ContributionsMagdy Selim --organized the trial hypotheses, designed the trial, provided guidance about the data analysis and interpretation and presentation of the data, and drafted most of the sections of the manuscript. Lydia Foster --involved in the statistical analysis and data interpretation, and Contributed to the development and revisions to the manuscript. Claudia Moy --involved in the oversight of the trial conduct and progress Guohua Xi --organized the trial hypotheses, and provided critical revisions to the manuscript. MH, MJ, VS, and WC contributed to recruitment and randomization of trial participants, and provided critical revisions to the manuscript. LM and SG were involved in the design of the trial and provided critical revisions to the manuscript. Casey Norton --provided volumetric measurements of imaging data. Yuko Palesch --involved in the design of the study, statistical analysis and data interpretation, and provided critical revisions to the manuscript. Sharon yeatts --involved in the design of the study, statistical analysis and data interpretation, and contributed to the development and revisions to the manuscript. The idef investigators (see appendix) --contributed to the identification and, when eligible, randomization of trial participants. DECLARATION OF INTERESTSThis was an investigator-initiated study, funded by the NINDS (U01 NS074425). Deferoxamine Mesylate is a generic drug, and there was no commercial or industrial support for the trial. None of the authors has any competing interests related to the submitted work. MS reports grants from the NIH/NINDS (i-DEF) and the American Heart Association (outside the submitted work), and personal fees for serving on the advisory board of CSL Behring (outside the submitted work) during the conduct of the trial. SDY reports grant support from the NINDS, personal fees from Genentech and other fees from CR Bard Inc. (outside the submitted work) during the conduct of the study. SG, LDF, YP, and GX report grants from the NIH/NINDS. MDH reports personal fees from Merck, nonfinancial support from Hoffmann-La Roche Canada Ltd, grants from Covidien (Medtronic), grants from Boehringer-Ingleheim, grants from Stryker Inc., grants from Medtronic LLC, grants from NoNO Inc., (outside the submitted work); In addition, MDH has a patent Systems and Methods for Assisting in Decision-Making and Triaging for Acute Stroke Patients pending to US Patent office Number: 62/086,077 and owns stock in Calgary Scientific Incorporated, a company that focuses on medical imaging software, is a director of the Canadian Federation of Neurological Sciences, a not-for-profit group and has received grant support from Alberta Innovates Health Solutions, CIHR, Heart & Stroke Foundation of Canada, and NINDS. LM, VS, WC, MJ, CM, and CN have nothing to disclose.

We report that OX40 stimulation drives all lineages of CD4 T cell development including Treg and the plasticity of the response is dependant on local cytokines. In TGF-β1-treated cultures, OX40 agonist increased IFN-γ and IL-4 production and diverted T cells from the Treg lineage. However, cytokine blockade in the context of OX40 stimulation promoted also enhanced Treg accumulation. This observation was evident in naive mice, as OX40 engagement enhanced Treg proliferation and accumulation in vivo. Lastly, OX40 agonist administration influenced EAE disease severity in opposing directions depending on the timing of administration. Given during Ag priming, OX40 agonist drove Treg expansion and inhibited disease, whereas, given later it enhanced T cell effector cytokine production in the CNS and exacerbated disease. Hence, OX40 signaling can augment the accumulation of all CD4 T cell lineages; however its accentuation of immune responses may have vastly different biologic outcomes depending upon the local cytokine milieu.

Ovarian hormones, including progesterone, are known to have immunomodulatory and neuroprotective effects which may alter the disease course of experimental autoimmune encephalomyelitis (EAE). In the current study, we examined the treatment potential of progesterone beginning at the onset of EAE symptoms. Progesterone treated animals showed reduced peak disease scores and cumulative disease indices, and decreased inflammatory cytokine secretion (IL-2 and IL-17). In addition, increased production of IL-10 was accompanied by increased numbers of CD19+ cells and an increase in CD8+ cells. Decreased chemokine and chemokine receptor expression in the spinal cord also contributed to decreased lesions in the spinal cord.

Although previous research has indicated that hormone replacement therapy benefits memory in menopausal women, several recent studies have shown either detrimental or no effects of treatment. These inconsistencies emphasize the need to evaluate the role of ovarian hormones in protecting against age-related cognitive decline in an animal model. The present study investigated the effects of long term hormone treatment during aging on the Morris water maze. Female Long Evans hooded rats were ovariectomized at middle age (12-13 months) and were immediately placed in one of five groups: no replacement, chronic 17 β-estradiol only, chronic 17 β-estradiol and progesterone, chronic 17 β-estradiol and medroxyprogesterone acetate (MPA), or cyclic 17 β-estradiol only. 17 β-estradiol was administered in the drinking water in either a chronic or cyclic (3 out of 4 days) fashion. Progesterone and MPA were administered via subcutaneous pellets. Following six months of hormone treatment, animals were tested on the Morris water maze. Animals performed four trials a day for four days and after the final day of testing a subset of animals completed a probe trial. Across four days of testing, rats receiving 17 β-estradiol in combination with MPA performed significantly worse than all other groups receiving hormone replacement. In addition on the last day of testing, chronic 17 β-estradiol administration was more beneficial than cyclic administration and no replacement. Thus compared to other hormone treated groups, long term 17 β-estradiol treatment in combination with MPA results in impaired performance on the spatial Morris water maze.

BackgroundRemission of multiple sclerosis during periods of high ovarian hormone secretion (such as pregnancy) has led to a great deal of interest in the potential for estrogens to treat autoimmune disease. Previous work has established that 17β-estradiol can inhibit onset of experimental autoimmune encephalomyelitis (EAE), while ethinyl estradiol (EE) can reduce the severity of established disease. In the current study, the influence of estrogen receptor-α (ERα) and the G-protein coupled estrogen receptor (GPR30 or GPER) on EE's ability to treat EAE was explored.ResultsEE reduced disease severity in wild-type and ERα knockout (ERKO) mice, but did not alter disease in the GPR30KO group. Production of anti-inflammatory IL-10 increased in EE-ERKO mice (which showed reduced disease) but not in EE-GPR30KO mice (who did not have improved disease).ConclusionsDifferential production of IL-10 following EE treatment in ERKO and GPR30KO animals may be responsible for the distinctly different effects on disease severity. Increased IL-10 in ERKO-EE compared to ERKO-Controls is likely to be an important factor in reducing established disease. The inability of EE to reduce disease in GPR30KO mice indicates an important but still undefined role for GPR30 in regulating immune reactivity.

The role of gender and hormones as determinants in the development of autoimmunity has been studied extensively, 1-3 with a higher frequency of disease susceptibility among women than men. Also, remission during pregnancy when oestrogen (E 2 ) levels are elevated followed by post-natal relapses suggest that this hormone exerts a regulatory effect on autoimmune diseases. 4 Oestrogen treatment arrests clinical manifestations of experimental autoimmune encephalomyelitis (EAE) 5 as well as collagen-induced arthritis 6 mediated by oestrogen receptor-a but not oestrogen receptor-b. 7,8

The size of the female rat corpus callosum decreases in response to pubertal ovarian hormone exposure, but the underlying changes in axonal composition have not been examined. In the current study, animals underwent ovariectomy or sham surgery at day 20, and the number of myelinated and unmyelinated axons were examined in young adulthood (2 mo.) using electron microscopy. Ovariectomized animals had a greater number of myelinated axons compared to intact animals, while total axon number was not affected. Ovarian hormone exposure seems to limit the number of axons that become myelinated in the splenium, while not affecting the number of axons crossing through the region. Keywordsestrogen; progesterone; myelin; oligdodendrocyte; adolescence; corticosteroids The corpus callosum is sexually dimorphic in the rat, with males having a larger total corpus callosum size than females (Berrebi et al, 1988;Fitch et al, 1991;Bimonte et al., 2000a;2000b;2000c;Denenberg et al., 1991). The splenium, defined as the posterior 20% of the total callosal length, carries axons from the visual cortex (Kim et al., 1996). Sex differences in the size of the splenium (Nunez and Juraska, 1998) are due to a greater number of myelinated axons within the splenium of males though there are no differences in total axon number (Kim et al., 1996). Differences in myelinated axon number are established by young adulthood (day 60), but are not seen in prepubertal animals examined at 25 days of age (Kim and Juraska, 1997). On the other hand, females have more total axons at day 25. However, because of continued axon elimination in females this difference is abolished by day 60 (Kim and Juraska, 1997). Thus, the onset of puberty around day 35 may affect both myelination and axon withdrawal.Prepubertal ovariectomy (OVX) at day 25 has been shown to increase the overall size of the corpus callosum in adulthood (Bimonte et al., 2000a(Bimonte et al., , 2000b(Bimonte et al., , 2000c, while OVX at day 70 is without effect (Bimonte et al, 2000c). The underlying structural changes responsible for this increase in size have not been examined. It is possible that the removal of ovarian hormones before puberty reduces axon elimination or increases the number of axons that get myelinated, resulting in a greater callosal size. In the primary visual cortex, which projects axons through Corresponding author: Janice M. Juraska, Ph.D., Department of Psychology, 603 E. Daniel St., Champaign, IL 61820, (217) 333-8546, Fax: (217) 244-5876, jjuraska@cyrus.psych.uiuc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Pu...

Although there are indications of growth in the size and myelination of the rat corpus callosum during adulthood, it is not known how long this growth continues. In addition, the potential for age-related changes in these measures to affect the sex differences seen in adulthood has not been examined. Here the size of callosal subregions and area occupied by myelin were examined in the genu and splenium of male and female rats in adulthood, middle-age, and old age. Our findings revealed increases both in size and in the area composed of myelin between adulthood and middle-age that were maintained into old age, with no indications of age-related loss in either the genu or splenium of the rat.