Sirtuin 1, Visfatin and IL-27 Serum Levels of Type 1 Diabetic Females in Relation to Cardiovascular Parameters and Autoimmune Thyroid Disease.

The loss of cardioprotection observed in premenopausal, diabetic women may result from the interplay between epigenetic, metabolic, and immunological factors. The aim of this study was to evaluate the concentration of sirtuin 1, visfatin, and IL-27 in relation to cardiovascular parameters and Hashimoto's disease (HD) in young, asymptomatic women with type 1 diabetes mellitus (T1DM). Thyroid ultrasound, carotid intima-media thickness (cIMT) measurement, electrocardiography, and echocardiography were performed in 50 euthyroid females with T1DM (28 with HD and 22 without concomitant diseases) and 30 controls. The concentrations of serum sirtuin 1, visfatin and IL-27 were assessed using ELISA. The T1DM and HD group had higher cIMT (p = 0.018) and lower left ventricular global longitudinal strain (p = 0.025) compared to females with T1DM exclusively. In women with a double diagnosis, the sirtuin 1 and IL-27 concentrations were non-significantly higher than in other groups and significantly positively correlated with each other (r = 0.445, p = 0.018) and thyroid volume (r = 0.511, p = 0.005; r = 0.482, p = 0.009, respectively) and negatively correlated with relative wall thickness (r = -0.451, p = 0.016; r = -0.387, p = 0.041, respectively). These relationships were not observed in the control group nor for the visfatin concentration. These results suggest that sirtuin 1 and IL-27 contribute to the pathogenesis of early cardiac dysfunction in women with T1DM and HD.

Anti-carbamylated protein antibodies in premenopausal rheumatoid arthritis women: relation to disease activity and bone loss.

OBJECTIVES: Anti-carbamylated protein antibodies (anti-CarP Abs) are present in patients with RA, however, their association with bone loss is not confirmed. The purpose of this study was to determine the relation between the serum level of anti-CarP Abs in premenopausal RA women and disease activity and bone loss. METHODS: This case-control study was conducted on 48 premenopausal women with RA and 48 matched healthy premenopausal women. All RA women were subjected to clinical examination, disease activity assessment using the 28-joint DAS (DAS28) and Clinical Disease Activity Index (CDAI), functional assessment using the HAQ, physical activity assessment using the International Physical Activity Questionnaire (IPAQ), fatigue assessment using the Modified Fatigue Impact Scale (MFIS), serological tests as well as anti-CarP Abs using ELISA. Moreover, the BMD was measured by DXA and plain X-ray of both hands was done to assess juxta-articular osteopenia and erosions. RESULTS: The anti-CarP Abs level was significantly higher in RA patients than in healthy controls. The serum level of anti-CarP Abs had a significant positive correlation with the RA DAS28, CDAI, HAQ, MFIS and original Sharp score, while a significant negative correlation was present with the IPAQ. Anti-CarP Abs were negatively correlated with either spine BMD or Z-score and positively correlated with the original Sharp score. CONCLUSION: Anti-CarP Abs were higher in premenopausal RA women compared with older and BMI matched healthy women. Anti-CarP Abs are associated with higher RA disease activity, increased disability and fatigability and decreased physical activity. Moreover, anti-CarP Abs are associated with systemic trabecular bone loss as well as local bone loss.

Differential Cytotoxic Function of Resident and Non-resident CD8+ T Cells in the Human Female Reproductive Tract Before and After Menopause.

The functional characterization and regulation of tissue resident and non-resident CD8+ T cells in the human female reproductive tract (FRT) as women age remains a gap in our knowledge. Here we characterized the cytotoxic activity and granular contents of CD8+ T cells from the FRT in pre- and postmenopausal women. We found that under steady-state conditions, CD8+ T cells from endometrium (EM), endocervix and ectocervix displayed direct cytotoxic activity, and that cytotoxicity increased in the EM after menopause. Cytotoxic activity was sensitive to suppression by TGFß exclusively in the EM, and sensitivity to TGFß was reduced after menopause. Under steady-state conditions, cytotoxic activity (measured as direct killing activity), cytotoxic potential (measured as content of cytotoxic molecules) and proliferation are enhanced in non-resident CD8+ (CD103-) T cells compared to tissue resident (CD103+) T cells. Upon activation, CD103+ T cells displayed greater degranulation compared to CD103- T cells, however the granular content of perforin, granzyme A (GZA) or granzyme B (GZB) was significantly lower. After menopause, degranulation significantly increased, and granular release switched from predominantly GZB in premenopausal to GZA in postmenopausal women. Postmenopausal changes affected both CD103+ and CD103- subpopulations. Finally, CD103+ T cells displayed reduced proliferation compared to CD103- T cells, but after proliferation, cytotoxic molecules were similar in each population. Our results highlight the complexity of regulation of cytotoxic function in the FRT before and after menopause, and are relevant to the development of protective strategies against genital infections and gynecological cancers as women age.

Dose-dependent effect of aerobic exercise on inflammatory biomarkers in a randomized controlled trial of women at high risk of breast cancer.

BACKGROUND: Increased levels of inflammation are associated with many diseases, including cancer. Physical activity can lower breast cancer risk as well as levels of inflammation. The Women In Steady Exercise Research (WISER) Sister trial was a randomized controlled trial that investigated the effects of a dosed, moderate to vigorous, aerobic exercise intervention on levels of inflammation in premenopausal women who were at high risk of developing breast cancer. METHODS: Participants were randomized to control (<75 minutes per week; 41 patients), low-dose exercise (150 minutes per week; 38 patients), or high-dose exercise (300 minutes per week; 37 patients) groups. The 5-menstrual cycles-long, home-based treadmill exercise intervention gradually increased in minutes per week and intensity up to a maximum of 80% of the age-predicted maximum heart rate. Blood was collected at baseline and at follow-up and assayed for chemokine (C-C motif) ligand 2 (CCL2), interleukin 10 (IL-10), interleukin 12 (IL-12), and tumor necrosis factor α (TNF-α). RESULTS: A linear dose-response relationship was observed for the proinflammatory biomarkers CCL2 (%Δ of -5.44% in the control group, -0.03% in the low-dose exercise group, and 1.54% in the high-dose exercise group), IL-12 (%Δ of -21.5% in the control group, 38.2% in the low-dose exercise group, and 25.8% in the high-dose exercise group,) and TNF-α (%Δ of -4.69% in the control group, 9.51% in the low-dose exercise group, and 15.7% in the high-dose exercise group) but not for the anti-inflammatory biomarker IL-10 (%Δ of 5.05% in the control group, 6.05% in the low-dose exercise group, and 10.6% in the high-dose exercise group). For IL-12 and TNF-α, the percentage change was significantly higher in the low-dose (IL-12: P < .001; and TNF-α: P = .01) and high-dose (IL-12: P < .001; and TNF-α: P < .001) exercise groups compared with the control group. CONCLUSIONS: Moderate to vigorous aerobic exercise appeared to increase levels of proinflammatory biomarkers in a dose-dependent manner in a population of healthy women at high risk of developing breast cancer. The results of the current study suggest that for healthy premenopausal women, the mechanism of reduced breast cancer risk observed in physically active individuals may not be a result of reduced levels of inflammation.

Dysregulation in Genital Tract Soluble Immune Mediators in Postmenopausal Women Is Distinct by HIV Status.

A rise in new HIV diagnoses among older adults is characterized by poor prognosis and reduced survival times. Although heterosexual transmission remains the main route of infection in women, little is known regarding immune functions in the genital tract of postmenopausal women, especially those who are HIV positive. Furthermore, effects of hormone replacement therapy (HRT) on the genital tract immune system are unclear. Using the Women's Interagency HIV Study repository, we obtained cervical-vaginal lavage (CVL) samples from premenopausal and postmenopausal HIV-positive and HIV-negative women, some of whom were on HRT. Samples were assayed for interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, secretory leukocyte protease inhibitor (SLPI), Elafin, human beta defensin-2 (HBD2), and macrophage inflammatory protein (MIP)-3α using ELISA. Anti-HIV activity in CVL was measured using TZM-bl indicator cells. Among HIV-positive women, the plasma viral load was significantly higher and CD4 count was significantly lower in postmenopausal compared with premenopausal women. Postmenopausal women, irrespective of HIV status, had significantly lower levels of HBD2 compared with premenopausal women. Among the HIV-negative individuals, postmenopausal women had significantly lower levels of MIP-3α, IL-6, and SLPI compared with premenopausal women. In contrast, HIV-positive postmenopausal women had significantly higher levels of TNF-α compared with HIV-positive premenopausal women. In most cases, HRT groups resembled the postmenopausal groups. No significant differences in anti-HIV activity by menopausal or by HIV status were noted. Our findings indicate that the female genital tract immune microenvironment is distinct by menopausal status and HIV status. Further studies are needed to assess the risk of HIV acquisition/transmission in this population.

Systematic and Cell Type-Specific Telomere Length Changes in Subsets of Lymphocytes.

Telomeres, the protective DNA-protein complexes at the ends of linear chromosomes, are important for genome stability. Leukocyte or peripheral blood mononuclear cell (PBMC) telomere length is a potential biomarker for human aging that integrates genetic, environmental, and lifestyle factors and is associated with mortality and risks for major diseases. However, only a limited number of studies have examined longitudinal changes of telomere length and few have reported data on sorted circulating immune cells. We examined the average telomere length (TL) in CD4+, CD8+CD28+, and CD8+CD28- T cells, B cells, and PBMCs, cross-sectionally and longitudinally, in a cohort of premenopausal women. We report that TL changes over 18 months were correlated among these three T cell types within the same participant. Additionally, PBMC TL change was also correlated with those of all three T cell types, and B cells. The rate of shortening for B cells was significantly greater than for the three T cell types. CD8+CD28- cells, despite having the shortest TL, showed significantly more rapid attrition when compared to CD8+CD28+ T cells. These results suggest systematically coordinated, yet cell type-specific responses to factors and pathways contribute to telomere length regulation.

The effect of menopause on the innate antiviral activity of cervicovaginal lavage.

OBJECTIVE: Reproductive hormones are known to impact innate mucosal immune function of the lower genital tract. Our objectives were to determine the effect of hormonal status on intrinsic antiviral (herpes simplex virus [HSV]-1, HSV-2, and human immunodeficiency virus [HIV]-1) activity of cervicovaginal lavage (CVL). STUDY DESIGN: CVL was collected from 165 asymptomatic women including postmenopausal women (n = 29); women not on contraception in days 1-14 (n = 26) or days 15-28 (n = 27) of the menstrual cycle; and women using the levonorgestrel intrauterine device (n = 28), depot medroxyprogesterone acetate (n = 28), or combined oral contraceptives (n = 27). The anti-HSV-1/-2 and the anti-HIV-1 activity of the CVL were measured using plaque assays and the Jurkat-Tat-CCR5 assay, respectively. RESULTS: CVL from all of the groups had modest antiviral activity. Anti-HIV-1 activity was decreased in CVL from postmenopausal women when compared to premenopausal women (11% vs 34%, P = .002). However, there was no difference in anti-HIV-1 activity among premenopausal women regardless of phase of menstrual cycle or contraceptive use. Anti-HIV-1 activity was associated with the protein content of the CVL (r = 0.44, P < .001). There was no difference in anti-HSV-1 or -2 activity by hormonal group. CONCLUSION: Menopause is associated with decreased innate HIV-1 activity in the lower genital tract, suggesting that factors in the vaginal fluid could play a role in increased susceptibility of HIV-1 infection in postmenopausal women. Hormonal contraceptive use, menopause, and phase of menstrual cycle did not have a measurable impact on the intrinsic anti-HSV-1 or -2 activity.

An agent-based modeling framework linking inflammation and cancer using evolutionary principles: description of a generative hierarchy for the hallmarks of cancer and developing a bridge between mechanism and epidemiological data.

Inflammation plays a critical role in the development and progression of cancer, evident in multiple patient populations manifesting increased, non-resolving inflammation, such as inflammatory bowel disease, viral hepatitis and obesity. Given the complexity of both the inflammatory response and the process of oncogenesis, we utilize principles from the field of Translational Systems Biology to bridge the gap between basic mechanistic knowledge and clinical/epidemiologic data by integrating inflammation and oncogenesis within an agent-based model, the Inflammation and Cancer Agent-based Model (ICABM). The ICABM utilizes two previously published and clinically/epidemiologically validated mechanistic models to demonstrate the role of an increased inflammatory milieu on oncogenesis. Development of the ICABM required the creation of a generative hierarchy of the basic hallmarks of cancer to provide a foundation to ground the plethora of molecular and pathway components currently being studied. The ordering schema emphasizes the essential role of a fitness/selection frame shift to sub-organismal evolution as a basic property of cancer, where the generation of genetic instability as a negative effect for multicellular eukaryotic organisms represents the restoration of genetic plasticity used as an adaptive strategy by colonies of prokaryotic unicellular organisms. Simulations with the ICABM demonstrate that inflammation provides a functional environmental context that drives the shift to sub-organismal evolution, where increasingly inflammatory environments led to increasingly damaged genomes in microtumors (tumors below clinical detection size) and cancers. The flexibility of this platform readily facilitates tailoring the ICABM to specific cancers, their associated mechanisms and available epidemiological data. One clinical example of an epidemiological finding that could be investigated with this platform is the increased incidence of triple negative breast cancers in the premenopausal African-American population, which has been identified as having up-regulated of markers of inflammation. The fundamental nature of the ICABM suggests its usefulness as a base platform upon which additional molecular detail could be added as needed.

Low levels of serum vitamin D3 are associated with autoimmune thyroid disease in pre-menopausal women.

BACKGROUND: Low serum vitamin D levels have been associated with several autoimmune diseases, but their association with thyroid autoimmunity is unclear. We evaluated the association of serum vitamin D levels with the prevalence of autoimmune thyroid disease (AITD). METHODS: Our cross-sectional study included subjects who underwent routine health checkups, which included assays of serum 25-hydroxy vitamin D3 [25(OH)D3] and anti-thyroid peroxidase antibody (TPO-Ab), as well as thyroid ultrasonography (US) between 2008 and 2012 at the Asan Medical Center. We defined AITD according to the levels of TPO-Ab and US findings. RESULTS: A total of 6685 subjects (58% male; 42% female) were enrolled for this study. Overall prevalence of TPO-Ab positivity and both TPO-Ab/US positivity were 10.1% (6.3% male; 15.3% female) and 5.4% (2.3% male; 9.7% female) respectively. In female subjects, mean serum 25(OH)D3 levels were significantly lower in the TPO-Ab(+) (22.0 vs. 23.5 ng/mL, p=0.030) and TPO-Ab(+)/US(+) groups (21.6 vs. 23.4 ng/mL, p=0.027) compared with the control group, respectively. According to the levels of serum 25(OH)D3, the prevalence of TPO-Ab positivity (21.2%, 15.5%, and 12.6% in deficient, insufficient, and sufficient group, respectively; p=0.001) and both TPO-Ab and US positivity (14.7%, 9.9%, and 7.1% in deficient, insufficient, and sufficient group, respectively; p<0.001) decreased in female subjects. Interestingly, this pattern was significant only in pre-menopausal women (p=0.003 and p<0.001; respectively), but not in postmenopausal women. Multivariate analysis indicated that the adjusted odds ratios (OR) for AITD among those in the 25(OH)D3-deficient [TPO-Ab(+): OR 1.95, p=0.001; TPO-Ab(+)/US(+): OR 2.36, p<0.001] and -insufficient groups [TPO-Ab(+): OR 1.31, p=0.043; TPO-Ab(+)/US(+): OR 1.50, p=0.017] were significantly increased when compared with the sufficient group. CONCLUSIONS: The levels of serum vitamin D were significantly lower in pre-menopausal women with AITD. Vitamin D deficiency and insufficiency were significantly associated with AITD in pre-menopausal women.

High prevalence of increased interleukin-17A serum levels in postmenopausal estrogen deficiency.

OBJECTIVE: Postmenopausal estrogen deficiency is associated with chronic inflammatory events that cause cardiovascular and osteoporosis diseases. The aim of this study was to investigate the relationship between interleukin (IL)-17 and serum estradiol levels, age, and postmenopausal duration, as well as bone loss. METHODS: The relationship between serum IL-17A and estradiol levels was studied in 72 postmenopausal women and 22 premenopausal women. Enzyme-linked immunosorbent assay and chemiluminescence were used to detect IL-17A and estradiol, respectively. RESULTS: Estradiol levels were significantly higher and IL-17A levels were significantly lower in premenopausal women compared with postmenopausal women (estradiol: 239.44 [226.17] vs 74.21 [4.44] pmol/L, P < 0.0001; IL-17A: 2.88 [0.08] vs 3.5 [0.56] ng/mL, P < 0.0001). Seventy-eight of 94 women had lower estradiol levels (<83 pmol/L) with elevated IL-17A levels, in comparison with 16 women who had normal estrogen levels (3.43 [0.56] vs 3.01 [0.38] ng/mL, P < 0.0001). IL-17A levels inversely correlated with the total lumbar T-scores calculated in all women (P < 0.0001). IL-17A levels showed age-related dependency and a remarkable association with the postmenopausal period (P < 0.03). CONCLUSIONS: The results demonstrate a high prevalence of increased serum IL-17A levels in postmenopausal estrogen deficiency, which can play an inducing role in chronic inflammatory events such as bone loss.

Gingival crevicular fluid levels of osteoprotegerin (OPG) in premenopausal and postmenopausal women with or without chronic periodontitis.

OBJECTIVES: Systemic conditions may affect host susceptibility, disease progression and severity as well as treatment response. Previously, low oestrogen (E(2)) levels were associated with increased bone resorption, due to increased osteoclastogenesis and decreased osteoclast apoptosis. Osteoprotegerin (OPG) is an essential cytokine for osteoclastogenesis. The aim of this study was to evaluate gingival crevicular fluid (GCF) OPG levels in menopausal and premenopausal patients with or without periodontitis, and effects of phase I periodontal therapy on GCF OPG levels. METHODS: Forty-four systemically healthy premenopausal and menopausal patients were recruited and divided into subgroups of periodontitis and control. Bone mineral density (BMD) and serum E(2) levels were measured. Before and after phase I periodontal therapy clinical indices, including clinical attachment levels (CAL) were recorded, and GCF samples were collected. GCF OPG levels were detected by enzyme-linked immunosorbent assay. Repeated measurement ANOVA and Spearman correlation tests were used. RESULTS: All clinical indices improved significantly after treatment(p<0.001), except Pre-M/C groups CAL reduction(p>0.05). Periodontitis groups' OPG levels were lower than gingivitis groups(p>0.05). Following periodontal phase I therapy, GCF OPG levels increased markedly in all groups, however this alteration was found statistically insignificant (p>0.05). CONCLUSIONS: The current data revealed that GCF OPG levels were lower in periodontitis patients and phase I therapy resulted with increased GCF OPG levels, however those alterations were statistically insignificant. In addition, present data suggested that menopause do not seem to have a significant effect on periodontal status or response to phase I treatment, within the limits of this study.

Circulating regulatory T cells in endometrial cancer: a role for age and menopausal status.

Regulatory T cells (Treg) are a sub-population of T cells that suppress self-reactivity and are implicated in immune tolerance towards malignant cells. Circulating Treg cells are increased in several cancers. In endometrial cancer Treg cells have been investigated only in tumour tissues and, in contrast to some other tumours, fewer Treg cells were reported in endometrial cancer compared with benign controls. Flow cytometry was used to determine the frequency of circulating Treg cells in women undergoing hysterectomy for either endometrial cancer (n = 24) or non- cancer-related conditions (n = 21). Circulating Treg cells were more abundant in women with cancer compared to those without (4.68% vs. 3.66%, p = 0.05, Mann-Whitney test). This relationship disappeared, however, when only data from post-menopausal women were included in the analysis. Mean Treg cell frequency was 4.65% in postmenopausal women with cancer (n = 23) and 4.73% in postmenopausal controls (n = 5) (p = 0.9). In women without cancer we found that mean Treg cell frequency was higher in postmenopausal women (4.73%, n = 5) in comparison to premenopausal controls (3.33%, n = 16) (p = 0.02). These results suggest that the increased proportion of Treg cells seen in endometrial cancer patients might be, at least in part, attributed to their postmenopausal status or age.

Relationship between the serum CA-125 level and bone mineral density in healthy pre- and post-menopausal women.

BACKGROUND: Osteoporosis and tumour-associated antigen (TAA) levels are associated with inflammatory processes, but little remains known about TAA levels and bone mineral density (BMD). AIMS: We determined whether or not high-normal TAA levels are associated with a lower BMD in healthy women. METHODS: A total of 3769 healthy women were enrolled from the health screening programme over 5 years. Each participant had undergone a basic health examination. Serum carbohydrate antigen (CA)-125, CA-19-9, carcinoembryonic antigen (CEA) and alpha-fetoprotein levels were evaluated as tumour markers. The correlations between serum TAA levels and BMD were analysed. RESULTS: Carbohydrate antigen 125 and CEA levels were positively associated with a higher BMD in the pre-menopause. In the post-menopause, the CA-125 level was positively associated with BMD. In the pre-menopause, CA-125 (r = 0.102; P < 0.001) and CEA levels (r = 0.134; P < 0.001) had a significant correlation with BMD. In the post-menopause, CA-125 was negatively associated with alkaline phosphatase (r = -0.298; P < 0.001). CONCLUSIONS: There was a significant positive association between CA-125 and BMD in healthy women. Additional basic and clinical studies on the relationship between CA-125 and bone are needed.

Bone density and depression in premenopausal South African women: a pilot study.

OBJECTIVE: It is posited that the effect of depression on BMD is dependent on the severity of depression. Conflicting evidence exists regarding this possible association. This study investigated the association between depression and low bone mineral density (BMD). METHODS: The hypothesis was investigated in a random sample of volunteers (n=40) and in premenopausal female psychiatric patients (n=5) diagnosed with recurrent severe major depression. The outcome measures were BMD (DEXA); depression (Beck Depression Inventory and Psychological General Well-being Scale) and 24-hour saliva cortisol levels (ELISA). In a comparison of women (4 of the 40 i.e. "control" subjects) with negligible symptoms of depression and the five patients with severe recurrent major depression- BMD, depression, saliva cortisol and bone turnover markers were measured and compared. Pro-inflammatory status (IL-1 and TNF-alpha) was investigated in the psychiatric patients only. RESULTS: In the random - non clinical - sample of women (n=40), 26 exhibited normal BDM and 14 exhibited low BMD. Drepressive symptoms and cortisol level were not significantly different between these two groups. Women with severe recurrent major depression (n=5)exhibited lower median BMD T-scores, higher overall bone turnover and higher 24-hour cortisol levels compared to "control" subjects (n=4). The psychiatric patients also exhibited elevated IL-1 levels. CONCLUSION: The effect of depression on BMD may be dependent on the depression severity, IL-1 and cortisol are possible mediators in depression-induced BMD loss.

Leukocyte density and composition in human cycling endometrium with uterine fibroids.

In this study, we evaluated the leukocyte density and composition in the human cycling endometrium with uterine fibroids (UF). The endometrium with neighboring nodule (NN group, n = 62), autologous endometrium without NN (non-NN group, n = 62), and allogeneic endometrium without UF (non-UF group, n = 24) were immunostained for the leukocyte common and subset-specific antigens. The immunoreactive cells in the unit areas were enumerated under a light microscope. The stromal pan-leukocyte density in the proliferative phase was significantly higher in the endometrium in the NN group than in the non-NN group. The macrophage density was higher in the NN group than in the non-NN group throughout the menstrual cycle. The NK cell density in the mid-to-late secretory phase was lower in the NN group than in the non-NN group. The T cell density in the midsecretory phase was higher in the non-NN group than in the non-UF group. The neutrophil density in the proliferative phase was higher in the non-NN group than in the non-UF group. The leukocyte density and composition in the endometrium with UF are different from those without UF, suggesting their local effects on endometrial leukocyte population.

Prevalence of antiphospholipid antibodies among women experiencing unexplained infertility and recurrent implantation failure.

The prevalences of antiphospholipid antibodies (APAs) among 1,325 women with a history of unexplained infertility and 676 women experiencing recurrent implantation failure were compared with 789 women experiencing recurrent pregnancy loss and 205 fertile control women. Eight percent and 9% of women with a history of unexplained infertility and recurrent implantation failure had more than one positive APA compared with 1.5% of fertile negative control women and 11% of positive control women experiencing recurrent pregnancy loss.

Estradiol increases IL-8 secretion of normal human breast tissue and breast cancer in vivo.

IL-8 or CXCL8 has been associated with tumor angiogenesis, metastasis, and poor prognosis in breast cancer. Estrogen is crucial in breast carcinogenesis and tumor progression. Whether sex steroids affect IL-8 secretion of normal breast tissue or breast cancer is not known. Several cell types in a tissue secrete IL-8. Hence, regulatory mechanisms of IL-8 need to be investigated in whole tissue. We used microdialysis to sample IL-8 in normal human breast tissue in situ in pre- and postmenopausal women, preoperatively in breast cancers of women, and in experimental breast cancer in mice. We found a significant positive correlation between IL-8 and estradiol in normal breast tissue and hormone-dependent breast cancer in vivo. Ex vivo, estradiol exposure increased the IL-8 secretion of normal whole breast tissue in culture. In experimental breast cancer, estradiol increased IL-8 whereas the anti-estrogen tamoxifen inhibited the secretion of IL-8 both in vitro and extracellularly in vivo in tumors of nude mice. An anti-IL-8 Ab inhibited endothelial cell proliferation induced by cancer cell produced IL-8 and tumors with low IL-8 levels exhibited decreased angiogenesis. Our results strongly suggest that estradiol has a critical role in the regulation of IL-8 in normal human breast tissue and human breast cancer. IL-8 may present a novel therapeutic target for estrogen driven breast carcinogenesis and tumor progression.

Anti-beta 2 glycoprotein I antibodies and the risk of myocardial infarction in young premenopausal women.

BACKGROUND: Contrasting data have been reported on the association between the presence of anti-phospholipid antibodies (aPL) and arterial thrombotic events, particularly those in coronary arteries. This discrepancy is perhaps related to the confounding effect of traditional risk factors. Among them, coronary atherosclerosis appears to be the most important in studies conducted in middle-aged and elderly patients. OBJECTIVE: To minimize such confounding effects, a multicenter case-control study on the association between aPL and myocardial infarction (MI) was carried out in a rare cohort of young premenopausal women. METHODS: We evaluated 172 cases hospitalized for a first MI before the age of 45 years and 172 controls individually matched with cases for age, sex and geographical origin. Clinical and laboratory data were collected and levels of anti-cardiolipin (aCL), anti-beta2 glycoprotein I (anti-beta2GPI) and anti-nuclear antibodies (ANA) were measured. RESULTS: A significant association between MI and IgG/IgM anti-beta2GPI antibodies was observed; the results were confirmed after adjusting for smoking and hypertension (anti-beta2GPI IgG OR = 2.47, 95% CI 1.81-3.38; anti-beta2GPI IgM 4th quartile OR 3.68, 95% CI 1.69-8.02). The association between anti-beta2GPI antibodies and MI was detected in both subgroups with and without coronary artery stenosis. Whereas the association of aCL IgG with MI was modest, ANA showed no significant association with MI. No aPL were found in unselected patients (mainly males) who recently developed acute MI. CONCLUSIONS: Anti-beta2GPI antibodies are a significant risk factor for MI in young premenopausal women independently of other risk factors, including the degree of coronary artery stenosis.

Lack of association between thyroid autoantibodies and parity in a population study argues against microchimerism as a trigger of thyroid autoimmunity.

BACKGROUND: Thyroid autoimmunity is more common in females than in males. One possible explanation for this female preponderance may be the effect of oestrogens on the immune system. It has also been suggested that foetal microchimerism involving transfer of foetal cells into maternal tissue during pregnancy may play an important role. OBJECTIVE: We investigated the association between the presence of circulating thyroid autoantibodies and previous pregnancy, parity and the use of oral contraceptives (OCs) and hormone replacement therapy (HRT) in a population cohort. METHODS: We examined 3712 women randomly selected from the general population. Serum was analysed for thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (Tg-Ab) using assays based on an RIA technique (DYNO test). Data were analysed in logistic regression models to adjust for possible confounders. Women previously treated for thyroid disease or with pregnancy within 1 year prior to the study were excluded from the analyses. RESULTS: In both univariate and multivariate models and whether the presence of TPO-Ab and Tg-Ab was investigated alone or in combination, findings were negative with respect to an association between circulating thyroid antibodies and previous pregnancy, number of pregnancies, parity and previous abortion. There was no association between thyroid autoantibodies and use of OCs. Women aged 60-65 years receiving HRT now or previously had a lower prevalence of Tg-Ab (univariate, P = 0.01; multivariate, P = 0.02). No such association was observed between HRT and TPO-Ab. CONCLUSION: In this population study there was no association between previous pregnancy, parity and thyroid antibodies, which argues against the role of microchimerism as a trigger of thyroid autoimmunity. Exogenous oestrogens may reduce aspects of autoimmunity.