text:
Oral estriol trial design and patients
Cell proliferation assay
Analysis of secreted cytokines by cytometric bead array
Intracellular cytokine and surface marker staining
Alterations in subpopulations of circulating PBMCs during oral estriol treatment
In vivo estriol treatment has no effect on proliferative responses
In vivo estriol treatment alters secreted cytokines from stimulated PBMCs
In vivo estriol treatment alters intracellular cytokine production from stimulated PBMCs
Correlation between enhancing lesion volumes and changes in cytokine profiles during oral estriol therapy in RRMS
Identification of cell phenotypes affected by in vivo estriol treatment
Immune Modulation in Multiple Sclerosis Patients Treated with the Pregnancy Hormone Estriol 1
Samantha S. Soldan;
Samantha S. Soldan
Department of Neurology, Reed Neurological Research Center, University of California School of Medicine, Los Angeles, CA 90095
Ana Isabel Alvarez Retuerto;
Ana Isabel Alvarez Retuerto
Nancy L. Sicotte;
Nancy L. Sicotte
Rhonda R. Voskuhl
Address correspondence and reprint requests to Dr. Rhonda R. Voskuhl, Reed Neurological Research Center, Room A145, 710 Westwood Plaza, Los Angeles, CA 90095. E-mail address: rvoskuhl@ucla.edu
Received: June 10 2003
Accepted: September 23 2003
Published: December 01 2003
Copyright © 2003 by The American Association of Immunologists
https://doi.org/10.4049/jimmunol.171.11.6267
Samantha S. Soldan, Ana Isabel Alvarez Retuerto, Nancy L. Sicotte, Rhonda R. Voskuhl; Immune Modulation in Multiple Sclerosis Patients Treated with the Pregnancy Hormone Estriol 1. J Immunol 1 December 2003; 171 (11): 6267–6274. https://doi.org/10.4049/jimmunol.171.11.6267
The protective effect of pregnancy on putative Th1-mediated autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, is associated with a Th1 to Th2 immune shift during pregnancy. The hormone estriol increases during pregnancy and has been shown to ameliorate experimental autoimmune encephalomyelitis and collagen-induced arthritis. In addition, estrogens induce cytokine changes consistent with a Th1 to Th2 shift when administered in vitro to human immune cells and in vivo to mice. In a pilot trial, oral estriol treatment of relapsing remitting multiple sclerosis patients caused significant decreases in enhancing lesions on brain magnetic resonance imaging. Here, the immunomodulatory effects of oral estriol therapy were assessed. PBMCs collected longitudinally during the trial were stimulated with mitogens, recall Ags, and glatiramer acetate. Cytokine profiles of stimulated PBMCs were determined by intracellular cytokine staining (IL-5, IL-10, IL-12 p40, TNF-α, and IFN-γ) and cytometric bead array (IL-2, IL-4, IL-5, IL-10, TNF-α, and IFN-γ). Significantly increased levels of IL-5 and IL-10 and decreased TNF-α were observed in stimulated PBMC isolated during estriol treatment. These changes in cytokines correlated with reductions of enhancing lesions on magnetic resonance imaging in relapsing remitting multiple sclerosis. The increase in IL-5 was primarily due to an increase in CD4+ and CD8+ T cells, the increase in IL-10 was primarily due to an increase in CD64+ monocytes/macrophages with some effect in T cells, while the decrease in TNF-α was primarily due to a decrease in CD8+ T cells. Further study of oral estriol therapy is warranted in Th1-mediated autoimmune diseases with known improvement during pregnancy.
Multiple sclerosis (MS) 3 is the most prevalent demyelinating disease of the CNS, affecting an estimated 1,100,000 individuals worldwide (1). While the etiology of MS is unknown, a Th1-mediated autoimmune component driven by myelin protein-specific, proinflammatory cytokine-secreting T lymphocytes is believed to be involved in the pathogenesis. A beneficial effect of pregnancy on clinical symptoms has been observed in MS and other Th1-mediated autoimmune diseases, including rheumatoid arthritis (RA), psoriasis, uveitis, and thyroiditis (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20). Interestingly, most of these diseases are characterized by temporary rebound exacerbations postpartum (2, 4, 5, 7, 8, 9, 14, 17, 20). Specifically in MS, the improvement in clinical symptoms during pregnancy entails a significant reduction in relapse rates in the last trimester, and the postpartum exacerbation involves a temporary increase in relapse rates to levels higher than prepregnancy levels for ∼6 mo. In contrast, a worsening of symptoms during pregnancy has been reported in systemic lupus erythematosus, an autoimmune disease with a putative Th2-mediated component in its pathogenesis (21, 22).
In general, Th1 lymphocytes secrete proinflammatory cytokines (e.g., IL-2, IL-12, IFN-γ, and TNF-α) that promote cellular immunity, while Th2 lymphocytes produce anti-inflammatory cytokines (e.g., IL-4, IL-5, IL-6, and IL-10) that promote humoral immunity. Th2 cytokines are associated with the down-regulation of Th1 cytokines and may confer protection from Th1-mediated autoimmune diseases. During pregnancy, there is a shift from Th1 to Th2 that occurs both locally, at the fetal maternal interface, (23, 24, 25), and systemically (26, 27, 28, 29, 30, 31). This immune shift is thought to be necessary to avoid fetal rejection (25, 29, 32, 33), since failure to achieve a Th1 to Th2 immune deviation has been associated with increased risk of spontaneous abortion (29, 31, 34). This naturally occurring, systemic shift in immune responses may underlie improvements in Th1-mediated autoimmune diseases during pregnancy.
A variety of pregnancy factors may be responsible for the immune shift during pregnancy, including sex hormones, vitamin D, α-fetoprotein, early pregnancy factor, human chorionic gonadotropin, and pregnancy-specific glycoproteins (35). The hormone estriol is an estrogen made by the fetal placental unit, and hence only becomes detectable when women are pregnant. Estriol levels increase progressively throughout pregnancy, peaking during the third trimester when the beneficial effects of pregnancy in relapsing remitting MS (RRMS) are most profound. Also, estriol levels drop precipitously postpartum when relapse rates rebound (7). Thus, there is a direct association of increased estriol levels with disease protection in RRMS.
Support for estriol as a candidate pregnancy factor that may contribute to the amelioration of Th1-mediated autoimmune diseases is derived from in vitro studies of T cells derived from humans and in vivo studies of experimental autoimmune diseases in mice. T cell lines and purified T cells have each been shown to switch their cytokine profile from Th1 to Th2 when cultured with pregnancy levels of estriol (36, 37). In addition, estriol has been shown to ameliorate experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis when administered in vivo at pregnancy levels (38, 39, 40). Moreover, shifts in cytokine profiles of immune cells from estrogen-treated EAE mice have supported the concept that at least one mechanism of estrogen's protection in these diseases involves a favorable alteration in cytokine production (38, 40, 41).
Collectively, the protective effect of pregnancy in MS and EAE and the anti-inflammatory effects of estriol have suggested that hormones associated with pregnancy, estriol in particular, may exert a beneficial influence on MS. Accordingly, a pilot clinical trial using oral estriol to treat 10 female MS patients (six with RRMS and four with secondary progressive MS (SPMS)) was completed (42). A cross-over design was used in which a pretreatment baseline was followed by a treatment period. Post-treatment and retreatment phases were also examined. During oral estriol therapy, RRMS patients demonstrated significantly decreased gadolinium-enhancing lesions on monthly cerebral magnetic resonance imaging (MRI), decreased delayed-type hypersensitivity responses to tetanus, and decreased IFN-γ message in unstimulated PBMC (42). Given these encouraging findings, it was of interest to determine whether the beneficial effect of oral estriol treatment observed in this small cohort of RR patients was associated with changes in cytokine profiles consistent with an anti-inflammatory, Th1 to Th2, shift in stimulated PBMCs. To our knowledge this is the first time alterations in cytokine production of stimulated PBMCs have been identified when an estrogen has been given in vivo to patients with an autoimmune disease.
Ten female patients with clinically definite MS (six RR and four SP) completed the study. The patients had not received steroid treatment for at least 3 mo or IFN-β or glatiramer acetate for 6 mo before participating in the study. Patients who were pregnant, nursing, taking oral contraceptives, or receiving hormone replacement therapy were excluded. The mean age was 44 years (range, 28–50 years). The mean Expanded Disability Status Scale (EDSS) score was 3.3 (range, 1.0–6.5), with a clear differences between RRMS and SPMS groups (mean EDSS of RRMS = 2.2; mean EDSS of SPMS = 5.0). The cross-over design consisted of a 6-mo pretreatment period, a 6-mo oral estriol treatment period (8 mg/day), and a 6-mo post-treatment period with brain MRIs monthly and clinic visits with blood sample collection every 3 mo. In the RRMS cohort, the trial was extended by a 4-mo retreatment period. Oral estriol was tapered over 2 wk after the treatment period to avoid a precipitous drop in hormone levels. During the retreatment period, oral estriol was used in combination with progesterone (100 mg/day) to protect against endometrial hyperplasia. Estriol levels during treatment were shown to approximate those that occur naturally at 6 mo of pregnancy (42). The study was approved by the University of California-Los Angeles human subjects protection committee, and informed consent was obtained from all patients enrolled in the trial.
PBMCs were isolated by a conventional Ficoll-Hypaque method from freshly drawn blood specimens and cryopreserved. PBMCs from all time points from a given patient were assayed in parallel on the same day in the following manner. Cryopreserved PBMC were thawed and cultured in triplicate on a 96-well, round-bottom tissue culture plate at 1 × 105 cells/well in X-Vivo 20 serum-free medium (BioWhittaker, Walkersville, MD) supplemented with 1× penicillin/streptomycin and 2 mM l-glutamine (BioWhittaker), either alone or with anti-CD3 (1 μg/ml; Sigma-Aldrich, St. Louis, MO), PHA (5 μg/ml; Sigma-Aldrich), glatiramer acetate/copolymer 1 (COP-1) (10 μg/ml; Teva, North Wales, PA), tetanus toxoid (10 LFA/ml; Canaught Laboratories, Swiftwater, PA), or Candida albicans lysate (CA) (40 μg/ml). Cells were plated with medium alone or with test Ags in triplicate. Three identical plates were prepared for harvest on days 2, 4, and 6. Cultured PBMCs were pulsed with 1 μCi/well of [methyl-3H]thymidine for the final 18 h of incubation. Cells were harvested with a cell harvester, and tritiated thymidine incorporation was measured by a liquid scintillation counter (Wallac, Gaithersburg, MD). Means and SDs were assessed from triplicate wells. Stimulation indexes were calculated by dividing the counts per minute in stimulated wells by the counts per minute in unstimulated wells.
Cryopreserved PBMC were thawed and cultured in a 96-well, round-bottom tissue culture plate at 1 × 105 cells/well for 48 h with media and Ags as described above for proliferation assays. Supernatants were harvested and stored at −70°C until cytokine testing was performed. IL-2, IL-4, IL-5, IL-10, TNF-α, and IFN-γ were detected simultaneously using the human Th1/Th2 cytokine cytometric bead array (CBA) kit (BD PharMingen, San Diego, CA). Briefly, 50 μl of each sample was mixed with 50 μl of mixed capture beads and 50 μl of the human Th1/Th2 PE detection reagent consisting of PE-conjugated anti-human IL-2, IL-4, IL-5, IL-10, TNF-α, and IFN-γ. The samples were incubated at room temperature for 3 h in the dark. After incubation with the PE detection reagent, the samples were washed once and resuspended in 300 μl of wash buffer before acquisition on the FACSCalibur (BD Biosciences, Sunnyvale, CA). Data were analyzed using CBA software (BD PharMingen). Standard curves were generated for each cytokine using the mixed cytokine standard provided by the kit. The concentration for each cytokine in cell supernatants was determined by interpolation from the corresponding standard curve. The range of detection was 20–5000 pg/ml for each cytokine measured by CBA.
Cryopreserved PBMC from all time points of a given patient were thawed in parallel. One aliquot of cells was stained for cell surface markers with a panel of FITC-conjugated Abs, including CD4, CD8, CD19, CD64, CD27, CD54 (ICAM), and CD106 (VCAM), or with Cy5-conjugated Abs (CD45 Ra, CD45 Ro, CD80, CD86, and CD25). The other aliquot of cells was cultured in a 96-well, round-bottom tissue culture plate at 1 × 105 cells/well with media and Ags as described above for 24 h. Brefeldin A was added during the last 5 h of stimulation. Cells were washed in staining medium (1× PBS, 2% FCS, and 0.1% NaN3) and stained with the same panel of FITC-conjugated Abs (CD4, CD8, CD19, CD64, CD27, CD54, and CD106) and Cy5-conjugated (CD45Ra, CD45Ro, CD80, CD86, and CD25) for 45 min at 4°C. Cells were washed twice with staining medium and fixed and permeabilized with Cytofix/Cytoperm solution (BD PharMingen). Cells were then resuspended in perm/wash buffer (BD PharMingen) and stained with PE-labeled Abs specific for IL-5, IL-10, IL-12p40, TNF-α, and IFN-γ (BD PharMingen) for 20 min at room temperature. After intracellular cytokine staining, cells were washed twice in perm/wash buffer and resuspended in 400 μl of staining medium before three-color FACS analysis on a FACSCalibur instrument (BD Biosciences) using CellQuest software (BD Biosciences). For each experiment cells were also stained with isotype control Abs to establish background staining and to set quadrants before calculation of the percentage of positive cells.
During treatment with the pregnancy hormone estriol, we had previously observed a decrease in the delayed-type hypersensitivity response to a recall Ag, a decrease in IFN-γ message in unstimulated PBMCs, and a decrease in gadolinium-enhancing lesions on brain MRI (42). Since pregnancy had previously been associated with changes in cytokine production by stimulated immune cells and also with changes in subpopulations of circulating immune cells (40, 41, 42), we examined whether these changes also occurred in the above MS patients treated with estriol.
PBMCs obtained during pretreatment, treatment, post-treatment, or retreatment phases of the estriol trial were stained ex vivo for cell surface marker expression (no in vitro culture). Subpopulations of circulating immune cells were altered during in vivo estriol treatment in both RRMS and SPMS groups; however, changes were slightly more robust in the RRMS group than in the SPMS group (Fig. 1, A and B). Oral estriol treatment was associated with significant decreases in CD4+ and CD8+ T cells and an increase in CD19+ B cells, with no changes in CD64+ monocytes/macrophages. Significant decreases in CD4+CD45Ro+ (memory T cells) and increases in CD4+CD45Ra+ (naive T cells) were also observed. There was a slight trend for decreases in CD4+CD25+ cells during treatment as well, but this did not reach significance, and no changes in the percentages of CD80+, CD86+, CD54+, or CD106+ cells were found (data not shown). During the post-treatment phase, levels of circulating cells returned to baseline pretreatment levels. During the retreatment phase, which took place only in RRMS patients, changes similar to the treatment phase reoccurred.
Subpopulations of circulating PBMCs from MS patients were altered by oral estriol treatment. PBMCs from RRMS (A) and SPMS (B) patients acquired during the estriol trial were stained ex vivo for cell surface marker expression (no in vitro culture). RRMS included pretreatment (mean of mo 3 and 6), estriol treatment (mo 9 and 12), post-treatment (mo 15 and 18), and retreatment (mo 22), while SPMS included pretreatment, treatment, and post-treatment only. Data are expressed as the percent change from the mean of the two baseline pretreatment samples (mo 3 and 6). Error bars represent variability (SEM) between patients within each group. ∗, p < 0.005, by Wilcoxon/Kruskal-Wallis rank-sum analysis. Oral estriol was associated with decreases in CD4+ and CD8+ T cells and an increase in CD19+ B cells with no changes in CD64+ monocytes/macrophages. Also, there were decreases in CD4+CD45Ro+ (memory T cells) and increases in CD4+CD45Ra+ (naive T cells). While significant changes occurred in both RRMS and SPMS, they were occasionally more robust in the RRMS group. Pre Tx, pretreatment; Est Tx, estriol treatment; Post Tx, post-treatment; Est Tx, estriol retreatment in combination with progesterone.
Lymphoproliferative responses to α-CD3, C. albicans, PHA, COP-1, tetanus toxoid, and C. albicans were assessed throughout the trial. The majority of MS patients had positive lymphoproliferative responses (stimulation index, >2) to α-CD3 (six of six RR; four of four SP), PHA (six of six RR, four of four SP), and COP-1 (six of six RR; four of six SP). Fewer patients had positive responses to C. albicans lysate (four of six RR, three of four SP) and tetanus toxoid (two of six RR, zero of six SP). No significant difference in lymphoproliferative response to any of the test Ags was demonstrated during oral estriol therapy (data not shown).
PBMCs from were stimulated with anti-CD3, glatiramer acetate, recall Ags (tetanus toxoid and C. albicans lysate), and PHA. Cytokine secretion (IL-2, IL-4, IL-5, IL-10, TNF-α, and IFN-γ) was measured from supernatants of samples with positive lymphoproliferative responses (stimulation index, >2 to a given Ag) by CBA. Data were analyzed as the mean percent change during the indicated treatment time point compared with the mean of two pretreatment baseline values. As demonstrated in Fig. 2, upon stimulation with αCD3, PHA, and Candida, IL-5 and IL-10 secretion were significantly increased, and TNF-α levels were significantly decreased in both RRMS and SPMS during the initial oral estriol treatment phase (mo 9 and 12) compared with pretreatment baseline values (mean of mo 3 and 6). During the post-treatment phase (mo 15 and 18), levels of secreted IL-5, IL-10, and TNF-α returned to baseline in both patient groups. Further, in the retreatment phase (mo 22) of the RRMS group, levels of IL-5 and IL-10 were again increased, and TNF-α was again decreased (Fig. 2 A). Oral estriol treatment did not have a statistically significant effect on IL-2, IL-4, or IFN-γ. There was, however, a trend that did not reach significance for decreased IFN-γ during treatment in the RRMS group. Similar changes in cytokine profiles were observed in supernatants from PBMC with positive lymphoproliferative responses to tetanus toxoid and COP-1 (data not shown).
In vivo estriol treatment increased secreted IL-5 and IL-10 and decreased secreted TNF-α from stimulated PBMCs. Secreted cytokine levels (IL-2, IL-4, IL-5, IL-10, TNF-α, and IFN-γ) were assessed in culture supernatants 48 h after stimulation by CBA. PBMC from RRMS (A; n = 6) and SPMS (B; n = 4) were stimulated with αCD3, PHA, or C. albicans lysate (CA). Cytokine levels are expressed as the mean percent change of the level in the samples at the indicated treatment time point compared with the mean from two pretreatment baseline time points (mo 3 and 6), with error bars indicating the SEs between patients within each group. ∗, p < 0.005, by Wilcoxon/Kruskal-Wallis rank-sum analysis). The range of detection was 20–5000 pg/ml for each cytokine.
To determine whether estriol affected cytokine production and as a complement to secreted cytokine determination in supernatants, intracellular production of IL-5, IL-10, IL-12p40, TNF-α, and IFN-γ was measured by FACS analysis after 24 h of stimulation with the same test Ags. As demonstrated in Fig. 3, intracellular IL-5 and IL-10 were again significantly increased, while TNF-α was again significantly decreased during treatment (mo 9 and 12), with changes generally more robust in the RRMS group (Fig. 3,A) than in the SPMS group (Fig. 3 B). Intracellular cytokine levels again returned to baseline during the post-treatment period (mo 15 and 18) in both MS groups. In the retreatment phase (mo 22) in the RRMS group, increased IL-5 and IL-10 with decreased TNF-α recurred. Oral estriol treatment did not have a statistically significant effect on intracellular IL-12 p40 or IFN-γ. Similar changes in cytokine profiles were demonstrated after stimulation with tetanus toxoid and COP-1 (data not shown).
In vivo estriol treatment increased intracellular IL-5 and IL-10 and decreased intracellular TNF-α from stimulated PBMCs. Intracellular cytokine levels (IL-5, IL-10, IL-12p40, TNF-α, and IFN-γ) were measured in PBMC from patients in the RRMS group (A) and the SPMS group (B) following 24-h stimulation with α-CD3, PHA, and C. albicans lysate (CA). Levels of cells with positive cytokine staining after subtracting staining observed with negative control Ab were determined at each time point and expressed as the percent change from baseline as in Fig. 2. Error bars indicate the SEs between patients within each group. ∗, p < 0.005, by Wilcoxon/Kruskal-Wallis rank-sum analysis.
Significant decreases in enhancing lesion volume and number were observed with oral estriol treatment (mo 7–12) compared with pretreatment baseline (mo 1–6) on monthly MRI in the RRMS, but not the SPMS, group (42). In the RRMS group, lesion volumes and numbers increased to pretreatment baseline after treatment was stopped (mo 13–18), then again significantly decreased with reinstitution of oral estriol therapy (mo 19–22). Therefore, it was of interest to determine whether these MRI findings, representing a clinical measure of disease activity, correlated with the changes in secreted cytokine profiles observed during oral estriol therapy. As demonstrated in Fig. 4, there was an inverse correlation between αCD3-stimulated levels of IL-5 and IL-10 with mean enhancing lesion volumes, while there was a direct correlation between TNF-α levels and enhancing lesions (cubic millimeters) in the RRMS group. Similar results were observed in PBMC from RRMS stimulated with PHA, COP-1, and C. albicans lysate (data not shown). Gadolinium-positive lesion volumes per scan were lower in the SPMS group (mean, 18.9; median, 0 mm3) than in the RRMS group (mean, 41.9; median, 19.5 mm3), and the above correlations between MRI and cytokine levels observed in the RRMS group were not observed in the SPMS group.
Brain MRI enhancing lesions in RRMS patients correlate inversely with IL-5 and IL-10 and directly with TNF-α. Type I regression analysis of gadolinium-enhancing lesion volumes (cubic millimeters) and secreted cytokine levels (picograms per milliliter) after αCD3 stimulation of PBMCs from RRMS patients.
Three-color flow cytometry with cell surface marker-specific Abs were used to determine which cells demonstrated the altered cytokine production during in vivo estriol treatment. As shown in Fig. 5, after stimulation with αCD3, the increase in IL-5 was primarily due to increases in CD4+ and CD8+ T cells. The increase in IL-10 during treatment was primarily due to an increase in CD64+ cells (macrophages), with a smaller increase in T cells. The decrease observed in TNF-α was primarily due to a decrease in CD8+ T cells, with a slight decrease in CD4+ T cells. No change in any of these cytokines was observed in the CD19+ population (B cells). Cell phenotype-specific changes in cytokine profiles were similar in RRMS (Fig. 5,A) and SPMS (Fig. 5 B), but were generally more robust in the RRMS group. Similar results were obtained for PBMC stimulated with PHA, C. albicans lysate, and COP-1.
Cell phenotype-specific effects of in vivo estriol treatment on cytokine profiles. Intracellular cytokine levels in αCD3-stimulated PBMCs double-stained for cell surface markers (CD4+ T cell, CD8+ T cell, CD19+ B cell, CD64+ monocytes/macrophage) and intracellular cytokines in RRMS (A) and SPMS (B). The increase in IL-5 was primarily due to an increase in CD4+ and CD8+ T cells, the increase in IL-10 was primarily due to an increase in CD64+ macrophages, with some effect in T cells, while the decrease in TNF-α was primarily due to a decrease in CD8+ T cells. Responses to treatment were generally more robust in RRMS than in SPMS. Cytokine levels are expressed as the mean percent change at the indicated time point compared with the mean of the two pretreatment baseline samples (mo 3 and 6). Error bars represent variability (SEM) between patients within each group.
A partial Th1 to Th2 shift was observed in stimulated PBMCs from MS patients during in vivo estriol treatment, which consisted of increased production of IL-5 and IL-10 and decreased TNF-α regardless of whether a mitogen or recall Ag was used for stimulation. Cytokine profiles of CD4+ and CD8+ T cells and CD64+ monocytes/macrophages were all significantly affected by in vivo estriol treatment, while cytokine production by B cells was unaffected. Of interest, increased levels of IL-5 and IL-10 and decreased TNF-α production correlated with the mean volume of enhancing lesions on MRI in the RRMS group. This correlation between changes in cytokine profiles and lesion volume suggests that the anti-inflammatory effects of estriol may have an effect on disease in the target organ. The partial Th1 to Th2 immune shift observed in female MS patients treated with in vivo estriol is consistent with the general shift away from a Th1-biased response observed in males receiving in vivo ethinyl estradiol and an antiandrogen for gender reassignment (43). To our knowledge, our data are the first to describe cytokine changes induced by administration of an estrogen alone in patients with an autoimmune disease. These results are in agreement with previous in vitro studies of human immune cells and in vivo studies of mice that demonstrated an anti-inflammatory role for estriol. Specifically, increased expression of IL-10 and decreased TNF-α were reported in human T cell lines and in unprimed T cells cultured in vitro in the presence of estriol (36, 37). Further, in vivo estriol treatment was shown to ameliorate both collagen-induced arthritis and EAE (38, 39, 40, 44). In adoptive EAE, estriol treatment increased IL-10 production by splenocytes stimulated with autoantigen and increased autoantigen-specific IgG1 Ab production consistent with an up-regulation of Th2 responses (38), while in active EAE, estriol treatment decreased TNF-α and IFN-γ production by lymph node cells stimulated with autoantigen, consistent with a down-regulation of Th1 responses (40, 41).
Since an alteration in circulating immune cells could theoretically influence cytokine production upon stimulation of PBMCs ex vivo, and since an alteration in circulating immune cells has been previously reported during pregnancy (45, 46, 47), we ascertained whether an alteration in circulating immune cells occurred during in vivo treatment with the pregnancy hormone estriol. In addition to an alteration in cytokine production by immune cells, subpopulations of circulating immune cells were indeed significantly altered during in vivo estriol treatment. In both RRMS and SPMS, there were significant decreases in CD4+ and CD8+ T cells and increases in B cells. Further, there were significant decreases in CD4+CD45Ro+ (memory T cells) and increases in CD4+CD45Ra+ (naive T cells). Together these data indicate that in vivo estriol treatment at pregnancy doses not only alters cytokine production from T cells and monocytes/macrophages, but also alters the repertoire of circulating cell types. Our findings of alterations in both cytokine production and circulating immune cell subpopulations have relevance to estrogen administration to patients with autoimmune diseases.
In addition to effects on cytokine production and on the repertoire of circulating immune cells, estriol may work through additional immune mechanisms. Recently, estriol has been shown to reduce trafficking of immune cells by inhibiting matrix metalloproteinase-9 (MMP-9) expression via down-regulation of the transcription factor NF-κB (37). MMP-9, an inducible form of MMP, is elevated in acute MS lesions and is thought to be important in T cell migration into the target organ in MS (48). Estriol may also operate through other immune molecules regulated by NF-κB, including several cytokines, chemokines, adhesion molecules, MHC molecules, and NO synthase. For example, the adhesion molecules ICAM and VCAM are induced by NF-κB, and their expression may also be down-regulated by estriol (49). While there was no significant effect of estriol treatment on VCAM or ICAM expression in PBMC from the relatively small cohort of patients examined in this study (data not shown), a direct influence of estriol on adhesion molecules at the blood-brain barrier could influence CNS permeability and disease activity. In MS, estriol may also work through additional mechanisms within the target organ, ranging from decreased microglial activation to protection from neuronal apoptosis (50, 51, 52, 53, 54).
The majority of MS patients have either RRMS or SPMS, representing a continuum of disease progression over decades. The early RR phase is characterized by frequent relapses and relatively little disability, with an MRI correlate of inflammation (enhancing lesions) and relatively less neuronal cell loss (atrophy and "T1 holes"). In contrast, the late SP phase is characterized by progressive disability in the absence of acute relapses, less inflammation, and more neuronal cell loss on MRI. The approved injectable treatments (the IFN-β drugs and copaxone) have all been shown to be of proven benefit in the early RRMS, but not the late SPMS. This is consistent with the fact that all of the above treatments are anti-inflammatory. It was interesting to compare the effects of estriol on the two distinct groups in our study (RRMS and late SPMS). In our previous study the SPMS group differed from the RRMS group in both the lack of a treatment effect on enhancing lesions on MRI and the lack of an effect on IFN-γ message levels in unstimulated PBMCs. This was consistent with the trend for a less robust effect of estriol treatment on cytokine production by mitogen and Ag-stimulated immune cells in SPMS compared with RRMS in this study. Together these data support observations that the immune dysregulation in RRMS and SPMS may differ and that the late SPMS group may ultimately become more refractory to some immunomodulatory therapies (55, 56, 57, 58, 59). Thus, the refractory nature of the SPMS stage may reside not only in the relatively greater contribution of neuronal cell loss to the pathogenesis of this stage, but also in the evolution of the immune dysregulation to a more refractory state.
Further studies are warranted in the treatment of RRMS with estriol. Treatment of other putative Th1-mediated autoimmune diseases should also be considered, since it is likely that estriol acts through anti-inflammatory mechanisms that may or may not involve additional neuroprotective effects. A neuroprotective role for estriol treatment remains speculative, requiring different MRI outcome measures and possibly longer treatment durations. On the other hand, an anti-inflammatory mechanism of action is supported not only by our findings, but also by the fact that other human autoimmune diseases that do not involve the CNS are improved during pregnancy when estrogen levels are increased. These include RA, uveitis, autoimmune thyroiditis, and psoriasis. Also, other experimental autoimmune disease models that do not involve the CNS are improved with estrogen treatment. These include collagen-induced arthritis, uveitis, and thyroiditis. Since estrogens can be administered orally, they would be a highly desirable treatment alternative. This may not be straightforward, however, since a retrospective study found that oral contraceptive use did not protect women from developing a first episode of MS (60). Also, in a prospective trial of 132 female patients with RA, oral contraceptive use did not significantly influence outcome in long term RA; however, there was a trend for patients with long term use to have less radiographic joint damage and a better functional level (61). Further, in a randomized, placebo-controlled trial in postmenopausal RA, hormone replacement therapy had no overall effect. However, 41.6% of the patients failed to achieve serum estradiol levels >100 pmol/liter and were considered poor compliers. In the remaining 58.4%, the compliers, there were significant improvements after 6 mo in articular index and visual analog pain scale compared with placebo results as well as reductions in erythrocyte sedimentation rate and early morning stiffness. This outcome suggested a potential beneficial effect in RA if sufficient estrogen levels were achieved (62).
Ultimately, the estrogen dose will need to be optimized for anti-inflammatory efficacy, then weighed against the known toxicities. Hormone replacement therapy is now considered to be of more risk than benefit in healthy menopausal women. While the risk/benefit ratio of estrogen treatment may be slightly of more risk than benefit in preventative medicine strategies in healthy menopausal women, in whom only minimum to no toxicity is tolerable, the risk/benefit ratio in patients with a chronic autoimmune disease is quite different, with modest toxicity tolerable. The use of pregnancy doses of estriol, the safest of the three estrogens (63, 64, 65), may provide an opportunity to optimize anti-inflammatory efficacy and minimize toxicity.
This work was supported by the National Institutes of Health Grants AI50839 and NS45443 (to R.R.V.) and National Multiple Sclerosis Society Grants RG3016 and RD3407 (to R.R.V.). N.S. is a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society (Grant JF2107).
Abbreviations used in this paper: MS, multiple sclerosis; CBA, cytometric bead array; EAE, experimental autoimmune encephalomyelitis; EDSS, Expanded Disability Status Scale; MMP-9, matrix metalloproteinase-9; MRI, magnetic resonance imaging; RA, rheumatoid arthritis; RRMS, relapsing remitting MS; SPMS, secondary progressive MS; COP-1, copolymer-1.
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. Psoriasis and pregnancy: hormone and immune system interaction.
Int. J. Dermatol.
Confavreux, C., M. Hutchinson, M. M. Hours, P. Cortinovis-Tourniaire, T. Moreau.
. Rate of pregnancy-related relapse in multiple sclerosis: Pregnancy in Multiple Sclerosis Group.
N. Engl. J. Med.
Da Silva, J. A., T. D. Spector.
. The role of pregnancy in the course and aetiology of rheumatoid arthritis.
Clin. Rheumatol.
Damek, D. M., E. A. Shuster.
Mayo Clin. Proc.
Davies, T. F..
. The thyroid immunology of the postpartum period.
Dunna, S. F., A. Y. Finlay.
. Psoriasis: improvement during and worsening after pregnancy.
Br. J. Dermatol.
McNeill, M. E..
. Multiple pregnancy-induced remissions of psoriatic arthritis: case report.
Am. J. Obstet. Gynecol.
Muller, A. F., A. Verhoeff, M. J. Mantel, A. Berghout.
. Thyroid autoimmunity and abortion: a prospective study in women undergoing in vitro fertilization.
Fertil. Steril.
Nelson, J. L., K. A. Hughes, A. G. Smith, B. B. Nisperos, A. M. Branchaud, J. A. Hansen.
. Remission of rheumatoid arthritis during pregnancy and maternal-fetal class II alloantigen disparity.
Am. J. Reprod. Immunol.
Ostensen, M..
. The effect of pregnancy on ankylosing spondylitis, psoriatic arthritis, and juvenile rheumatoid arthritis.
Park, B. S., J. I. Youn.
. Factors influencing psoriasis: an analysis based upon the extent of involvement and clinical type.
J. Dermatol.
Runmarker, B., O. Andersen.
. Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis.
Terry, A. J., W. M. Hague.
. Postpartum thyroiditis.
Semin. Perinatol.
van Walderveen, M. A., M. W. Tas, F. Barkhof, C. H. Polman, S. T. Frequin, O. R. Hommes, J. Valk.
. Magnetic resonance evaluation of disease activity during pregnancy in multiple sclerosis.
Whitacre, C. C., S. C. Reingold, P. A. O'Looney.
. A gender gap in autoimmunity.
Jungers, P., M. Dougados, C. Pelissier, F. Kuttenn, F. Tron, P. Lesavre, J. F. Bach.
. Lupus nephropathy and pregnancy: report of 104 cases in 36 patients.
Arch. Intern. Med.
Huizinga, T. W., M. W. van der Linden, V. Deneys-Laporte, F. C. Breedveld.
. Interleukin-10 as an explanation for pregnancy-induced flare in systemic lupus erythematosus and remission in rheumatoid arthritis.
Lin, H., T. R. Mosmann, L. Guilbert, S. Tuntipopipat, T. G. Wegmann.
. Synthesis of T helper 2-type cytokines at the maternal-fetal interface.
Sacks, G. P., L. M. Clover, D. R. Bainbridge, C. W. Redman, I. L. Sargent.
. Flow cytometric measurement of intracellular Th1 and Th2 cytokine production by human villous and extravillous cytotrophoblast.
Wegmann, T. G., H. Lin, L. Guilbert, T. R. Mosmann.
. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?.
Immunol. Today
Dudley, D. J., C. L. Chen, M. D. Mitchell, R. A. Daynes, B. A. Araneo.
. Adaptive immune responses during murine pregnancy: pregnancy-induced regulation of lymphokine production by activated T lymphocytes.
Elenkov, I. J., R. L. Wilder, V. K. Bakalov, A. A. Link, M. A. Dimitrov, S. Fisher, M. Crane, K. S. Kanik, G. P. Chrousos.
. IL-12, TNF-α, and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times.
J. Clin. Endocrinol. Metab.
Fabris, N., L. Piantanelli, M. Muzzioli.
. Differential effect of pregnancy or gestagens on humoral and cell-mediated immunity.
Clin. Exp. Immunol.
Hill, J. A., K. Polgar, D. J. Anderson.
. T-helper 1-type immunity to trophoblast in women with recurrent spontaneous abortion.
J. Am. Med. Assoc.
Krishnan, L., L. J. Guilbert, A. S. Russell, T. G. Wegmann, T. R. Mosmann, M. Belosevic.
. Pregnancy impairs resistance of C57BL/6 mice to Leishmania major infection and causes decreased antigen-specific IFN-γ response and increased production of T helper 2 cytokines.
Marzi, M., A. Vigano, D. Trabattoni, M. L. Villa, A. Salvaggio, E. Clerici, M. Clerici.
. Characterization of type 1 and type 2 cytokine production profile in physiologic and pathologic human pregnancy.
Formby, B..
. Immunologic response in pregnancy: its role in endocrine disorders of pregnancy and influence on the course of maternal autoimmune diseases.
Endocrinol. Metab. Clin. North Am.
Raghupathy, R..
. Th1-type immunity is incompatible with successful pregnancy.
Krishnan, L., L. J. Guilbert, T. G. Wegmann, M. Belosevic, T. R. Mosmann.
. T helper 1 response against Leishmania major in pregnant C57BL/6 mice increases implantation failure and fetal resorptions: correlation with increased IFN-γ and TNF and reduced IL-10 production by placental cells.
Voskuhl, R..
. Sex hormomes and other pregnancy-related factors with therapeutic potential in multiple sclerosis. D. Cohen, and R. Rudick, eds. In
Multiple Sclerosis Therapeutics
. Martin Dunitz, London.
Correale, J., M. Arias, W. Gilmore.
. Steroid hormone regulation of cytokine secretion by proteolipid protein-specific CD4+ T cell clones isolated from multiple sclerosis patients and normal control subjects.
Zang, Y. C., J. B. Halder, J. Hong, V. M. Rivera, J. Z. Zhang.
. Regulatory effects of estriol on T cell migration and cytokine profile: inhibition of transcription factor NF-κB.
J. Neuroimmunol.
Kim, S., S. M. Liva, M. A. Dalal, M. A. Verity, R. R. Voskuhl.
. Estriol ameliorates autoimmune demyelinating disease: implications for multiple sclerosis.
Jansson, L., T. Olsson, R. Holmdahl.
. Estrogen induces a potent suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis in mice.
Bebo, B. F., Jr, A. Fyfe-Johnson, K. Adlard, A. G. Beam, A. A. Vandenbark, H. Offner.
. Low-dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strains.
Ito, A., B. F. Bebo, Jr, A. Matejuk, A. Zamora, M. Silverman, A. Fyfe-Johnson, H. Offner.
. Estrogen treatment down-regulates TNF-α production and reduces the severity of experimental autoimmune encephalomyelitis in cytokine knockout mice.
Sicotte, N. L., S. M. Liva, R. Klutch, P. Pfeiffer, S. Bouvier, S. Odesa, T. C. Wu, R. R. Voskuhl.
. Treatment of multiple sclerosis with the pregnancy hormone estriol.
Giltay, E. J., J. C. Fonk, B. M. von Blomberg, H. A. Drexhage, C. Schalkwijk, L. J. Gooren.
. In vivo effects of sex steroids on lymphocyte responsiveness and immunoglobulin levels in humans.
Jansson, L., R. Holmdahl.
. Oestrogen-induced suppression of collagen arthritis; 17β-oestradiol is therapeutically active in normal and castrated F1 hybrid mice of both sexes.
Tallon, D. F., D. J. Corcoran, E. M. O'Dwyer, J. F. Greally.
. Circulating lymphocyte subpopulations in pregnancy: a longitudinal study.
Watanabe, M., Y. Iwatani, T. Kaneda, Y. Hidaka, N. Mitsuda, Y. Morimoto, N. Amino.
. Changes in T, B, and NK lymphocyte subsets during and after normal pregnancy.
Mahmoud, F., H. Abul, A. Omu, S. Al-Rayes, D. Haines, K. Whaley.
. Pregnancy-associated changes in peripheral blood lymphocyte subpopulations in normal Kuwaiti women.
Gynecol. Obstet. Invest.
Avolio, C., M. Ruggieri, F. Giuliani, G. M. Liuzzi, R. Leante, P. Riccio, P. Livrea, M. Trojano.
. Serum MMP-2 and MMP-9 are elevated in different multiple sclerosis subtypes.
Xia, Y. F., L. P. Liu, C. P. Zhong, J. G. Geng.
. NF-κB activation for constitutive expression of VCAM-1 and ICAM-1 on B lymphocytes and plasma cells.
Biochem. Biophys. Res. Commun.
Nilsen, J., R. Diaz Brinton.
. Mechanism of estrogen-mediated neuroprotection: regulation of mitochondrial calcium and Bcl-2 expression.
Drew, P. D., J. A. Chavis.
. Female sex steroids: effects upon microglial cell activation.
Jover, T., H. Tanaka, A. Calderone, K. Oguro, M. V. Bennett, A. M. Etgen, R. S. Zukin.
. Estrogen protects against global ischemia-induced neuronal death and prevents activation of apoptotic signaling cascades in the hippocampal CA1.
Harms, C., M. Lautenschlager, A. Bergk, J. Katchanov, D. Freyer, K. Kapinya, U. Herwig, D. Megow, U. Dirnagl, J. R. Weber, et al
. Differential mechanisms of neuroprotection by 17β-estradiol in apoptotic versus necrotic neurodegeneration.
Behl, C., T. Skutella, F. Lezoualc'h, A. Post, M. Widmann, C. J. Newton, F. Holsboer.
. Neuroprotection against oxidative stress by estrogens: structure-activity relationship.
Mol. Pharmacol.
Balashov, K. E., M. Comabella, T. Ohashi, S. J. Khoury, H. L. Weiner.
. Defective regulation of IFNγ and IL-12 by endogenous IL-10 in progressive MS.
Correale, J., W. Gilmore, S. Li, J. Walsh, M. M. Bassani, B. Lund, M. Arias, L. P. Weiner.
. Resistance to glucocorticoid-induced apoptosis in PLP peptide-specific T cell clones from patients with progressive MS.
Galboiz, Y., S. Shapiro, N. Lahat, H. Rawashdeh, A. Miller.
. Matrix metalloproteinases and their tissue inhibitors as markers of disease subtype and response to interferon-β therapy in relapsing and secondary-progressive multiple sclerosis patients.
Sorensen, T. L., F. Sellebjerg.
. Distinct chemokine receptor and cytokine expression profile in secondary progressive MS.
van Boxel-Dezaire, A. H., S. C. Hoff, B. W. van Oosten, C. L. Verweij, A. M. Drager, H. J. Ader, J. C. van Houwelingen, F. Barkhof, C. H. Polman, L. Nagelkerken.
. Decreased interleukin-10 and increased interleukin-12p40 mRNA are associated with disease activity and characterize different disease stages in multiple sclerosis.
Hernan, M. A., M. J. Hohol, M. J. Olek, D. Spiegelman, A. Ascherio.
. Oral contraceptives and the incidence of multiple sclerosis.
Drossaers-Bakker, K. W., A. H. Zwinderman, D. van Zeben, F. C. Breedveld, J. M. Hazes.
. Pregnancy and oral contraceptive use do not significantly influence outcome in long term rheumatoid arthritis.
Ann. Rheum. Dis.
Hall, G. M., M. Daniels, E. C. Huskisson, T. D. Spector.
. A randomised controlled trial of the effect of hormone replacement therapy on disease activity in postmenopausal rheumatoid arthritis.
Follingstad, A. H..
. Estriol, the forgotten estrogen?.
Head, K. A..
. Estriol: safety and efficacy.
Altern. Med. Rev.
Lauritzen, C..
. Results of a 5 years prospective study of estriol succinate treatment in patients with climacteric complaints.
Horm. Metab. Res.


text:
HomeMovies
Disney+ Will Feature Every Disney Movie
Disney's CEO, Bob Iger, was apparently breaking all kinds of news during the company's Annual Meeting of Shareholders yesterday. In addition to details on Disneyland and Walt Disney World's Star Wars: Galaxy Edge, Iger also dropped fresh details on the upcoming Disney+ streaming platform. Specifically, that the outlet is said to encompass Disney's entire film library.
During the meeting, Iger was specifically asked whether Disney+ would incorporate films that have received the "vaulted" designation. And while Iger didn't go as far as specifically mentioning movies by name, he did infer that the streaming service would include every film in Disney's library – including those in the Disney vault.
Iger also went on to mention that it's not just Disney developed movies that will be featured upon its streaming service. Marvel Studios' entire Marvel Cinematic Universe will be available to subscribers. As will the entirety of the Star Wars library.
But while Iger intends on getting all of Disney's properties as exclusives to Disney+, that doesn't mean that the studio will be pulling all of their content from other sources. At least, not immediately.
Bob Iger explained to investors that "the strategy will be long term pretty heavily weighted toward internally sourced, but there will be occasions where we will be glad to license from third parties. Because the Fox deal hasn't closed yet — so we can't take advantage of some of their capabilities — and because we need to launch the [Disney+] service with some volume and it takes time to ramp up, we're buying certain products from the outside opportunistically."
There will also be a ton of original content coming to the platform too. At this point, we know about The Mandalorian, a few potential Star Wars spinoffs, and the MCU limited series that are potentially coming our way. And with all of this content in one package, it sounds like this could be one hell of a bargain. Expect more fleshed-out details on Disney+ later this year.
Devolver Digital Confirms E3 2019 Press Conference
New TV Shows Premiering in 2019 (That We Actually Care About) [Guide]

redpajama_set_name: RedPajamaCommonCrawl


text:
Town Council Meeting Minutes November 2011
Nov 14, 2011 | Town Council Meeting Minutes
Home > Town Government > Posted Minutes > Town Council Meeting Minutes > Town Council Meeting Minutes November 2011
[ Minutes Archive ]
14 November 2011 | Approved: 12 December 2011
Mayor Cole called the regular meeting of the Town Council to order at 7:32 p.m. In attendance were Councilors Joe Clark, Sylvie Favret, Audrey Maskery, Joli McCathran, Alice Negin and Bill Robertson. Also present were Treasurer Mary Challstrom, Planning Commission Chair Charlie Challstrom and residents Ann Briggs, Aimee Coogan, Gary Gordon, Birgit Henninger,
Don Henninger, Meredith Horan, John Hutchinson, Janet Lottero, John McClelland, Ed Roberts, Bruce Rothrock, Jane Seegal, Mimi Styles, Sandy Styles and John Tomlin. Robert Krebs and Steve Varga from the Saybrooke community were also in attendance.
Bill Robertson moved, Joe Clark seconded that the agenda be approved. Vote: 6-0.
Robert Krebs from Saybrooke expressed his gratitude for the letter of support concerning the removal of two (2) trees that have been failing in health for a number of years in the West Woods to aid in his quest to get enough sun for the installation of solar panels on his roof. He went on to explain that Saybrooke currently does not allow the installation of solar panels and he will need to challenge that rule before proceeding any further. He believes that the ban is in violation of a Maryland State Law. He listed the benefits of solar power and requested the removal of another tree as stated in his original letter. The third tree is a large, healthy tulip poplar and his request was previously denied. Mayor Cole stated that she and the Council will continue to discuss this while Mr. Krebs gets his other issues with the home owners association resolved.
Steve Varga from Saybrooke came to ask the Town's help concerning our chain link fence in the West Woods. He explained that the Saybrooke community erected a 12 foot wooden fence between their common property and the Towne Crest apartments for the purpose of trying to stop people from walking through privately owned land in the community. The Town's chain link fence meets their wooden fence and it is getting cut in order to continue the undesirable activity. A discussion about reasons for cutting through, additional cutting elsewhere if the hole is repaired and private fencing ensued. Charlie Challstrom said the Planning Commission will be assembling ideas to present to the Towne Crest developers and these could include replacing the chain link fence in that area with an iron fence as part of the re-development requirements. Mr. Varga thanked the Mayor and Council for their help.
The Rev. Judy Young came to thank everyone for their generous donations of canned goods for their food drive. She also announced their Annual Interfaith Thanksgiving Service on Wednesday, November 23, 2011.
Gary Gordon came to support the Town's current level of maintenance. He stated that he was pleased with the way things are being done. He gave many examples of the things that pleased him and said that in the 40 years that he has lived here things have never looked so good. He suggested that the Maintenance Supervisor be given a raise.
Ed Roberts seconded Gary's remarks and said he'd also come to discuss maintenance priorities. He stated that branches were coming down all over Town and that pruning should be a priority. He talked about shifting funds within the budget and expressed the concern that someone could get hurt by these branches. Mayor Cole explained that the current budget includes money specifically for pruning.
Approval of Minutes
Alice Negin moved, Bill Robertson seconded that the Town Council minutes for October 10, 2011 be approved. Vote: 6-0.
Joe Clark moved, Audrey Maskery seconded that the Treasurer's Report for October 2011 be accepted. There was a brief discussion about the streetlight conversion. Vote: 6-0.
Sylvie Favret moved, Joe Clark seconded the motion to transfer funds from savings to checking in order to pay bills. Vote: 6-0.
Treasurers Report 2011-11 pdf
Maintenance Policy for the Town
The Mayor stated that the reason for this agenda item was to be sure that the current level of maintenance is on the right track. She stated that the Mayor and Council had received eight (8) written testimonies of which 7 were strongly favorable and one neutral about the current level of maintenance. Several residents attending the Council meeting made very positive comments about the maintenance supervisor and his crew. Mayor Cole stated that based on the discussion, the current direction of maintenance is the way Town residents wish to go.
Woodward Park Use Policy
Mayor Cole reported that recent testimony shows a significant concern about enforcement of the Town Ordinance and Resolution that regulate the use of Woodward Park. She stated that testimony ranged from ending the use by adult soccer players completely to allowing the current rules to stand unchanged. She presented some information about hiring a security guard to help with the enforcement and said that a group of sponsors for non-Town groups is being organized as well. There was a lengthy discussion about enforcement, how residents want the field to be used, who should be allowed to use the field, Program Open Space requirements, Resolution 2011-07, allowing adult soccer play on only one (1) Sunday per month, removing the goalposts completely, maintenance issues, sponsor's responsibility, fines if violations occur, changing the weekend day to Saturday, banning tournaments, increasing current permit fees and how Town fees compare to the County fees. Charlie Challstrom made the following points; Times have changed, especially from a maintenance and use standpoint. Our Town field has become a regional field for adult soccer which is contrary to the original intent. Taking down the soccer goals is a good option because it would engender varied use of the field. Montgomery County has started to address the adult soccer issue by directing play to the larger soccerplexes in the area. He urged the Council not to hire a security guard, to change the weekend day of play to Saturday and to remove the goals now while it is off-season. He also stated that doing things to discourage the current use would help the Town reclaim Woodward Park as a community park rather than a regional park. The current use has outgrown the Town. Councilor Alice Negin volunteered to organize a group of residents for a one-time meeting where they will review the current policy, the recent testimony and come up with some recommendations for Council consideration. The meeting is set for November 28th. In the meantime, no permits with be issued for spring soccer.
Minor corrections were made to the October Council Reports. Joe Clark moved, Audrey Maskery seconded that the October Council Reports be approved for posting on the Town website. There was a discussion about the removal of invasive species along Ridge Road. A summary of what is going on will be included in the next Bulletin. The Mayor and Council also discussed a request from Kathie Evans for a memorial for her husband Bob, a former Mayor, Council member, Planning Commission member and PC chairman, who passed away earlier this year. Kathie would like to place one or two rocks with a plaque in Morgan Park or, perhaps, another spot. Alice Negin did a quick inventory of some memorials in Town. There are trees (with and without memorial signs), a rock at the McCauley Street entrance to the East woods, a small statue in Howard Park and several benches with memorial plaques. There was a discussion about the existence of a Memorials Policy. The Clerk indicated that she remembered one from around 1997 and that she would locate it and send the information to the Mayor and Council. Jane Seegal asked why pruning had not yet been done on a tree that was reported a while ago. She believes that the branches pose a danger to all who walk in the area. A discussion ensued about setting pruning priorities, the ownership of the tree, the ownership of her porch and the fact that a tree expert had examined the tree. There was no more discussion about the Council Reports. Vote: 6-0.
Town Council Reports – November 2011 pdf
Mayor's Announcements
Deer Park Bridge Update – Mayor Cole reported that meetings with Montgomery County Traffic Safety and with Montgomery County Drainage & Permitting folks were very helpful in the Town's efforts to gather information about the effects of the CSX National Gateway Initiative on the Town.
300 Ridge Road (well failure) – Mayor Cole reported that she has been communicating with Robert Kronenberg from M-NCPPC about this issue. Mr. Kronenberg stated that M-NCPPC has no responsibility for exactly which homes are covered in the agreement to help with wells on Ridge Road should they become compromised. The Town and M-NCPPC are not likely to change their positions on this issue.
Alice Negin reported that Myles Ambrose had approached Ann Briggs and Charlie Challstrom about an Eagle Scout Project. She asked the Mayor and Council to think about an appropriate project for Myles.
Alice Negin asked if Mr. Krebs' request to remove the Tulip Poplar tree would be discussed next time as she was concerned about the potential removal. Audrey Maskery agreed saying that it is a large, healthy tree and if we remove this tree we would likely be asked to remove a lot of other trees in our woods by other residents living around them. The Council discussed this and agreed that we would not allow the removal of a healthy tree. Audrey also reported that the Town applied to the MD Historical Trust for permission to remove two (2) trees that have been failing in health for a number of years and to fix a drainage swale around McCathran Hall.
Bill Robertson reported that the roads have been marked for crack sealing by Teniseal. This will happen during our next stretch of dry above freezing weather.
John McClelland asked about residents who have cars on their property that exceed the number allowed by the Town Ordinance. There was a brief discussion. This subject was tabled for another meeting.
The meeting was adjourned at 10:02 p.m.


text:
What raids? ICE suddenly goes quiet
Bill Curry
(Getty/Mark Makela/AP/Pablo Martinez Monsivais)
Trump denies that he requested Comey end investigation into Flynn
In a joint press conference with the Colombian president, Trump denied telling Comey to end the Flynn investigation
Check out this article! https://www.salon.com/2017/05/18/trump-denies-that-he-requested-comey-end-investigation-into-flynn/
May 18, 2017 10:16PM (UTC)
While taking questions at a Thursday afternoon joint press conference between President Trump and Colombian President Michael Santos, Trump flat out denied that he requested former FBI Director James Comey to end the ongoing investigation into his former national security adviser Michael Flynn.
During the question period, a reporter asked Trump if he "urged" Comey to "close or to back down the investigation into Michael Flynn?" But before the reporter had the chance to finish his question, Trump interrupted him with an assertive "no" and said "next question." The same reporter then asked if Trump thought that he had done anything over the last year that was worthy of criminal charges or his impeachment.
"I think it's totally ridiculous," the president replied. He went on to say that Comey was widely "unpopular" and that he made the decision to fire the director on Deputy Attorney General Rod Rosenstein's recommendation. However, shortly before the news conference began, Rosenstein informed the Senate that he knew Comey would be fired even before he had penned his recommendation.
"He learned [of] the president's decision to fire him and then he wrote his memo with his rationale," Sen. Richard Durbin, D-Ill., told the Washington Post on Thursday.
Early on Thursday morning, Trump tweeted that he believed he was a victim to "the single greatest witch hunt of a politician in American history!"
When Trump was asked during the joint press conference about the investigation of his campaign's alleged collusion with the Russian government, he doubled down on his Twitter claims. "Well, I respect the move, but the entire thing has been a witch hunt."
"There is no collusion between certainly myself and my campaign. But I can always speak for myself and the Russians, zero. I think it divides the country, I think we have a very divided country because of that and many other things. So I can tell you that we want to bring this great country of ours together," the president added. Trump also said that his own enemies believe there was no collusion, which is far from true.
Charlie May is a news writer at Salon. You can find him on Twitter at @charliejmay
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Here is the link to the time lpase video I made of my painting at Polperro on Wednesday 26th May 2013.
Here is the time lapse video of the painting I did of Porthleven Harbour on Friday 21st June 2013.
Here are some pictures of my Coverack exhibition on Saturday 15th June and Sunday 16th June 2013. Fantastic location overlooking the sea and Chynhalls Point. Sunny on Saturday and very wet on Sunday but lots of visitors on both days. Thanks to everyone in Coverack for your help and support, Ian and John in the Paris Hotel, all at the post office, harbour lights, Mill Gallery, Old Mill shop. the Bay Hotel, Archies Loft, Seine Loft and the Lifeboat House (keep the faith Damien). Thanks also to Andrea & Richard, Ingrid and all at the Coverack Art Club, Sandra, Jeremy, Mel & Cath, Cheryl, Jane, Reg, Rick, Geoff & Tracy and especially to Robin who visited my exhibition several times over the weekend and can be seen in the last photo watching the time lapses. See you all next year.
I will be doing a Painting Workshop at the Wembury Marine Centre on Sunday 30th June 2013 In the workshop I will try to pass on some of the many lessons I have learned while painting outdoors on the coast path in the hope of encouraging more people to have a go at something that has brought me such pleasure and freedom.
Here are some photos of my Braunton Exhibition. Had a great couple of days. Even though the exhibition space was smaller then usual it seem to work really well. Thanks to everyone at Braunton for all you support especially Becky, Melanie, Guy and Sarah from the Sandleigh Tea Room and Garden at Croyde. Well worth a visit if you go to Croyde Beach or Baggy Point for a really excellent Cream Tea.
Here is the time lapse film of the painting I did at Perranporth on Friday 31st May 2013.
Here are some photos of my Mevagissey exhibition on the 8th & 9th June 2013.
Here is the time lapse video of the painting I did in Mevagissey on Friday 7th June 2013.
Here is the time lapse of the painting I did of Bats Head from Durdle Door on Tuesday 4th June 2013. Just after my spare car keys were delivered by a courier after I had locked my set inside the day before, "Doh!" "I don't think you wanted to do that". Quotes from my two key role models.
Here is the time lapse video of the painting I did at Lyme Regis on Monday 3rd June 2013.
Here are some photos of my Lyme Regis exhibition on Thursday 6th June 2013. Thanks to Elliot and all the staff at Lyme Regis for you assistance in arranging this exhibition. Some of you may have noticed that now I have completed the 365 paintings in a year the sun is shining on a very regular basis.
Here are some pictures of my exhibition at West Lulworth on Wednesday 5th June 2013. A very special visitor at West Lulworth was ZieJu, who can be seen in the last photo paying particular attention to the time lapse video of the Crackington Haven painting.
Here are a couple of photos from my Perranporth exhibition on Saturday 1st June 2013. Mark, Nicky, Thomas, Patrick and Millie with the painting they watched me complete at Perranporth the day before the exhibition.


text:
Gene Chip for Rapid Detection of Neuroblastoma
Medgadget Editors Diagnostics, News
Another interesting gene chip, this one for a common childhood malignancy called neuroblastoma, is being developed by scientists at The Children's Hospital of Philadelphia and Thomas Jefferson University:
Genetics researchers have developed a customized gene chip to rapidly scan tumor samples for specific DNA changes that offer clues to prognosis in cases of neuroblastoma, a common form of children's cancer. Rather than covering the entire genome, the microarray focuses on suspect regions of chromosomes for signs of deleted genetic material known to play a role in the cancer.
The investigators, from The Children's Hospital of Philadelphia and Thomas Jefferson University, say their technique may be readily adapted for other types of cancer. The proof-of-principle study appears in the August issue of Genome Research.
One advantage of their technique is its flexibility, said co-author John M. Maris, M.D., a pediatric oncologist at The Children's Hospital of Philadelphia. "As future research identifies other genes active in neuroblastoma, we can modify the microarray to include such regions," he added…
Microarrays are silicon chips that contain tightly ordered selections of genetic material upon which sample material can be tested. When DNA bases from a sample bind to complementary sequences on the microarray, they cause fluorescent tags to shine under laser light. This is a signal that a particular gene variation is present in the sample.
"We can test DNA from peripheral blood and from the tumor, and we should see a loss of signal in the cancer," said Dr. Fortina. He noted that the researchers can simultaneously evaluate seven chromosomal regions known to be involved in neuroblastoma.
Unlike gene expression microarrays, which detect varying levels of RNA to measure the activity levels of different genes as DNA transfers information to RNA, the current microarray directly identifies changes in DNA. "These DNA changes, involving gain or loss of genetic material, are important for neuroblastoma prognosis," said Dr. Maris.
Researchers also report that this technique could potentially be used to identify other forms of cancer.
The press release…
More at the BBC…
The Importance of New Devices in Dentistry


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text:
'Priceless' Handmade Polish Folk Costumes Stolen From Car In Wicker Park
Filed Under:Jim Williams, Local TV, Mike Krauser, Robbery, Smash And Grab, Wicker Park
CHICAGO (CBS/AP) — A Chicago woman spent Christmas day searching dumpsters after someone smashed her car window and stole costumes that she calls "priceless."
Five handmade Polish folk costumes were stolen between Saturday night and Sunday morning from a car in Wicker Park during a smash-and-grab robbery.
The owner of the car, Marlena Dzis said the five costumes, each custom made with beads and embroidery, would be very difficult to replace.
"They are very, very ornate. They are handmade and sewn in Poland. They are so special to me," Dzis said.
Each costume represents a different region in Poland. They are on loan from The Lira Ensemble, a professional performing arts company specializing in Polish music, song and dance. Dzis is a singer with the ensemble.
The costumes were taken from her car in the 1400 block of Wicker Park Avenue. She has talked with pawn shops, resale shops and checked dumpsters. Dzis even followed a garbage truck brought to a dump.
"He was like, 'honestly your chances are one-in-a-million if they were thrown away,'" Dzis said.
She has performances coming up this weekend and hopes they turn up before then.
"For someone to steal something that represents your culture, your heritage and your family, it's just so sad," Dzis said.
If anyone has seen the garments, or has tips, email marlenadzis@gmail.com.
Attorney Donna Makowski, a member of the Polish Advocates Society, said she was offering a $1,000 reward for the safe return of the costumes, no questions asked. She can be reached at her offices at 53 W. Jackson Blvd.
(© Copyright 2017 CBS Broadcasting Inc. All Rights Reserved. The Associated Press contributed to this report.)


text:
Teaching Strides
MRU Faculty Daring Greatly
Season 4, Episode 3: All aboard the Medieval school bus: making Old and Middle English Literature come alive in the classroom
Dr. Kenna Olsen has been teaching in MRU's Department of English, Languages and Culture since 2008. She teaches Old and Middle English Literature, but the tools she uses are anything but medieval — from tweeting the field's best-regarded academics to feasting in the MRU Library's Immersion Studio to Twitter.
You can follow Dr. Olsen on Twitter @KennaOlsen
SHOW TRANSCRIPT:
Meg Wilcox: I'm Meg Wilcox and this is Teaching Strides, MRU faculty daring greatly. In this episode, how Twitter can better help students understand medieval literature.
What do popular culture and old English literature have in common? Well, an MRU classroom. Dr Kenna Olsen is a professor in the department of English Languages and Culture. She teaches Old and Middle English Literature, but that doesn't just mean reading the texts. Dr. Olsen brings popular TV shows and social media into the classroom to keep students engaged and that's what we'll be talking about today. Thank you so much for joining me.
Kenna Olsen: It's amazing to be here, thank you. What a nice introduction!
MW: So your students have often commented on how enthusiastic you are in the classroom. Do you have a tactic or a reason behind your enthusiasm or is it just there?
KO: It's just there, it's just there. I can even just think of yesterday I was teaching literature in the age of Chaucer and on the docket was the Friar's tale. And I just get a lot of energy. I think just feeding off of the students, you know, when I can illuminate it for them, something that's in the text that maybe they didn't know was there or weren't quite comfortable with those things.
And then just to have that conversation, I don't know, it's so energizing that to me it's just so wonderful when you can say, yes, these are how the pieces fit together. And by the end of a class…it takes me hours to come down after class teaching. So I think it's just my interest in the material and when I can see that the students are generating that same kind of interest, it's just, it's so, it's so wonderful and it just, you know, sparks this energy. So how can you not be enthusiastic about it?
MW: Well, and you mentioned your enthusiasm for the topic itself and then the students are really into it. Do you think that's rubbing off of you or do you think that it's a chicken and egg thing?
KO: It's kind of hard to tell. Yeah, I don't know. I don't know where the origin is for that. And maybe you've noticed my egg that there seems to be like a lot of medieval tropes in popular culture. And so I think students come with sometimes like an expectation or an anticipation of what a class might be like. And I really like to turn those expectations upside down and we do a lot of that. And that I think has some, you know, fulfilling conversations.
MW: And I want to get to some of those examples that you're using in a minute. But first I wanted to just ask you a bit about the culture of the department that you work in. How would you describe the overall teaching culture there?
KO: Well, all of my colleagues are incredible teachers. The thing about English literature as a discipline is we're so varied, right? So I have colleagues who are studying Canadian literature. I have colleagues who study theory. I have colleagues who do film, but I think what brings us all together is that we are all really interested in rhetoric and how rhetoric can inspire, how it can create, how it can destroy, how it can illuminate truth, how it can hide.
And so we all have our different ways of approaching those things. So we are, we all have a lot of autonomy in our classrooms. But we feel, I think all of us, that there is an essence about textual media and research that is crucial that we sort of want to communicate to students. So we all are sort of individual, I would say in our select disciplines. But there's a lot of coming together and thinking about like how can we shape things for students and what do we want them to agree to look like? And why would, why would students, you know, why would they take this class? And just like a lot of conversation that is really student focused. And I love that about my department.
MW: And so in the collaborations, in the conversations you have with your colleagues, but also the autonomy you have in designing your classes, what would you say has become your focus or your goal when you're creating that class or that experience for students?
KO: I don't know, actually. I think what started to happen for me, a few years ago was that I realized that the more I brought in my own natural curiosity about the subject I'm studying. So really bringing in my own research into the classroom, sometimes in very gentle ways. And just the more I could do that, the more the students could see how studying a text that is, say, 800 years old, maybe is still, you know, within their interests or has relevance today, kind of thing. So I think what I'm trying to do constantly is just model for themmy curiosity about what drives me to keep pursuing my questions and my research.
And then I can see that, you know, that starts to generate some sort of interesting and powerful thought processes for students. So it's like, here's the other thing, it's just a heck of a lot of fun, right? It's just a heck of a lot of fun to show students. Like, here's a text written on, you know, animal skin, 800 years old. You're holding it in your hand. Like how does that make you feel? Right? Like that's just fun. And so I think it's great to just see the smiles and to sometimes see the furrowed brows, you know, because thinking is this work and it's necessary work. And that's, I think what I'm wanting my students to take away, right? It's that our gaze can go many places, but if we have a if we have a focus, a question, a leading question, you know the dialogue is worthwhile. Does that make sense?
MW: And I guess my other thought is, as you mentioned, is the idea of creating relevance for the students. Right? And we're in a world where many of the students who arrive care more about what's on their phones, stuff that's old is not super interesting. So, I guess I'm curious about some of the ways that you create that relevance part of it as you said, is turning expectations on their head when they come into class. But what are some other ways that you engage to help make the content more relevant for students?
KO: Yeah, it's interesting. Sometimes we hear that don't we? That students are less engaged, more screen driven, and it's true, you walk into a classroom at the beginning of class then, you know, 15 years ago when I started teaching, I think it was 15 years ago, something like that. Don't tell anybody. You know, you'd walk into a classroom and the students would be talking to each other, right? Sometimes about the class and maybe some anxiety about an assignment or something or they were talking about TV show or what have you.
But now, generally when I walk into a classroom at the beginning, and I'm sure you've experienced this, it's very silent and students are on their devices. And that used to worry me a little bit. And this idea that students are less engaged because they are more internal and looking at their phones. I'm not sure that that's the root of all the anxiety that we see in students. I think students are anxious because of things that should be alarming, like climate change and mental health and, you know, how do I communicate and feel like I'm and, you know, a citizen who contributes to society but also is getting what I need? And those are really good, deep socially driven questions. Well, guess what? They had those same questions in the 14th century and the texts that were circulating articulate those questions.
You know, we have the rise of the middle class and medieval England in the 14th century. We've got some, you know, really unjust tax and labor laws. People feel like they have no agency, no autonomy. And so when we start discussing those things for students, this conversation was happening. I mean, there are texts that are written that have to do with, how does one sustain the environment? And how to be environmentally friendly.
There's a text called winner and waster and I mean, you'd think that winner is the one coming out, but there's actually a surprise ending. But the students are so I think bolstered by the fact that idea of being a citizen that feels that they are contributing and that their voices are heard, isn't necessarily a 21st century issue. Right? These issues were circulating, here's how people dealt with them, here's how people found solutions. And I think that that's really amazing to see that sort of bolstering attitude and to see the links, you know, 600 years back I think is really neat for students. Right?
MW: Well, especially because it's something they're not expecting when they sign up for a medieval literature course.
KO: That's right. I mean, to be fair, I still nerd out and make them, you know, like recite old English or recite middle English and usually they take up the challenge and you know, they sound amazing. And there we are in course reading like some crazy middle English texts together. And that's a lot of fun too.
MW: So you've mentioned how part of connecting your content with students is about finding similar themes that they still face in their everyday. You've also talked about using technology to immerse them in and understand the space that this would've been created. But you also work with social media and get the students engaged with pop culture and using social media. So tell me a bit about how you do that.
KO: So social media is something that's much more profound and like an everyday event for many of our students. And I think that that does perhaps contribute to a certain kind of anxiety. Medievalists have always been on the, surprising for some people, but the cutting edge of technology, right. We were really the first to forge into digital humanities. And because it's all about making texts accessible, right? And digital humanities was great for that.
So there we are on Twitter, having conversations with each other, talking about our research, talking about our issues on this hashtag medieval Twitter. And I thought, I'm going to get my students to start checking this out. And what do you know then for some assignments, they reach out via Twitter and they get the most upstanding, famous colleague who works say, on Marjorie Kemp, tweeting back at them saying, 'I love your assignment here. You know, here's what I would ask you.' And then they're getting, you know, the benefit of not just me as a professor but then somebody else who is, you know, so interested in what they're doing and they feel so inspired, right? To get that sort of communication back from yet another expert.
And then two, we're creating a community outside of the classroom, which is wonderful because I mean, as you know, as a teacher, it's right at that moment, sometimes when you hit like the heavy, wonderful energizing stuff and your time for classes up and the conversation has to come to an end. So for class I create or get the students to decide on, I shouldn't say I create, use a hashtag that brings us together and they'll just tweet to the hashtag like, 'Hey, I'm thinking about the politicization of medieval isms and Game of Thrones.' And someone else will tweet. And that conversation that we've started in class continues and it's wonderful.
So that's one way that I'm using Twitter and I will never go back. I will always use Twitter. In and without the classroom. I've been told by students, you know, honor students that have been here for five years, that it's the first time they felt like such a concrete essence of community. And you know, so that's kind of what we're thinking about in those classes, it's a lot.
MW: But that's what makes it good.
KO: Yeah, well maybe that's what makes it good. Yeah. And it's a lot of fun too.
MW: Thank you so much for joining me.
KO: Oh, well thank you for having me.
MW: That was Dr. Kenna Olsen, a professor at MRUs, department of English Languages and Culture. You can find her on Twitter @KennaOlsen. Teaching Strides is produced by Hadeel Abdel-Nabi and me, Meg Wilcox, in conjunction with the Academic Development Center at Mount Royal University in Calgary, Alberta.
We're proud to broadcast from the traditional territories of the Blackfoot Confederacy, the Siksika, Kainai, Piikani, the Tsuut'ina, the Îyâxe, Nakoda Nations, the Métis Nation (Region 3). We look forward to sharing the stories and experiences of the many people who live, learn and teach in the treaty seven region. You can find us wherever you podcast and at teachingstrides.ca.
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