Simian hemorrhagic fever virus infection of rhesus macaques as a model of viral hemorrhagic fever: Clinical characterization and risk factors for severe disease

AbstractSimian Hemorrhagic Fever Virus (SHFV) has caused sporadic outbreaks of hemorrhagic fevers in macaques at primate research facilities. SHFV is a BSL-2 pathogen that has not been linked to human disease; as such, investigation of SHFV pathogenesis in non-human primates (NHPs) could serve as a model for hemorrhagic fever viruses such as Ebola, Marburg, and Lassa viruses. Here we describe the pathogenesis of SHFV in rhesus macaques inoculated with doses ranging from 50PFU to 500,000PFU. Disease severity was independent of dose with an overall mortality rate of 64% with signs of hemorrhagic fever and multiple organ system involvement. Analyses comparing survivors and non-survivors were performed to identify factors associated with survival revealing differences in the kinetics of viremia, immunosuppression, and regulation of hemostasis. Notable similarities between the pathogenesis of SHFV in NHPs and hemorrhagic fever viruses in humans suggest that SHFV may serve as a suitable model of BSL-4 pathogens

The estrogen-injected female mouse: new insight into the etiology of PCOS

<p>Abstract</p> <p>Background</p> <p>Female mice and rats injected with estrogen perinatally become anovulatory and develop follicular cysts. The current consensus is that this adverse response to estrogen involves the hypothalamus and occurs because of an estrogen-induced alteration in the GnRH delivery system. Whether or not this is true has yet to be firmly established. The present study examined an alternate possibility in which anovulation and cyst development occurs through an estrogen-induced disruption in the immune system, achieved through the intermediation of the thymus gland.</p> <p>Methods, Results and Conclusion</p> <p>A putative role for the thymus in estrogen-induced anovulation and follicular cyst formation (a model of PCOS) was examined in female mice by removing the gland prior to estrogen injection. Whereas all intact, female mice injected with 20 ug estrogen at 5–7 days of age had ovaries with follicular cysts, no cysts were observed in animals in which thymectomy at 3 days of age preceded estrogen injection. In fact, after restoring immune function by thymocyte replacement, the majority of thymectomized, estrogen-injected mice had ovaries with corpora lutea. Thus, when estrogen is unable to act on the thymus, ovulation occurs and follicular cysts do not develop. This implicates the thymus in the cysts' genesis and discounts the role of the hypothalamus. Subsequent research established that the disease is transferable by lymphocyte infusion. Transfer took place between 100-day-old estrogen-injected and 15-day-old naïve mice only when recipients were thymectomized at 3 days of age. Thus, a prerequisite for cyst formation is the absence of regulatory T cells. Their absence in donor mice was judged to be the result of an estrogen-induced increase in the thymus' vascular permeability, causing de facto circumvention of the final stages of regulatory T cell development. The human thymus has a similar vulnerability to steroid action during the fetal stage. We propose that in utero exposure to excessive levels of steroids such as estrogen has a long-term effect on the ability of the thymus to produce regulatory T cells. In female offspring this can lead to PCOS.</p

Daidzein Prevents the Increase in CD4+CD28null T Cells and B Lymphopoesis in Ovariectomized Mice: A Key Mechanism for Anti-Osteoclastogenic Effect

Estrogen deficiency leads to an upregulation of TNF-α producing T cells and B-lymphopoesis which augments osteoclastogenesis. Estrogen deficiency also increases the population of premature senescent CD4+CD28null T cells which secrete a higher amount of TNF-α thus leading to enhanced osteoclastogenesis. Isoflavonoids like daidzein and genistein are found mostly in soybeans, legumes, and peas. These share structural similarity with 17β-stradiol (E2) and have osteoprotective role. This study explores the effect of daidzein (Daid) on the proliferation of TNF-α producing T cells, premature senescent T cells and B cell lymphopoesis under estrogen deficient conditions. For this study adult Balb/c mice were treated with Daid at 10 mg/kg body weight dose by oral gavage daily post ovariectomy (Ovx). After six weeks animals were autopsied and bone marrow and spleen cells were collected for FACS analysis. Blood serum was collected for ELISA. It was observed that Ovx mice treated with Daid for six weeks show reduction in Ovx induced expansion of CD4+ T cells in bone marrow and spleen when analysed by flow cytometry. Estrogen deficiency led to increased prevalence of TNF-α secreting CD4+CD28null T cells, however, treatment with Daid increased the percentage of CD4+CD28+ T cells. Co-culture of CD4+CD28null T cells and bone marrow resulted in enhanced osteoclastogenesis as evident by increased tartarate resistant acid phosphatase (TRAP) expression, an osteoclast marker. However, treatment with Daid resulted in reduced osteoclastogenesis in CD4+CD28null T cells and bone marrow cell co-culture. Daid also regulated B lymphopoesis and decreased mRNA levels of RANKL in B220+ cells. Taken together, we propose that one of the mechanisms by which Daid prevents bone loss is by reversing the detrimental immune changes as a result of estrogen deficiency

Engineering Nano- and Microparticles to Tune Immunity

The immune system can be a cure or cause of disease, fulfilling a protective role in attacking cancer or pathogenic microbes but also causing tissue destruction in autoimmune disorders. Thus, therapies aimed to amplify or suppress immune reactions are of great interest. However, the complex regulation of the immune system, coupled with the potential systemic side effects associated with traditional systemic drug therapies, has presented a major hurdle for the development of successful immunotherapies. Recent progress in the design of synthetic micro- and nano-particles that can target drugs, deliver imaging agents, or stimulate immune cells directly through their physical and chemical properties is leading to new approaches to deliver vaccines, promote immune responses against tumors, and suppress autoimmunity. In addition, novel strategies, such as the use of particle-laden immune cells as living targeting agents for drugs, are providing exciting new approaches for immunotherapy. This progress report describes recent advances in the design of micro- and nano-particles for immunotherapies and diagnostics.National Institutes of Health (U.S.) (AI095109)National Institutes of Health (U.S.) (CA140476)United States. Dept. of Defense (Contract W81XWH-10-1-0290)United States. Dept. of Defense (Contract W911NF-07-D-0004)Ragon Institute of MGH, MIT and Harvar

The Phytoestrogen Genistein Induces Thymic and Immune Changes: A Human Health Concern

119 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2002.Use of soy-based infant formulas has aroused concern due to potential estrogenic effects of the soy isoflavones genistein and daidzein. Here we show that subcutaneous genistein injections in ovariectomized adult mice produced dose-responsive decreases in thymic weight of up to 80%. Genistein's thymic effects occurred through both estrogen receptor (ER) and non-ER mediated mechanisms, as the genistein effects on thymus were only partially blocked by the estrogen receptor (ER) antagonist ICI 182,780. ERbeta was not necessary for genistein's actions, as it caused similar degree of thymic atrophy in betaERKO and wild-type animals. Genistein decreased thymocyte numbers up to 86% and doubled apoptosis, indicating that the mechanism of the genistein effect on loss of thymocytes is due in part to increased apoptosis. Genistein injection caused decreases in relative percentages of thymic CD4+CD8- and double-positive CD4+CD8+ thymocytes, providing evidence that genistein may affect early thymocyte maturation and the maturation of the CD4+CD8- helper T cell lineage. Decreases in the relative percentages of CD4+CD8- thymocytes were accompanied by decreases in relative percentages of splenic CD4+CD8- cells and a systemic lymphocytopenia. In addition, genistein produced a dose-dependent suppression of humoral and cell-mediated immunity. Genistein injected at 8 mg/kg/day serum genistein levels comparable to those reported in soy-fed human infants, and this dose caused significant thymic and immune changes in mice. Critically, dietary genistein at concentrations which produced genistein levels less than those in soy-fed infants produced marked thymic atrophy. Furthermore, the effects of genistein on the thymus and the immune system were temporary and reversible. These results suggest that serum genistein concentrations found in soy-fed infants may be capable of producing thymic and immune impairments.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

Investigating the Connection Between Mental Health and Internet Addiction.

Addiction is generally viewed as a grave issue among today’s youth. Most commonly, many fear young people potentially becoming addicted to drugs and alcohol. However, there is one form of addiction that is heavily neglected amongst the others. That is cyber addiction. Obsession with constant use of the internet and cellular devices has become more and more frequent and has been argued to be especially common among those who suffer from mental conditions such as anxiety, social isolation, and hyperactivity. As we have become more and more digitally dependent in our daily lives, there is an argument to be made that today’s youth who do suffer from such states risk an even greater level of exposure and vulnerability to internet addiction. This study aimed to see if any underlying connection exists between cyber addiction & ADHD/OCD/social anxiety, and whether that connection shows a greater potential for cyber addiction for these individuals. A 20-question survey constructed from 3 major scales for mental health one scale for internet addiction was completed by 150 participants. After careful analysis of the results, the study showed that a strong underlying connection does indeed exist between internet addiction and these 3 mental states: as one grows, so does the other. The findings of this research could prove beneficial to understanding proper diagnosis and treatment of both internet addiction and mental health in the future