  A human glucocorticoid receptor gene variant that increases the stability of the glucocorticoid receptor beta-isoform mRNA is associated with rheumatoid arthritis.

  . The Journal of rheumatology, 28(11), 2383-8.
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  To study the occurrence and function of polymorphism in the human glucocorticoid receptor (hGR) gene in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)..We used single stranded conformation polymorphism (SSCP) and direct sequencing to study the hGR gene in 30 patients with RA, 40 with SLE, and 24 controls. A newly identified polymorphism was transfected in COS-1 cells and the stability of the mRNA containing the polymorphism was tested using real-time PCR..A polymorphism in the hGR gene in exon9beta, in an "ATTTA" motif, was found to be significantly associated with RA. Introduction of this polymorphism in the hGRb mRNA was found to significantly increase stability in vitro compared to the wild-type sequence..Our findings show an association between RA and a previously unreported polymorphism in the hGR gene. This polymorphism increased stability of hGRbeta mRNA, which could contribute to an altered glucocorticoid sensitivity since the hGRbeta is thought to function as an inhibitor of hGRalpha activity.
• Webster, J. I., Tonelli, L. H., Sternberg, E. M., & Rapp, K. L. (2001).

  Neuroendocrine responses regulating susceptibility and resistance to autoimmune/inflammatory disease in inbred rat strains.

  . Immunological reviews, 184(1), 203-11. doi:10.1034/j.1600-065x.2001.1840118.x
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  Rodent animal models of inflammatory and autoimmune disease have been important tools in the study of the interaction between neuroendocrine physiology and the immune responses. The rat has been particularly useful in part because, in contrast to other species, most rat models of autoimmune/inflammatory disease are induced rather than spontaneous. This allows for systematic and controlled manipulations of the neuroendocrine system in relation to exposure to the antigen or proinflammatory trigger. The most frequently used immune challenges include lipopolysaccharide-induced septic shock, carrageenan-induced local inflammation and adjuvant or bacterial cell wall-induced arthritis. By analyzing the responses to these challenges in different strains of rats and mice it has been possible to define the relationships between the neuroendocrine and immune systems and to identify some mechanisms through which these connections confer susceptibility and resistance to autoimmune and inflammatory diseases. The present review will discuss data obtained from rodent physiology, indicating that an important component in the susceptibility or resistance to development of these diseases is due to dysfunctional regulation of the immune response by the neuroendocrine hypothalamic-pituitary-adrenal axis. In particular, the importance of neurons of the paraventricular hypothalamic nucleus in determining susceptibility or resistance to autoimmune and inflammatory disease will be discussed.
• Sternberg, E. M., Michaud, A., Listwak, S. J., Jafarian-tehrani, M., Corvol, P., & Barrientos, R. M. (2000).

  Exclusion of angiotensin I-converting enzyme as a candidate gene involved in exudative inflammatory resistance in F344/N rats.

  . Molecular Medicine, 6(4), 319-331. doi:10.1007/bf03401940
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  Inbred LEW/N and F344/N rats respectively, are susceptible and relatively resistant to a broad range of inflammatory/autoimmune diseases. We recently identified a quantitative trait locus (QTL) on chromosome 10 that protects the F344/N rat from carrageenan-induced exudation in a dominant fashion. Angiotensin I-converting enzyme (ACE) is one of the candidate genes located in this QTL region that plays an important role in inflammation. RNA was extracted from both LEW/N and F344/N rat strains and used to produce full length cDNA by reverse transcription polymerase chain reaction (RT-PCR). Both strands of the PCR products were entirely sequenced to determine nucleotide differences between strains. ACE activity was measured using the synthetic substrate 3H-hip-puryl-glycylglycine. ACE protein levels were determined by Western blot using a specific ACE antibody. ACE kinetic and inhibition studies were performed using specific substrates (Hip-His-Leu and Acetyl-Seryl-Aspartyl-Acetyl-Lysyl-Proline) and inhibitors (lisinopril, captopril and quinaprilat) for each C- and N-terminal active site. Finally, the dose-effects of lisinopril treatment on carrageenen-induced exudate volume and ACE activity was studied. In this study, we report for the first time a missense mutation in the coding region of ACE cDNA at 5′ 1021 from C to T, resulting in a Leu-341 to Phe substitution, close to the N-domain active site in the F344/N rats. Full characterization of soluble and tissue ACE in both LEW/N and F344/N rat strains showed that soluble ACE levels in serum and exudate were 1.5 fold higher in the F344/N rats than those in LEW/N rats. In addition, the soluble ACE level was inversely correlated with the exudate volume. However, the specific ACE activity and its catalytic properties were identical in both strains. Furthermore, the chronic inhibition of serum and exudate ACE levels by lisinopril treatment did not affect the exudate volume in F344/N rats, indicating that several factors besides ACE were involved in the control of carrageenan-induced exudation. This report describes a complete molecular, biochemical, enzymatic and pharmacologic study of a missense mutation in the ACE cDNA in F344/N rats, that taken together, excludes ACE as a candidate gene involved with resistance to carrageenan-induced exudation in F344/N rats.
• Sternberg, E. M., Smith, C. C., Schulkin, J., Schmidt, L. A., Gold, P. W., & Fox, N. A. (2000).

  Adrenocortical reactivity and social competence in seven year-olds

  . Personality and Individual Differences, 26(6), 977-985. doi:10.1016/s0191-8869(98)00099-3
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  Abstract We examined temporal changes in salivary cortisol in response to a peer self-presentation task in a group of seven year-olds, some of whom scored high, average, and low on the Harter, 1983 Perceived Social Competence Scale. Salivary cortisol was measured pre-task, and 20 and 35 min post-task. We found a significant relation between individual differences in perceived social competence and salivary cortisol reactivity in response to the task. Children who perceived themselves as socially competent exhibited a significantly greater decrease in salivary cortisol from 20 to 35 min following the task compared with children who self-reported a relatively lower degree of social competence. We speculate on the meaning of salivary cortisol changes in childrens socio-emotional development.
• Sternberg, E. M., & Jafarian-tehrani, M. (1999).

  Animal models of neuroimmune interactions in inflammatory diseases.

  . Journal of neuroimmunology, 100(1-2), 13-20. doi:10.1016/s0165-5728(99)00207-6
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  Animal models have been used successfully to study various aspects of neural-immune interactions. Although different approaches carry certain advantages and disadvantages, current high sensitivity screening and manipulation methods coupled with molecular and genetic approaches can be successfully used to tease out the neural pathways that regulate inflammatory disease and the effects of immune molecules, such as interleukins, on neuronal function and pathology. Newer methodologies that measure gene expression of thousands of genes will in the future add to the ability to evaluate complex systems interactions in whole animal models. This review addresses the advantages and disadvantages of some of these approaches in the context of application to neural-immune interactions.
• Zelazowska, E. B., Sternberg, E. M., Singh, A., & Deuster, P. A. (1999).

  Expression of lymphocyte subsets after exercise and dexamethasone in high and low stress responders.

  . Medicine and science in sports and exercise, 31(12), 1799-806. doi:10.1097/00005768-199912000-00016
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  Recent work indicates that among the normal population, persons can be classified as low (LR) or high (HR) stress responders based on hypothalamic-pituitary-adrenal (HPA) axis responses to high-intensity exercise. We studied whether differential activation of the HPA axis affected cytokine production and expression of selected lymphocyte subsets in HR and LR in response to high-intensity exercise after placebo and dexamethasone (DEX; 4 mg)..Healthy HR (N = 12) and LR (N = 10) underwent two exercise tests at 90% of VO2max, 8 h after placebo or DEX. Expression of lymphocyte surface markers (CD3+, CD4+, CD8+, CD56+), adhesion molecule markers (intercellular adhesion molecule-1/ICAM-1: CD54+ and L-selectin: CD62L+), and concentrations of plasma interleukin 6 (IL-6) were examined before and after exercise..Baseline percentages of CD8+ and CD56+ cells were significantly higher, and concentrations of IL-6 and percentages of CD4+ cells were significantly lower in HR as compared with LR. The percentage of CD54+ and CD62L+ cells was not significantly different in HR and LR. DEX significantly reduced the percentage of CD3+ and CD4+ and increased the percentage of CD8+ and CD56+ subsets; the percent of cells expressing CD54+ increased, whereas CD62L+ decreased. Exercise-induced changes in the percentage of lymphocyte subsets were similar to those induced by DEX..In summary, HR and LR have different baseline patterns of IL-6 and lymphocyte subsets, which may reflect differential sensitivity to endogenous glucocorticoids. However, exogenous glucocorticoids induced similar patterns of lymphocyte expression in HR and LR.
• Sternberg, E. M. (1998).

  Overview of the conference and the field.

  . Annals of the New York Academy of Sciences, 840(1), 1-8. doi:10.1111/j.1749-6632.1998.tb09543.x
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  The field of neuroimmune interactions is a prime example of interdisciplinary research spanning immunology, neurobiology, neuroendocrinology, and behavioral sciences. It also exemplifies research from the molecular to the clinical domain. The greatest challenge of the field, which this conference seeks to stimulate, is research that is at the same time precise, focused, and integrative. Several levels of interdisciplinary overlap will be highlighted. At the molecular level, neuro- and immune mediator molecules or their receptors may be members of the same superfamily or may regulate each other's expression or function. Most extensively studied are cytokine-neuropeptide/neurotransmitter interactions, including expression of cytokines within the central nervous system and production of neuropeptides by immune cells or at inflammatory sites. Advances relating cytokine-neurohormone interactions to mechanisms of apoptosis will ultimately shed light on the role of neuroimmune interactions in neuronal cell death and survival and immune cell selection, processes important in neuronal plasticity and immune specificity. At a systems level, advances have been made in cross-disciplinary application of modes of thinking. Incorporation of neurobiology's appreciation of anatomical organization, endocrinology's temporal dimension of neurohormonal secretion, and immunology's understanding of stimulus specificity all contribute to a more precise definition of how these complex systems interact at multiple levels. More precise understanding of effects of disruptions of these communications on disease susceptibility and expression will clarify how perturbations of one system, such as stimulation of the neuroendocrine stress response, might affect expression of disease in the other, such as autoimmune/inflammatory or infectious diseases.
• Sternberg, E. M. (1997).

  Emotions and disease: from balance of humors to balance of molecules.

  . Nature medicine, 3(3), 264-7. doi:10.1038/nm0397-264
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  A new field of research investigates how the Immune and nervous systems communicate with each other.
• Sternberg, E. M., & Derijk, R. H. (1997).

  Corticosteroid resistance and disease.

  . Annals of medicine, 29(1), 79-82. doi:10.3109/07853899708998746
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  Both the unpredictability of side-effects and efficacy of glucocorticoid treatment can be problematic during clinical treatment. Here we discuss the evidence that exists for the hypothesis that individual glucocorticoid sensitivity underlies this problem. We suggest that glucocorticoid sensitivity is actually much more dynamic and common than previously thought. It is postulated that acquired tissue-specific glucocorticoid resistance could play a role in the origin and pathogenesis of depression, autoimmune disorders and AIDS. Moreover, recent genetic research has shown mutations in the glucocorticoid receptor (GR) gene and GR protein which are suggested to play a role in the pathogenesis of leukaemia, hereditary glucocorticoid resistance and Nelson's syndrome. These findings indicate that variations in the GR and in glucocorticoid resistance play a central role in a wide variety of diseases.
• Sternberg, E. M., Petrides, J. S., Paciotti, G., Michelson, D., Karp, B., Gold, P. W., Galliven, E., Deuster, P., & Derijk, R. (1997).

  Exercise and circadian rhythm-induced variations in plasma cortisol differentially regulate interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) production in humans: high sensitivity of TNF alpha and resistance of IL-6.

  . The Journal of clinical endocrinology and metabolism, 82(7), 2182-91. doi:10.1210/jcem.82.7.4041
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  Although we have previously shown that the integrity of inflammatory mediator-induced activation of the hypothalamic-pituitary-adrenal axis is essential for conferring resistance to inflammatory disease in susceptible Lewis rats, the role of endogenous glucocorticoid secretion in human immune function in either health or disease is less clear. To further understand the relevance of physiological variations in plasma cortisol on immune function in humans, we evaluated ex vivo lipopolysaccharide-induced interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) production in the whole blood of healthy volunteers studied under conditions chosen to approximate either physiological or pharmacological glucocorticoid levels. Administration of a pharmacological dose of hydrocortisone suppressed the production of all three cytokines, whereas administration of a physiological dose of hydrocortisone suppressed only TNF alpha production. Stress-induced levels of glucocorticoids, achieved during exercise at 100% maximal oxygen utilization, suppressed IL-1 beta and TNF alpha production, but were without effect on IL-6 production. In addition, circadian variations of cortisol were associated with decreased TNF alpha production, but were without effect on IL-1 beta or IL-6 production. These studies challenge the generally accepted idea that glucocorticoids consistently suppress cytokine production and indicate a hierarchy of sensitivity, with TNF alpha having the greatest sensitivity, IL-1 beta having intermediate sensitivity, and IL-6 being resistant. The resistance of IL-6 production to glucocorticoid suppression is compatible with data suggesting an antiinflammatory as well as a proinflammatory action for this cytokine.
• Sternberg, E. M., Smith, C. C., Schulkin, J., Schmidt, L. A., Rubin, K. H., Gold, P. W., & Fox, N. A. (1997).

  Behavioral and neuroendocrine responses in shy children.

  . Developmental psychobiology, 30(2), 127-40. doi:10.1002/(sici)1098-2302(199703)30:2<127::aid-dev4>3.0.co;2-s
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  Previous research has shown that infants who display a high frequency of motor activity and negative affect at 4 months of age are likely to be behaviorally inhibited toddlers. We examined social behaviors, maternal report of temperament, salivary cortisol, and baseline startle responses at age 4 in a sample of children, some of whom displayed a high frequency of motor activity and negative affect at 4 months of age. Infants who displayed this temperamental profile were reported by their mothers as more shy at age 4 compared with other children. We also found that 4-year-olds who displayed a high frequency of wary behavior during peer play exhibited relatively high morning salivary cortisol, were reported as contemporaneously shy by their mothers, and were behaviorally inhibited at 14 months of age. There were no significant relations found between baseline startle and morning salivary cortisol and measures of shyness at age 4. We speculate that high levels of cortisol in shy children may induce changes in the amygdala, exacerbating their fearfulness.
• Gold, P. W., Sternberg, E. M., Petrides, J. S., Gold, P. W., Deuster, P. A., & Derijk, R. H. (1996).

  Changes in corticosteroid sensitivity of peripheral blood lymphocytes after strenuous exercise in humans.

  . The Journal of clinical endocrinology and metabolism, 81(1), 228-35. doi:10.1210/jcem.81.1.8550757
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  Although plasma corticosteroid concentrations can be measured accurately, the biological effect on the target tissue is uncertain. The availability of an accurate measure of corticosteroid sensitivity would potentially clarify the putative roles of endogenous glucocorticoids in illnesses such as inflammatory disease and obesity and allow evaluation of an additional regulatory level of glucocorticoid action. To measure corticosteroid sensitivity, we developed an assay based on the inhibition by dexamethasone (Dex) of lipopolysaccharide (LPS)-induced Interleukin-6 (IL-6) production and release in whole unseparated blood in vitro. LPS induced a dose-dependent increase in IL-6 concentrations up to 34 +/- 6.6 ng/mL, reaching plateau levels after 8 h, whereas Dex dose dependently inhibited LPS-induced IL-6 production. Involvement of the glucocorticoid receptor in this response was supported by abrogation of Dex (10(-7) mol/L) inhibition of IL-6 production by the glucocorticoid receptor antagonist RU 38486. To determine whether corticosteroid sensitivity is a dynamic phenomenon, we subjected healthy males to a graded quantifiable exercise associated with increases in plasma ACTH and cortisol. Before exercise, 3 x 10(-8) mol/L Dex inhibited LPS-induced IL-6 production in vitro; after exercise, 3 x 10(-8) and 10(-7) mol/L Dex were unable to inhibit IL-6 production. We conclude that Dex suppression of LPS-induced IL-6 production is an effective means of determining corticosteroid sensitivity, and that corticosteroid sensitivity in human subjects is a dynamic, rather than a static, phenomenon.
• Sternberg, E. M. (1996).

  Pathogenesis of L-tryptophan eosinophilia myalgia syndrome.

  . Advances in experimental medicine and biology, 398, 325-30. doi:10.1007/978-1-4613-0381-7_50
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  Taken together, these studies suggest that many different etiologic agents alone or together may initiate the common final pathways of tissue pathologic response resulting in the clinical syndrome of eosinophilia, myalgias and fasciitis. Tryptophan itself may contribute to some of the scarring features of the illness, while impure L-tryptophan, and one or more of the impurities cause the characteristic features of the illness. The altered tryptophan metabolism in EMS is secondary to inflammation.
• Sternberg, E. M., & Smith, C. C. (1996).

  Overview of the 3rd International Congress of the Society for Neuroimmunomodulation

  . Neuroimmunomodulation, 3(6), 323-324. doi:10.1159/000097287
• Sternberg, E. M., Lempereur, L., Iurato, M. P., Chiarenza, A., Calogero, A. E., & Bernardini, R. (1996).

  Adenylate-cyclase-dependent pituitary adrenocorticotropin secretion is defective in the inflammatory-disease-susceptible Lewis rat.

  . Neuroendocrinology, 63(5), 468-74. doi:10.1159/000127073
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  Susceptibility to arthritis in the Lewis rat is associated with a defect of the hypothalamic-pituitary-adrenal axis. We examined the pituitary corticotropes of both intact and dexamethasone-treated male and female inflammatory-disease-susceptible Lewis and inflammatory-disease-resistant Fischer rats. We determined adrenocorticotropin levels in the media from primary cultures of anterior pituitary cells of both strains. In other experiments we have measured intracellular cyclic adenosine monophosphate and inositol monophosphate accumulation. Cells were incubated with corticotropin-releasing hormone, arginine vasopressin, forskolin, phorbol myristate acetate, or thyrotropin-releasing hormone. Corticotropin-releasing hormone stimulated adrenocorticotropin secretion from both male and female Lewis rat pituitary cells in a concentration-dependent manner. Basal and stimulated adrenocorticotropin levels in cells from Lewis rats were lower than those measured in the incubation media of Fischer rat dispersed pituitary cells. Arginine vasopressin, as well as forskolin and phorbol myristate acetate, induced a significant release of adrenocorticotropin from pituitary cells of both strains. Incubation with corticotropin-releasing hormone did not produce a significant accumulation of intracellular cyclic adenosine monophosphate in Lewis rat dispersed pituicytes of both sexes. On the other hand, forskolin induced a significant increase of intracellular cyclic adenosine monophosphate in the same cultures. Finally, inositol monophosphate accumulation was comparable in pituitary cells from both Lewis and Fischer rats of both sexes incubated with thyrotropin-releasing hormone. Adrenocorticotropin secretion from pituitary cells of male Lewis rats treated in vivo with dexamethasone was either reduced or abolished following incubation with different secretagogues. A defect in pituitary adrenocorticotropin secretion could be among the causes of the hyporesponsiveness of the hypothalamic-pituitary-adrenal axis in the Lewis rat. Such a defect appears to be associated with dysfunction of receptor-coupled events related to adenylate cyclase.
• Ueno, Y., Tatsuno, Y., Sternberg, E. M., Smith, C. C., Gomez, M., & Adachi, J. (1996).

  A comparative study of tissue distribution and excretion among three substances implicated in eosinophilia-myalgia syndrome.

  . Advances in experimental medicine and biology, 398, 365-70. doi:10.1007/978-1-4613-0381-7_56
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  Epidemiological studies have suggested that L-tryptophan(L-TRP) produced by a specific manufacturer may be implicated in eosinophilia-myalgia syndrome(EMS) in the United States and other countries(Belongia et al., 1990). The implicated L-TRP has been shown to contain more than 60 impurities(Hill et al., 1993), some of which might contribute to EMS(Centers for Disease Control, 1990; Crofford et al., 1990). Of these, the first impurity statistically associated with EMS was identified as l,l’-ethylidenbis [tryptophan] (EBT) (Mayeno et al., 1990). EBT was vulnerable to acid and readily decomposed to 1-methyltetrahydro-β-carboline(MTCA) in artificial gastric fluid(CDC 1990). In addition MTCA was detected in blood and urine of rats treated with EBT(Adachi et al., 1993). A second impurity has now been isolated(Toyo’oka et al., 1991), and its chemical structures has been determined to be 3-(phenylamino)alanine(PAA) (Goda et al., 1992). We administered EBT, MTCA and PAA to rats to compare their distributions and excretions. We then investigated the effect of chronic treatment of PAA on the tissue concentration and the retention of PAA in their tissues following the animals’ return to a standard control diet. Finally, we investigated its metabolites in rat urine.
• Zelazowska, E. B., Sternberg, E. M., Raybourne, R. B., Misiewicz, B., Griebler, C., Gomez, M., & Gold, P. W. (1996).

  The estrogen antagonist tamoxifen inhibits carrageenan induced inflammation in LEW/N female rats.

  . Life sciences, 58(16), PL281-6. doi:10.1016/0024-3205(96)00106-3
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  Carrageenan induces a measurable inflammatory response in susceptible animals, and mature females are more responsive to carrageenan, than males. In the present study, we tested whether the estrogen antagonist tamoxifen influences carrageenan-induced inflammatory responses. Female LEW/N rats were treated with tamoxifen and compared to a control group of animals injected with vehicle. Tamoxifen significantly reduced estrous phase of estrous cycle during treatment, consistent with its functional anti-estrogen effects. Moreover, tamoxifen significantly decreased exudate volume but did not significantly influence relative white blood cell counts in the exudate. Interestingly, tamoxifen induced differential dose-dependent alterations in peripheral blood lymphocyte subpopulations. Low dose of tamoxifen increased CD25 cells. The high tamoxifen dose significantly increased CD8 blood lymphocytes counts. Our data indicate that tamoxifen treatment decreases carrageenan-induced inflammatory response in female LEW/N rats and suggest therefore that this inflammatory response is, at least in part, estrogen related. Moreover, our results suggest a possible role for tamoxifen in treatment of inflammatory disorders.
• Sternberg, E. M., & Licinio, J. (1995).

  Overview of neuroimmune stress interactions. Implications for susceptibility to inflammatory disease.

  . Annals of the New York Academy of Sciences, 771(1), 364-71. doi:10.1111/j.1749-6632.1995.tb44695.x
• Sternberg, E. M., Smith, C. C., Gomez, M., & Adachi, J. (1995).

  Accumulation of 3-(phenylamino)alanine, a constituent in L-tryptophan products implicated in eosinophilia-myalgia syndrome, in blood and organs of the Lewis rats.

  . Archives of toxicology, 69(4), 266-70. doi:10.1007/s002040050169
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  3-(Phenylamino)alanine (PAA), a newly discovered impurity in case-associated L-tryptophan tablets, has been investigated as a possible contributing factor in the etiology of eosinophilia-myalgia syndrome (EMS). We have studied distribution and elimination of PAA in rats which were administered a single 5 mg/kg dose of PAA by gastric gavage. PAA concentrations in blood, brain, kidney and liver were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. The concentration of PAA in each tissue reached a maximum at 5 h, and then gradually declined. A high level of PAA still remained at 24 h, indicating gradual elimination. The concentration of PAA in brain at 5 h was 2139 ng/g tissue, demonstrating passage through the blood-brain barrier. Consecutive administration of PAA (5 mg/kg) for 4 days resulted in approximately double the concentration in all tissues. Chronic treatment using PAA incorporated into food pellets for 6 weeks resulted in similar accumulations in each tissue, and following 12 days on a PAA free diet, levels of this drug were still detectable in all tissues.
• Sternberg, E. M., & Cizza, G. (1994).

  The role of the hypothalamic-pituitary-adrenal axis in susceptibility to autoimmune/inflammatory disease.

  . ImmunoMethods, 5(1), 73-8. doi:10.1006/immu.1994.1039
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  The central nervous system (CNS) affects the immune system through endocrine, paracrine, and neuronal mechanisms. The immune system in turn communicates with the CNS through many of the same mechanisms. Evidence that this bidirectional communication plays a vital role in susceptibility to inflammatory and infectious disease is derived largely from animal models in which the communication has been interrupted or reconstituted surgically, pharmacologically, or on a preexisting genetic basis. The advantage of animal models for studying the pathophysiologic relevance of such connections is that the systems can be manipulated at several levels and at different times in relation to development of the inflammatory disease and the outcome of the manipulation can be quantified. While in vitro studies may be used to further define the subcellular and molecular mechanisms of these interactions, only an intact organism, in which the central nervous system is connected to the immune system, can be used to fully define the nature of these interconnections. This review describes approaches to studying CNS-immune system interactions, using relatively inflammatory-susceptible and inflammatory-resistant Lewis and Fischer rats as models for evaluating the role of the HPA axis in susceptibility to inflammatory disease.
• Sternberg, E. M., & Derijk, R. (1994).

  Brain Corticosteroid Receptors: Studies on the Mechanism, Fuction, and Neurotoxicity of Corticosteroid Action.

  . Annals of the New York Academy of Sciences, 746(1), 33-41; discussion 64-7. doi:10.1111/j.1749-6632.1994.tb39208.x
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  Glucocorticoid feedback during inflammation depends on several factors, including effective corticosteroid concentrations, the temporal coordination between the immune system and the HPAA, and sensitivity of the target organ to corticosteroids. In the case of LEW/N rats, several lines of evidence indicate that CRH is aberrantly regulated, and as a consequence, the circulating corticosterone concentrations are blunted. In addition, basal ACTH and corticosterone responses differ compared to SD and F344/N rats. Therefore glucocorticoid feedback during inflammation is impaired leading to uncontrolled inflammation as observed in various models. We found that in the LEW/N rat, the regulation of the GR and MR, at least in the hippocampus, is different from F344/N rats. A similar impaired upregulation of the GR has been described in aged rats, and this has been postulated to be the cause of the altered HPAA reactivity after various stimuli in these rats. Moreover, adult LEW/N rats exhibit HPAA responses which resemble those observed during the stress hyporesponsive period of immature SD or F244/N rats. These latter data suggest that in the LEW/N rat the ontogeny and/or regulation of the HPAA is disturbed. Taken together, the impaired regulation of HPAA reactivity observed in LEW/N rats could be due to an impaired regulation of the central MR and/or GR. Although no data of GR dynamics in the context of local inflammation are available yet, this could be an additional factor determining tissue sensitivity and immune responses to corticosteroids. In humans, determination of the role of the HPAA in inflammation is more complex due to the much higher intrinsic variability between subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
• Sternberg, E. M., Smith, C. C., Greibler, C., Gomez, M., Gold, P. W., & Cizza, G. (1994).

  The estrous cycle and pituitary-ovarian function in Lewis and Fischer rats.

  . Neuroimmunomodulation, 1(4), 231-5. doi:10.1159/000097170
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  We have characterized the estrous cycle by obtaining vaginal smears, and quantitating estradiol (E), progesterone (P), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) plasma levels at different phases of the estrous cycle in Lewis (LEW/N) and Fischer (F344/N) rats. Comparison of the duration of the component phases of estrous showed LEW/N metestrous to be significantly longer than in F344/N rats while diestrous and estrous were significantly shorter; proestrous was identical. E levels in LEW/N rats were significantly greater than in F344/N rats only in the estrous phase of the cycle. P levels were significantly greater in LEW/N rats in all phases. LH and FSH levels in the two strains did not differ. Elevated E and P levels would be expected to be associated with increased corticosterone through inhibition of the glucocorticoid negative-feedback pathway. The data reported suggest that other modulating factors in corticotropin-releasing-factor synthesis/release could be overriding both the E and P effects upon hypothalamic-pituitary-adrenal axis responsiveness.
• Sternberg, E. M., Smith, M. A., Michelson, D., Gold, P. W., & Burnet, P. W. (1994).

  The effect of chronic imipramine administration on the densities of 5-HT1A and 5-HT2 receptors and the abundances of 5-HT receptor and transporter mRNA in the cortex, hippocampus and dorsal raphe of three strains of rat.

  . Brain research, 638(1-2), 311-24. doi:10.1016/0006-8993(94)90664-5
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  We have recently demonstrated that the LEW/N rat contains lower concentrations of cortical and hippocampal 5-HT1A receptors compared with the F344/N and out-bred HSD rats. To further characterize these strains, we investigated the effect of chronic (8 wk) imipramine administration (5 mg/kg/day) on 5-HT1A and 5-HT2 receptor densities and mRNA in the cortex and hippocampus and 5-HT transporter mRNA in the dorsal raphe of LEW/N, HSD, and F344/N rats, using quantitative autoradiography and in situ hybridization histochemistry. After imipramine treatment, a significant increase in the levels of hippocampal 5-HT1A receptors, but not mRNA, was observed in LEW/N rats while the abundance of hippocampal 5-HT1A receptor mRNA, but not 5-HT1A receptor densities, decreased in F344/N rats. Cortical and hippocampal 5-HT2 receptor densities, but not mRNA, significantly decreased after imipramine administration in all three strains. Finally, 5-HT1A receptor densities and the abundance of mRNAs encoding the 5-HT1A receptor and 5-HT transporter in the dorsal raphe remained unaltered after imipramine administration in all three strains. The effects of imipramine on the levels of cortical and hippocampal 5-HT1A and 5-HT2 receptors and their transcripts, therefore, appear to be strain-dependent. The implications of these findings are discussed.
• Zelazowski, P., Zelazowski, E., Thomas, F. S., Sternberg, E. M., Smith, C. C., Raybourne, R. B., Rader, J. L., Page, S. W., Misiewicz-poltorak, B., Lynn, A. B., Love, L. A., Gold, P. W., Crofford, L. J., & Brady, L. S. (1994).

  1,1'-Ethylidenebis[L-tryptophan], a contaminant implicated in L-tryptophan eosinophilia myalgia syndrome, suppresses mRNA expression of hypothalamic corticotropin-releasing hormone in Lewis (LEW/N) rat brain.

  . Neuroimmunomodulation, 1(1), 59-65. doi:10.1159/000097091
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  The L-tryptophan eosinophilia myalgia syndrome (L-Trp-EMS), related to ingestion of impure L-Trp, occurred in epidemic proportions in the United States in 1989. Epidemiologic studies implicated 1,1'-ethylidenebis[L-tryptophan] (EBT) as the impurity most highly associated with development of human L-Trp-EMS. We have previously shown that Lewis (LEW/N) rats fed L-Trp implicated in the L-Trp-EMS epidemic (case-associated L-Trp) develop fasciitis and perimyositis which is associated with a reduction in corticotropin-releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus (PVN). In this study, we report the effects of EBT- and case-associated L-Trp on CRH mRNA expression in the hypothalamic PVN and secretion of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) into the plasma over a time course of 1-6 weeks in the same rats in which we have found fascial thickening and immune cell activation induced by these compounds. Both control L-Trp and EBT stimulated the secretion of ACTH and CORT at 1-2 weeks, whereas case-associated L-Trp did not. EBT and case-associated L-Trp decreased CRH mRNA expression in the PVN at 2-6 weeks, while control L-Trp had no effect. The striking contrast in the effects of case-associated L-Trp and EBT on the HPA axis suggests that the reduction in CRH mRNA levels in the PVN seen in each case may be related to different mechanisms. It is possible that EBT suppresses CRH mRNA expression directly, in the absence of inflammation, while case-associated L-Trp may act through multiple mechanisms, including that associated with inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)
• Szemeredi, K., Stull, R., Sternberg, E. M., Pacak, K., Listwak, S. J., Kopin, I. J., Hoffman, A., Goldstein, D. S., Gold, P. W., Garty, M., Deka-starosta, A., Chang, P. C., & Bagdy, G. (1993).

  Role of CRH in glucopenia-induced adrenomedullary activation in rats.

  . Journal of neuroendocrinology, 5(5), 475-86. doi:10.1111/j.1365-2826.1993.tb00511.x
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  Acute glucoprivation profoundly stimulated hypothalamic-pituitary-adrenocortical (HPA) and adrenomedullary outflows. Whether these responses reflect a single central mechanism regulated by corticotropin-releasing hormone (CRH) has been unclear. This study examined the role of endogenous CRH in HPA and adrenomedullary responses to hypoglycemia in Sprague-Dawley rats, by using anti-CRH immune serum or a CRH antagonist (alpha-helical h/r CRH9-41, and in Lewis rats, a strain characterized by deficient hypothalamic CRH responses during stress. In conscious Sprague-Dawley rats with indwelling arterial and venous cannulas, insulin (0.3 U/kg was injected iv, and responses of serum glucose concentrations and plasma levels of corticotropin (ACTH) and catechols (including epinephrine, EPI; norepinephrine, NE; dihydroxyphenylalanine, DOPA; dihydroxyphenylglycol, DHPG; and dihydroxyphenylacetic acid, DOPAC) were assessed, with or without pretreatment with anti-CRH immune serum (0.5 or 1.0 ml iv or 10 microl icv) or alpha-helical h/r CRH9-41 (130 nmol iv or 13 nmol icv). Responses to insulin (1.0 U/kg iv) were also measured in conscious juvenile Lewis and Fischer 344/N rats. Insulin-induced hypoglycemia markedly increased plasma levels of EPI and ACTH in all groups. Pretreatment iv with 1/0 ml of anti-CRH immune serum blocked the ACTH response to insulin but failed to attenuate the EPI response. alpha-helical h/r CRH9-41, whether given iv or icv, failed to alter ACTH or EPI responses to insulin, although the antagonist did block EPI responses to icv CRH. Hypoglycemia elicited similar increments in ACTH levels in Lewis rats and Fischer 344/N control rats; and although Lewis rats had lower baseline EPI and smaller responses of NE, DHPG, DOPA, and DOPAC levels, the groups did not differ in proportionate increments in EPI levels. The results indicate that the ACTH response to hypoglycemia depends on availability of CRH outside the blood-brain barrier--presumably in the pituitary gland. The findings with icv alpha-helical h/r CRH9-41 can be explained by failure of the antagonist to reach effective concentrations at central sites of action of endogenous CRH, or by mechanisms other than CRH release determining the adrenomedullary response to hypoglycemia. Lewis rats seem to have less adrenomedullary secretion at baseline and smaller responses of NE synthesis and release during hypoglycemia than do Fischer 344/N rats. Neurochemical evidence for differential adrenomedullary and sympathoneural responses during hypoglycemia in all three rat strains is inconsistent with Cannon's view of a functionally unitary sympathoadrenal system. Lewis rats have deficient CRH responses to some stressors but not to others, or else pituitary-adrenomedullary responses in this setting depend on mechanisms other than CRH release in the brain. Both explanations are inconsistent with the doctrine of non-specificity, the main tenet of Selye's stress theory.
• Zelazowski, P., Thomas, F. S., Sternberg, E. M., Schultzberg, M., Page, S. W., Burnet, P. W., Brenneman, D. E., & Avidor, R. (1993).

  A decomposition product of a contaminant implicated in L-tryptophan eosinophilia myalgia syndrome affects spinal cord neuronal cell death and survival through stereospecific, maturation and partly interleukin-1-dependent mechanisms.

  . The Journal of pharmacology and experimental therapeutics, 266(2), 1029-35.
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  The L-tryptophan eosinophilia myalgia syndrome (L-TRP-EMS), an inflammatory syndrome characterized by eosinophilia, myalgias, perimyositis, fasciitis and neuropathies, occurred in epidemic proportions in the United States in the summer and fall of 1989. The neuropathic clinical features in L-TRP EMS are complex and mixed. In the present study, one of the impurities most highly associated with development of L-TRP EMS, 1,1'-ethylidenebis[L-tryptophan] (EBT), and two of its diastereoisomeric breakdown products, were compared for evidence of neurotoxicity in vitro. In 1-month-old spinal cord cultures derived from fetal mice, synthetic (-)-(1S,3S)-1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (1S-beta-C) produced a 30 to 35% loss in numbers of neurons. Toxicity was not apparent after treatment with the R-isomer of the same compound or with the parent compound, EBT. Cotreatment of cultures with 1S-beta-C and neutralizing antiserum to interleukin-1 alpha (IL-1 alpha), or with 1S-beta-C and neutralizing antiserum against the murine IL-1 receptor, prevented neuronal cell death associated with 1S-beta-C. Recombinant IL-1 alpha also produced neuronal killing that was not additive to that observed with the 1S-beta-C treatment. In contrast, in immature spinal cord neuronal cultures, the 1S-beta-C, but not the 1R-beta-C or EBT, prevented the 30% cell death which normally occurs in these cultures. Neither neutralizing anti-IL-1 antibody, nor anti-IL-1 receptor antibody blocked the neuronal survival effect, suggesting that 1S-beta-C induces neuronal survival through a receptor-mediated mechanism independent of IL-1.(ABSTRACT TRUNCATED AT 250 WORDS)
• Zelazowski, P., Zelazowska, E. B., Sternberg, E. M., Patchev, V. K., Gold, P. W., & Chrousos, G. P. (1993).

  Release of hypothalamic corticotropin-releasing hormone and arginine-vasopressin by interleukin 1 beta and alpha MSH: studies in rats with different susceptibility to inflammatory disease.

  . Brain research, 631(1), 22-6. doi:10.1016/0006-8993(93)91181-q
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  The susceptibility of Lewis rats is related to blunted hypothalamic-pituitary-adrenal (HPA) axis responsiveness to a variety of inflammatory and neuroendocrine stimuli. In contrast resistance to inflammatory disease of histocompatible Fischer rats is associated with their intact HPA axis responses to the same stimuli. We have examined the contribution of IL-1 beta to in vitro corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) release from hypothalamic explants derived from LEW/N and F344/N rats. The same animal model has been used to investigate the regulatory effect of alpha MSH, an immunosuppressive neurohormone, on IL-1 beta stimulated CRH and AVP secretion. CRH basal release in both strains was similar. However, LEW/N hypothalamic AVP basal secretion was significantly elevated. CRH relative response of LEW/N hypothalamic explants to IL-1 beta stimulation was lower compared to Fischer, which is consistent with their hyporesponsiveness to inflammatory mediators. AVP secretion however, was significantly decreased in hypothalamic explants from both strains after 40 min exposure to IL-1 beta. alpha MSH suppressed basal CRH and AVP release in both LEW/N and F344/N rats and prevented IL-1 beta stimulated CRH secretion in these strains. AVP was further diminished in F344/N explants following incubation with alpha MSH + IL-1 beta, while LEW/N level was significantly elevated. However, AVP levels remained significantly below baseline in explants from both strains after final incubation with IL-1 beta. Although our findings indicate a modulatory action of alpha MSH in HPA axis regulation in vitro, the physiological importance of this phenomenon in Lewis and Fischer rats requires further investigation.
• Gallucci, W. T., Wt, G., Wilder, R. L., Sternberg, E. M., Gold, P. W., Gallucci, W. T., Crofford, L. J., Chrousos, G. P., & Cash, J. M. (1992).

  Pituitary-adrenal axis responsiveness to ovine corticotropin releasing hormone in patients with rheumatoid arthritis treated with low dose prednisone.

  . The Journal of rheumatology, 19(11), 1692-6.
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  Ovine corticotropin-releasing hormone (oCRH) stimulation tests were performed in 8 female patients with active rheumatoid arthritis treated chronically with daily low dose prednisone and 16 age matched female controls. Patients were tested on the day of treatment, 12 h after their last prednisone dose, and after withholding prednisone for 36 h. Basal levels of plasma ACTH and to a lesser extent plasma cortisol levels were elevated before each test, and significant increases in ACTH and cortisol were induced with oCRH. The dose response relationship between total ACTH and total cortisol was shifted to the right, suggesting that the patient group had mildly deficient adrenocortical responsiveness compensated for by elevated basal evening ACTH concentrations. It is not known whether the neuroendocrine abnormalities demonstrated are due to an intrinsic preexisting abnormality, active disease, drug therapy or all these factors.
• Sternberg, E. M., Mefford, I. N., Maddoux, G. L., Kephart, G. M., Heyes, M. P., Hertzman, P. A., & Gleich, G. J. (1992).

  Repeated coronary artery spasm in a young woman with the eosinophilia-myalgia syndrome.

  . JAMA, 267(21), 2932-2934. doi:10.1001/jama.1992.03480210094039
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  We report a case of repeated coronary artery spasm with myocardial injury in a 37-year-old woman with the eosinophilia-myalgia syndrome. This patient did not have a medical history of cardiac-related illness or risk factors for coronary artery disease. The presence of eosinophil granule major basic protein in otherwise normal-appearing myocardial tissue, along with normal plasma levels of tryptophan metabolites, suggests that the mechanism of vasospasm in this patient might involve toxic eosinophil proteins or focal myocardial lesions, but not the production of excess tryptophan metabolites. ( JAMA . 1992;267:2932-2934)
• Wilder, R. L., Sternberg, E. M., Gold, P. W., & Chrousos, G. P. (1992).

  The stress response and the regulation of inflammatory disease.

  . Annals of internal medicine, 117(10), 854-66. doi:10.7326/0003-4819-117-10-854
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  The molecular and biochemical bases for interactions between the immune and central nervous systems are described. Immune cytokines not only activate immune function but also recruit central stress-responsive neurotransmitter systems in the modulation of the immune response and in the activation of behaviors that may be adaptive during injury or inflammation. Peripherally generated cytokines, such as interleukin-1, signal hypothalamic corticotropin-releasing hormone (CRH) neurons to activate pituitary-adrenal counter-regulation of inflammation through the potent antiinflammatory effects of glucocorticoids. Corticotropin-releasing hormone not only activates the pituitary-adrenal axis but also sets in motion a coordinated series of behavioral and physiologic responses, suggesting that the central nervous system may coordinate both behavioral and immunologic adaptation during stressful situations. The pathophysiologic perturbation of this feedback loop, through various mechanisms, results in the development of inflammatory syndromes, such as rheumatoid arthritis, and behavioral syndromes, such as depression. Thus, diseases characterized by both inflammatory and emotional disturbances may derive from common alterations in specific central nervous system pathways (for example, the CRH system). In addition, disruptions of this communication by genetic, infectious, toxic, or pharmacologic means can influence the susceptibility to disorders associated with both behavioral and inflammatory components and potentially alter their natural history. These concepts suggest that neuropharmacologic agents that stimulate hypothalamic CRH might potentially be adjunctive therapy for illnesses traditionally viewed as inflammatory or autoimmune.
• Wilder, R. L., Sternberg, E. M., Smith, C. C., Gold, P. W., Chrousos, G. P., Calogero, A. E., Bernardini, R., Bagdy, G., & Aksentijevich, S. (1992).

  Neurotransmitter-induced hypothalamic-pituitary-adrenal axis responsiveness is defective in inflammatory disease-susceptible Lewis rats: in vivo and in vitro studies suggesting globally defective hypothalamic secretion of corticotropin-releasing hormone.

  . Neuroendocrinology, 55(5), 600-8. doi:10.1159/000126173
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  The susceptibility of female Lewis (LEW/N) rats to the development of streptococcal cell wall (SCW)-induced arthritis and other autoimmune phenomena is associated with the inability of their hypothalamic-pituitary-adrenal (HPA) axis to adequately respond to inflammatory stimuli. In contrast, resistance to the development of SCW-induced arthritis and other inflammatory autoimmune manifestations in histocompatible female Fischer rats (F344/N) is related to their intact HPA axis response to inflammatory mediators. To evaluate the mechanism and the specificity of the HPA axis defect in LEW/N rats, we examined the ability of three major excitatory neurotransmitter systems to activate the HPA axis in both Lewis and Fisher rats. The responsiveness of plasma ACTH and corticosterone to the cholinergic muscarinic receptor agonist arecoline, the alpha 1-adrenergic receptor agonist methoxamine and the serotonin (5-HT) type 2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane were significantly blunted and/or abolished in LEW/N compared to F344/N rats. To localize the HPA axis defect to the hypothalamic CRH neuron, we evaluated the ability of explanted hypothalami from the two strains to secrete immunoreactive CRH in vitro, in response to acetylcholine (ACh), norepinephrine (NE), 5-HT and the 5-HT agonist quipazine. LEW/N hypothalami released less immunoreactive CRH (iCRH) in response to ACh, NE, 5-HT and quipazine than F344/N hypothalami. The dose-response curves of these compounds in the former were shifted to the right and/or abolished, suggesting decreased sensitivity of LEW/N hypothalami to these neurotransmitters.(ABSTRACT TRUNCATED AT 250 WORDS)
• Young, W. S., Wilder, R. L., Whitfield, H. J., Sternberg, E. M., Gold, P. W., Chrousos, G. P., & Aksentijevich, S. (1992).

  Arthritis-susceptible Lewis rats fail to emerge from the stress hyporesponsive period.

  . Brain research. Developmental brain research, 65(1), 115-8. doi:10.1016/0165-3806(92)90014-n
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  Susceptibility to streptococcal cell wall (SCW)-induced arthritis in 4- to 6-week-old Lewis (LEW/N) rats is associated with blunted glucocorticoid production secondary to a profound defect in inflammatory mediator-induced hypothalamic corticotropin-releasing hormone (CRH) biosynthesis and secretion. The relative SCW arthritis resistance in histocompatible Fischer (F344/N) rats, on the other hand, is associated with robust hypothalamic-pituitary-adrenal (HPA) axis responses to inflammatory mediators. In this study, we investigated HPA axis responses to SCW during the postnatal developmental period in LEW/N and F344/N rats. We found that SCW-induced plasma corticosterone (CORT) responses do not significantly increase during development in LEW/N, while such responses clearly appear at postnatal day 14 in F344/N and outbred Harlan-Sprague-Dawley (HSD) rats. Additionally, LEW/N rats fail to exhibit the normal ontogenic increase in CRH mRNA levels in the paraventricular nucleus (PVN), whereas their SCW-induced PVN CRH mRNA responses are blunted compared to F344/N at postnatal day 14. Taken together, these results suggest that LEW/N rats fail to emerge completely from their stress hyporesponsive period. This may account for the lack of stress responsiveness in young adult LEW/N rats, and consequently, for their susceptibility to SCW-induced arthritis and other inflammatory diseases.
• Yocum, D. E., Wilder, R. L., Sternberg, E. M., Sano, H., Remmers, E. F., Lafyatis, R., Kumkumian, G. K., Crofford, L. J., & Case, J. P. (1991).

  Endothelial cells and the pathogenesis of rheumatoid arthritis in humans and streptococcal cell wall arthritis in Lewis rats.

  . Journal of cellular biochemistry, 45(2), 162-6. doi:10.1002/jcb.240450207
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  Endothelial cells play a fundamental role in the pathogenesis of chronic inflammatory arthritis in humans such as rheumatoid arthritis (RA), as well as experimental animal models such as streptococcal cell wall (SCW) arthritis in Lewis (LEW/N) rats. This review summarizes data in support of this concept. The earliest apparent abnormalities in synovial tissues of patients with RA and Lewis rats with SCW arthritis appear to reflect microvascular endothelial cell activation or injury. At the molecular level, the abnormalities include enhanced expression by endothelial cells of activation markers such as class II major histocompatibility complex antigens, phosphotyrosine, leukocyte adhesion molecules, oncoproteins such as c-Fos and c-Myc, and metalloproteinases such as collagenase and transin/stromelysin. The development of severe, chronic, destructive arthritis is dependent upon thymic-derived lymphocytes and is accompanied by tumorlike proliferation of cells in the synovial connective tissue stroma (blood vessels and fibroblastlike cells), which results in resorptive destruction of bone and cartilage. Multiple criteria support the analogy to a neoplastic process. Paracrine and autocrine factors such as interleukin-1 (IL-1), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), and heparin-binding fibroblast growth factors (HBGF, FGF) appear to play important roles in the generation of these lesions. Finally, in addition to the autocrine and paracrine regulatory factors, neuroendocrine factors, particularly the hypothalamic-pituitary-adrenal axis, appear to be involved in the counterregulation of the inflammatory process. The counterregulatory effects are mediated, in part, by inhibition of endothelial cell activation by corticosteroids.
• Gold, P. W., Wilder, R. L., Sternberg, E. M., Gold, P. W., & Chrousos, G. P. (1990).

  A defect in the central component of the immune system--hypothalamic-pituitary-adrenal axis feedback loop is associated with susceptibility to experimental arthritis and other inflammatory diseases.

  . Annals of the New York Academy of Sciences, 594(1), 289-92. doi:10.1111/j.1749-6632.1990.tb40488.x
• Silver, R. M., Maize, J. C., Sternberg, E. M., Maize, J. C., Sternberg, E. M., Silver, R. M., Katz, P., Heyes, M. P., Hertzman, P. A., Gleich, G. J., & Clauw, D. J. (1990).

  Treatment of the eosinophilia-myalgia syndrome.

  . The New England journal of medicine, 323(6), 417-8. doi:10.1056/nejm199008093230613
• Silver, R. M., Maize, J. C., Sternberg, E. M., Maize, J. C., Vionnet-fuasset, M., Sternberg, E. M., Silver, R. M., Quearry, B. J., & Heyes, M. P. (1990).

  Scleroderma, fasciitis, and eosinophilia associated with the ingestion of tryptophan.

  . The New England journal of medicine, 322(13), 874-81. doi:10.1056/nejm199003293221302
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  An association between the ingestion tryptophan and a syndrome characterized by scleroderma-like skin abnormalities, fasciitis, and eosinophilia has recently been recognized in the United States. We report the clinical and histopathological findings in nine patients and the results of biochemical analyses of tryptophan metabolism in seven patients with this syndrome. Edema of the extremities, frequently accompanied by pruritus, paresthesia, and myalgia, developed in the nine patients (six women and three men; age range, 30 to 66 years) 1 to 18 months after the start of therapy with tryptophan (1.5 to 3.0 g daily) for insomnia, depression, or obesity. Five patients were taking drugs (benzodiazepines) known to inhibit hypothalamic-pituitary-adrenal function, and one had adrenal insufficiency. All had blood eosinophilia in the acute phase of their illness (mean eosinophil count [+/- SD], 3.62 +/- 2.87 X 10(9) cells per liter). All had histopathological changes in the dermis and subcutaneous tissue typical of scleroderma, and seven patients had eosinophils. The fascia was inflamed and fibrotic, and adjacent skeletal muscle often showed perifascicular inflammation. Tryptophan was discontinued in all patients, and eight received prednisone. The cutaneous symptoms improved, but only two patients had complete resolution of their illness. The patients had plasma levels of tryptophan before and after an oral dose of tryptophan that were similar to those in normal subjects. Plasma levels of L-kynurenine and quinolinic acid, which are metabolites of tryptophan, were significantly higher in four patients with active disease than in three patients studied after eosinophilia had resolved or in five normal subjects (P less than 0.001)--findings consistent with the activation of the enzyme indoleamine-2,3-dioxygenase. This illness resembles eosinophilic fasciitis and probably represents one aspect of the recently reported eosinophilia-myalgia syndrome. The development of the syndrome may result from a confluence of several factors, including the ingestion of tryptophan, exposure to agents that activate indoleamine-2,3-dioxygenase, and possibly, impaired function of the hypothalamic-pituitary-adrenal axis.
• Young, W. S., Wilder, R. L., Sternberg, E. M., Gold, P. W., Chrousos, G. P., Calogero, A. E., & Bernardini, R. (1989).

  A central nervous system defect in biosynthesis of corticotropin-releasing hormone is associated with susceptibility to streptococcal cell wall-induced arthritis in Lewis rats.

  . Proceedings of the National Academy of Sciences of the United States of America, 86(12), 4771-5. doi:10.1073/pnas.86.12.4771
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  We have recently found that susceptibility to streptococcal cell wall (SCW)-induced arthritis in Lewis (LEW/N) rats is due, in part, to defective inflammatory and stress mediator-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Conversely, the relative arthritis resistance of histocompatible Fischer (F344/N) rats is related to their intact responses to the same stimuli. Specifically, LEW/N rats, in contrast to F344/N rats, have markedly impaired plasma corticotropin and corticosterone responses to SCW, recombinant human interleukin 1 alpha, the serotonin agonist quipazine, or synthetic rat/human corticotropin-releasing hormone (CRH). To explore the mechanism of this defect, we examined the functional integrity of the hypothalamic CRH neuron in LEW/N rats compared to F344/N rats. LEW/N rats, in contrast to F344/N rats, showed profoundly deficient paraventricular nucleus CRH mRNA levels and hypothalamic CRH content in response to SCW. Compared to F344/N rats, there was no increase in LEW/N hypothalamic CRH content or CRH release from explanted LEW/N hypothalami in organ culture in response to recombinant interleukin 1 alpha. These data provide strong evidence that the defective LEW/N corticotropin and corticosterone responses to inflammatory and other stress mediators, and the LEW/N susceptibility to experimental arthritis, are due in part to a hypothalamic defect in the synthesis and secretion of CRH. The additional finding of deficient expression in LEW/N rats of the hypothalamic enkephalin gene, which is coordinately regulated with the CRH gene in response to stress, suggests that the primary defect is not in the CRH gene but is instead related to its inappropriate regulation.
• Williams, P., Williams, P. D., Sternberg, E. M., Smith, C. C., Sacerdote, P., Ruff, M. R., Pert, C. B., Martin, B. M., & Hallberg, P. L. (1988).

  Tritiated D‐ala1‐peptide T binding: A pharmacologic basis for the design of drugs which inhibit HIV receptor binding

  . Drug Development Research, 15(4), 371-379. doi:10.1002/ddr.430150404
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  The HIV virus initiates its infectious cycle through a high-affinity binding interaction between the envelope protein gp 120 and its receptor, the T4 (or CD4) molecule. An octapeptide sequence, termed peptide T, present in the second variable region of gp 120 from the ARV isolate, has been implicated as the attachement site. The core peptide required for activity has been further refined to a pentapeptide, and homologous pentapeptides are similarly positioned in 21 other sequenced HIV isolates. Utilizing a novel direct binding assay of 3H-D-ala1-peptide T, we now report that synthetic peptides derived from these other isolates are potent competitors of peptide T binding to T4-positive lymphocytes and brain membranes. Direct peptide T binding is also competable by purified virion gp 120, indicating that these ligands are interactive at the same receptor. Peptide T has sequence relatedness to the peptide vasoactive intestinal peptide (VIP), and VIP and its relevant homologous pentapeptide, VIP[7–11], are also potent inhibitors of peptide T binding. To determine the essential structural features responsible for receptor activity we have studied a series of synthetic peptides substituted with single D-amino acid residues. These data reveal that the tyrosine of position 7 in peptide T, present in all natural viral isolates, is obligate for receptor activity. Structure/function analysis for a large number of analogs is presented. Significantly, this binding assay is highly correlated with peptide bioactivity in several independent systems, indicating that this methodology can be used for rapid screening of novel, potential anti-AIDS therapeutics whose target is inhibition of virus gpl20 binding.

Proceedings Publications

• Runyon, J. R., Jia, M., Jia, M., Goldstein, M. R., Skeath, P., Abrell, L. M., Sternberg, E. M., Chorover, J. D., Skeath, P. R., Runyon, J. R., & Chorover, J. D. (2019).

  Dynamic behavior of cortisol and cortisol metabolites in human eccrine sweat

  . In International Journal of Prognostics and Health Management.
• Skeath, P., Sternberg, E., Mehl, M. R., Ram, S., Srinivasan, K., Currim, F., Lindberg, C., Herzl, D., Herzl, R., Lunden, M., Goebel, N., Andrews, S., Najafi, B., Razjouyan, J., Lee, H., Gilligan, B., Heerwagen, J., Kampschroer, K., & Canada, K. (2017).

  A Regularization Approach for Identifying Cumulative Lagged Effects in Smart Health Applications

  . In Proceedings of the 2017 International Conference on Digital Health.
• Sternberg, E. M., Srinivasan, K., Currim, F., & Ram, S. (2016, April 2016). Feature importance and predictive modeling for multi-source healthcare data with missing values.. In 6th International Conference on Digital Health.

Presentations

• Sternberg, E. M. (2021, April). DASH-SAFE: A Multi -Modal Geographic Information System (GIS) Dashboard for Near Real-time Mapping of Perceived COVID Risk/Safety in a Campus Environment. Integrative Medicine & Health SymposiumIntegrative Medicine & Health Symposium.
• Sternberg, E. M. (2021, December). Annual Meeting NSF IUCRC Center to Stream Healthcare in Place. Annual Meeting NSF IUCRC Center to Stream Healthcare in Place. Pasadena, CA: (C2SHIP).
• Sternberg, E. M. (2021, December). HealthTech Connect Faculty Executive Committee Meeting. HealthTech Connect Faculty Executive Committee Meeting. Phoenix, AZ: HealthTech Connect.
• Sternberg, E. M. (2021, June). Creating Healing Spaces. LGA Architects Fireside ChatLGA Architects.
• Sternberg, E. M. (2021, June). Objective Sleep Measures and Psychological Outcomes (A Danvers). Society of Ambulatory Assessment ConferenceSociety of Ambulatory Assessment.
• Sternberg, E. M. (2021, March). Presenter. IN2WIBE NSF ConferenceIN2WIBE.
• Sternberg, E. M. (2021, May). Healing Spaces: Environments that Promote Health. Integrative Medicine SummitIntegrative Medicine Summit.
• Sternberg, E. M. (2021, May). Impacts on Sleep and Cognitive Performance in Aging Populations towards Mitgation with Real-time Automatic Adaptive Connection of Human Responses to Building Systems through the Internet of Things. RESTRUCT Symposium Ambient and Personal CO2RESTRUCT.
• Sternberg, E. M. (2021, November). An Integrative Framework for Wellbeing in the Built Environment. Panelist European Congress for Integrative MedicineEuropean Congress for Integrative Medicine.
• Sternberg, E. M. (2021, November). Wellbeing in the Built Environment. Workshop International Network of NetworksNSF sponsored.
• Sternberg, E. M. (2021, October). Designing the Built Environment for Health and Wellbeing During COVID and Beyond. Semana Binacional de Salud. Phoenix, AZ: Semana Binacional de Salud.
• Sternberg, E. M. (2021, October). Mind-Body-Stress-Wellbeing-Environment Relationships. International Symposium on Nature & Health. Sao Paolo, Brazil: International Symposium.
• Sternberg, E. M. (2021, September). DASH-Well: A Real-Time, Real-Place Emotion Mapping Tool for Built Environment Stress Reduction, Well-being, and Risk Reduction Post-COVID Re-Entry and Beyond. Greenbuild International Conference and Expo, Health & Wellness SummitGreenbuild.
• Sternberg, E. M. (2021, September). Improving Healthy Building and Clean Office Space Standards. RETHINK Office: Filter Change:RETHINK Office.
• Alschuler, L., Weil, A. T., Maizes, V., Horwitz, R. J., Chiasson, A. M., & Sternberg, E. M. (2020, April). An Integrative Approach to COVID-19. University of Arizona COVID-19 Webinar Series. Tucson, Arizona.
• Sternberg, E. M. (2020, April). Speaker, Healing Spaces. Calm with Rina Raphael webcast Topic: Healing Spaces. webcast Tucson: Calm with Rina Raphael.
• Sternberg, E. M. (2020, May). Speaker, Healing Spaces. Living Lab BHAG Topic: Healing Spaces. webcast Tucson: Living Lab BHAG.
• Sternberg, E. M. (2020, May). Speaker, Places matter to stress and immunity Explore how stress can impact your immune health. International WELL Building Institute webcast Title:Places matter to stress and immunity Explore how stress can impact your immune health. webcast Tucson: International WELL Building Institute.
• Sternberg, E. M. (2020, November). Speaker, DASH-SAFE: A personal real-time risk-assessment risk-management navigation and automated alarm tool. University of Arizona Health Science Center COVID-19 Symposium: DASH-SAFE: A personal real-time risk-assessment risk-management navigation and automated alarm tool. Zoom: University of Arizona Health Science Center COVID-19 Symposium.
• Sternberg, E. M. (2020, October). Speaker, Panel Member Shaping Collaboration Health and the Built Environment: Introduction and wearable health from molecules to environment. Conscious Cities Festival 2020: Shaping Collaboration Health and the Built Environment: Introduction and wearable health from molecules to environment. Zoom: Conscious Cities Festival 2020.
• Sternberg, E. M. (2020, September). Speaker, Panel Chair A Multi-Modal Geographic Information System(GIS) Dashboard for Real-time Mapping of Perceived Risk/Safety Facilities Design and Operations and Movement: Mitigation of At-Risk Spaces for a Clustered Population in a Post-COVID-19 Environment. RESTRUCT Zoom Symposium: Title:A Multi-Modal Geographic Information System(GIS) Dashboard for Real-time Mapping of Perceived Risk/Safety Facilities Design and Operations and Movement: Mitigation of At-Risk Spaces for a Clustered Population in a Post-COVID-19 Environment. RESTRUCT Zoom Symposium: RESTRUCT.

Poster Presentations

• Engineer, A. A., Youssef, O. M., & Sternberg, E. M. (2020, January). Wearable devices to measure the impact of built environments on health. Department of Medicine Annual Poster Session, University of Arizona. University of Arizona, Tucson AZ..

Others

• Sternberg, E. M. (2020, September 2020-present). DASH-SAFE GIS-based Real-time Risk-Assessment Risk-Management Tool. Numerous DASH-SAFE Briefings including to: UArizona Asst VP for Facilities Management; Facilities Management Supervisors; ICS Public Health Committee; ICS Privacy Committee; UArizona Office of the General Council representative; Tech Launch Arizona and TLA Commercialization partners: Dean, UArizona College of Medicine; UArizona Foundation officer.
• Sternberg, E. M. (2020, September). DASH-SAFE GIS-based Real-time Risk Assessment Risk-Management Tool. Briefing to Dr. Richard Carmona, 17th U.S. Surgeon General and Director, UArizona COVID Incident Command System (ICS).