| 1. |
- Islander, Ulrika, 1975, et al.
(författare)
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Influence of oestrogen receptor alpha and beta on the immune system in aged female mice.
- 2003
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Ingår i: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 110:1, s. 149-57
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Tidskriftsartikel (refereegranskat)abstract
- Oestrogen has a dichotomous effect on the immune system. T and B lymphopoiesis in thymus and bone marrow is suppressed, whereas antibody production is stimulated by oestrogen. In this study the importance of the oestrogen receptors (ER) ER-alpha and ER-beta in the aged immune system was investigated in 18 months old-wild type (WT), ER-alpha (ERKO), ER-beta (BERKO) and double ER-alpha and ER-beta (DERKO) knock-out mice, and compared with 4 months old WT mice. Cell phenotypes in bone marrow, spleen and thymus, and the frequency of immunoglobulin (Ig) spot forming cells (SFC) were determined. We show here that the 17-beta-oestradiol (E2)-induced downregulation of B lymphopoietic cells in bone marrow of young ovariectomized mice can be mediated through both ER-alpha and ER-beta. However, only ER-alpha is required for the age-related increased frequency of immunoglobulin M (IgM) SFC in the bone marrow, as well as for the increased production of interleukin-10 (IL-10) from cultured splenocytes in aged mice. Furthermore, increased age in WT mice resulted in lower levels of both pro- and pre-B cells but increased frequency of IgM SFC in the bone marrow, as well as increased frequency of both IgM and IgA SFC in the spleen. Results from this study provide valuable information regarding the specific functions of ER-alpha and ER-beta in the aged immune system.
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| 2. |
- Carlsten, A, et al.
(författare)
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Antidepressant medication and suicide in Sweden
- 2001
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Ingår i: Pharmacoepidemiology and Drug Safety. - : Wiley. - 1053-8569 .- 1099-1557. ; 10:6, s. 525-530
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To explore a possible temporal association between changes in antidepressant sales and suicide rates in different age groups. METHODS: A time series analysis using a two-slope model to compare suicide rates in Sweden before and after introduction of the selective serotonin reuptake inhibitors, SSRIs. RESULTS: Antidepressant sales increased between 1977-1979 and 1995-1997 in men from 4.2 defined daily doses per 1000 inhabitants and day (DDD/t.i.d) to 21.8 and in women from 8.8 to 42.4. Antidepressant sales were twice as high in the elderly as in the 25-44-year-olds and eight times that in the 15-24-year-olds. During the same time period suicide rates decreased in men from 48.2 to 33.3 per 10(5) inhabitants/year and in women from 20.3 to 13.4. There was significant change in the slope in suicide rates after the introduction of the SSRI, for both men and women, which corresponds to approximately 348 fewer suicides during 1990-1997. Half of these 'saved lives' occurred among young adults. CONCLUSION: We demonstrate a statistically significant change in slope in suicide rates in men and women that coincided with the introduction of the SSRI antidepressants in Sweden. This change preceded the exponential increase in antidepressant sales.
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| 3. |
- Carlsten, A, et al.
(författare)
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The role of benzodiazepines in elderly suicides
- 2003
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Ingår i: Scandinavian Journal of Public Health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 31:3, s. 224-228
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Tidskriftsartikel (refereegranskat)abstract
- Aims: In Sweden, suicides by drug poisoning have decreased in the population at large during the past two decades. However, drug poisoning suicides increased among the elderly during this period. Suicides by benzodiazepine poisoning increased in this age group despite a reduction in prescription sales of these drugs. This study aims therefore to determine the role of benzodiazepines in suicide late in life. Methods: Information concerning all definite suicides and deaths due to "undetermined" causes recorded among Swedish citizens aged 65 and above during 1992-96 was obtained from the Cause-of-Death Register. Death certificates were scrutinized to determine the type of drug employed in drug-related suicides. Results of the post mortem screening for drugs and alcohol were then examined. Results: A benzodiazepine was implicated in 216/548 (39%) of the drug poisoning suicides recorded among the elderly. Death certificates revealed that a benzodiazepine was the sole agent in 72% of these cases. Flunitrazepam or nitrazepam were implicated in 90% of the single benzodiazepine suicides. In addition to the suicides classified as drug poisonings, 82 cases were found in which a drug may have contributed to the cause of death. Benzodiazepines predominated. The terminal cause of death was drowning, often in the victim's own bathtub, in three-quarters of these cases. The annual fatality ratios for the newer benzodiazepine-like hypnotics zopiclone and zolpidem appear to be on the rise. Conclusion: Benzodiazepines, especially the hypnotics flunitrazepam and nitrazepam, are common in drug poisoning suicides in the elderly and should be prescribed with caution for this age group.
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| 4. |
- Carlsten, Hans, 1954, et al.
(författare)
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The impact of a new immunomodulator oxo-quinoline-3-carboxamide on the progression of experimental lupus
- 2004
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Ingår i: Int Immunopharmacol. - : Elsevier BV. - 1567-5769. ; 4:12, s. 1515-23
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune, lupus-prone MRL lpr/lpr mice were treated orally with oxo-quinoline-3-carboxamide (ABR-25757), a newly developed immunomodulator. Treatment was initiated in one set of experiment at the age of 10 weeks, before the onset of clinically apparent disease, and in another set at 15 weeks, after the development of established lupus disease. Beneficial therapeutic effects were obtained even when ABR-25757 was administered at the lowest dose tested (7.5 microg/mouse/week) to 15 weeks old mice with established lupus disease. The effects of ABR-25757 on longevity, as well as on development of glomerulonephritis were pronounced and comparable with those of LS-2616, a potent immunomodulator. Administration of ABR-25757 did not significantly alter T cell responses in vivo nor in vitro. In addition, it only marginally suppressed B cell responses measured as frequencies of immunoglobulin secreting cells. By the same token this compound did not affect overall leukocyte content in primary (bone marrow) or secondary (spleen) lymphoid tissues. In contrast, treatment with ABR-25757 up regulated expression of pro-inflammatory transcription factors NF-kappaB and AP-1. These results suggest (a) a potential therapeutic role of ABR-25757 in the treatment of experimental lupus and (b) that the effect of the treatment is mediated by immunodeviation rather than by immunosuppression.
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| 5. |
- Erlandsson, M C, et al.
(författare)
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Oestrogen receptor specificity in oestradiol-mediated effects on B lymphopoiesis and immunoglobulin production in male mice.
- 2003
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Ingår i: Immunology. - 0019-2805. ; 108:3, s. 346-51
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Tidskriftsartikel (refereegranskat)abstract
- Oestrogen treatment down-regulates B lymphopoiesis in the bone marrow of mice. Meanwhile it up-regulates immunoglobulin production. To understand better the oestrogen action on bone marrow male mice lacking oestrogen receptor alpha (ERalpha; ERKO mice), lacking ERbeta (BERKO mice), lacking both receptors (DERKO mice) or wild-type (wt) littermates were castrated and treated for 2.5 weeks with 30 microg/kg 17beta-oestradiol (E2) or vehicle oil as controls. The B lymphopoiesis in the bone marrow was examined by flow cytometry and mature B-cell function was studied using an ELISPOT assay enumerating the B cells in bone marrow and spleen that were actively producing immunoglobulins. In wt mice the frequency of B-lymphopoietic (B220+) cells in the bone marrow decreased from 15% to 5% upon E2 treatment. In ERKO and BERKO mice significant reduction was seen but not of the same magnitude. In DERKO mice no reduction of B lymphopoiesis was seen. In addition, our results show that E2 mediated reduction of different steps in B lymphopoiesis require only ERalpha or both receptors. In wt and BERKO mice E2 treatment resulted in significantly increased levels of B cells actively producing immunoglobulin, while in ERKO and DERKO mice no such change was seen. Similar results were found in both bone marrow and spleen. In conclusion our results clearly show that both ERalpha and ERbeta are required for complete down-regulation of B lymphopoiesis while only ERalpha is needed to up-regulate immunoglobulin production in both bone marrow and spleen.
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| 6. |
- Erlandsson, M C, et al.
(författare)
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Raloxifene- and estradiol-mediated effects on uterus, bone and B lymphocytes in mice.
- 2002
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Ingår i: The Journal of endocrinology. - 0022-0795. ; 175:2, s. 319-27
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Tidskriftsartikel (refereegranskat)abstract
- Raloxifene is a selective estrogen receptor modulator approved for the prevention of osteoporosis in postmenopausal women. It is selective by having estrogen-agonistic effects on bone, vessels and blood lipids while it is antagonistic on mammary and uterine tissue. Our aim was to study the agonistic and antagonistic properties of the raloxifene analogue LY117018 (LY) on uterus, bone, B lymphopoiesis and B cell function. Oophorectomized and sham-operated animals were treated with s.c. injections of equipotent anti-osteoporotic doses of 17beta-estradiol (E2) (0.1 mg/kg) or LY (3 mg/kg) or vehicle as controls. Effects on bone mineral density (BMD) were studied using peripheral quantitative computed tomography, uterine weight was examined, B lymphopoiesis was examined using flow cytometry and B cell function in bone marrow and spleen was studied by the use of an ELISPOT assay. E2 and LY had similar effects on BMD and bone marrow B lymphopoiesis, while LY had a clear antagonistic effect on endogenous estrogen in uterine tissue and no stimulating effect on the frequency of Ig-producing B cells in sham-operated animals. Our results are discussed in the context of estrogen receptor biology, relations between the immune system and bone metabolism and also with respect to the estrogen-mediated effects on rheumatic diseases.
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| 7. |
- Erlandsson, M C, et al.
(författare)
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Role of oestrogen receptors alpha and beta in immune organ development and in oestrogen-mediated effects on thymus.
- 2001
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Ingår i: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 103:1, s. 17-25
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Tidskriftsartikel (refereegranskat)abstract
- Oestrogens affect the development and regulation of the immune system. To determine the role of oestrogen receptors alpha (ER-alpha) and beta (ER-beta) on the development of the immune system, male ER-alpha (ERKO) and ER-beta (BERKO) mice, as well as alphabeta-double knockout (DERKO) mice, were studied. Deletion of ER-alpha led to hypoplasia of both thymus and spleen. Interestingly, a higher frequency of immature double CD4+ CD8+ thymocytes was found in ER-alpha(-) mice compared with ER-alpha(+) mice. Female oophorectomized BERKO mice given oestradiol (E2) displayed a similar degree of thymic atrophy compared with the wild-type strain but showed only limited involution of thymus cortex and no alteration of thymic CD4/CD8 phenotype expression. Our data demonstrate that expression of ER-alpha, but not ER-beta, is mandatory in males for development of full-size thymus and spleen, whereas expression of ER-beta is required for E2-mediated thymic cortex atrophy and thymocyte phenotype shift in females. A potential background for the above findings may be down-regulated activity in the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis in males lacking ER-alpha and suppressed sensitivity of females lacking ER-beta to E2-mediated suppression of IGF-1.
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| 8. |
- Forsblad d'Elia, Helena, 1961, et al.
(författare)
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Radiographic joint destruction in postmenopausal rheumatoid arthritis is strongly associated with generalised osteoporosis.
- 2003
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 62:7, s. 617-23
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To investigate determinants of joint destruction and reduced bone mineral density (BMD) in postmenopausal women with active rheumatoid arthritis (RA) not treated with bisphosphonates or hormone replacement therapy and to evaluate if there are common markers of erosive disease and bone loss. METHODS: BMD was measured using dual x ray absorptiometry and joint damage was examined by x ray examination according to the Larsen method in 88 patients with RA. Associations between BMD and Larsen score, and between demographic and disease related variables, including proinflammatory cytokines, HLA-DR4 epitopes, and markers of bone and cartilage turnover, were examined bivariately by simple and multiple linear regression analyses. RESULTS: 49/88 (56%) patients had osteoporosis in at least one site. Reduced BMD and increased joint destruction were associated with: at the forearm and femoral neck, high Larsen score, low weight, and old age (R(2)=0.381, p<0.001; R(2)=0.372, p<0.001, respectively); at the total hip, low weight, high Larsen score, and dose of injected glucocorticosteroids (R(2)=0.435, p<0.001); at the lumbar spine, low weight, reduced cartilage oligomeric matrix protein, and increased carboxyterminal propeptide of type I procollagen (R(2)=0.248, p<0.001). Larsen score was associated with long disease duration and increased C reactive protein (CRP) (R(2)=0.545, p<0.001). CONCLUSIONS: Osteoporosis is common in postmenopausal patients with RA. Low weight and high Larsen score were strongly associated with BMD reduction. Increased CRP and long disease duration were determinants of erosive disease in postmenopausal women with RA. These findings indicate common mechanisms of local and generalised bone loss in RA.
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| 9. |
- Lindberg, Marie K, 1975, et al.
(författare)
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Estrogen receptor alpha, but not estrogen receptor beta, is involved in the regulation of the OPG/RANKL (osteoprotegerin/receptor activator of NF-kappa B ligand) ratio and serum interleukin-6 in male mice.
- 2001
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Ingår i: The Journal of endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 171:3, s. 425-33
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens are important for the male skeleton. Osteoprotegerin (OPG), receptor activator of NF-kappa B ligand (RANKL), interleukin-6 (IL-6), IL-1 and tumor necrosis factor alpha (TNFalpha) have been suggested to be involved in the skeletal effects of estrogen. We treated orchidectomized mice with estradiol for 2 weeks and observed a 143% increase in the trabecular bone mineral density of the distal metaphysis of femur that was associated with a decreased OPG/RANKL mRNA ratio in vertebral bone. A similar decreased OPG/RANKL ratio was also seen after estrogen treatment of ovariectomized female mice. The effect of estrogen receptor (ER) inactivation on the OPG/RANKL ratio was dissected by using intact male mice lacking ER alpha (ERKO), ER beta (BERKO) or both receptors (DERKO). The expression of OPG was increased in ERKO and DERKO but not in BERKO male mice, resulting in an increased OPG/RANKL ratio. Furthermore, serum levels of IL-6 and tartrate-resistant acid phosphatase 5b (TRAP 5b) were decreased in ERKO and DERKO, but not in BERKO male mice. These results demonstrate that ER alpha, but not ER beta, is involved in the regulation of the vertebral OPG/RANKL ratio, serum levels of IL-6 and TRAP 5b in male mice.
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| 10. |
- Lindberg, Marie K, 1975, et al.
(författare)
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Estrogen receptor specificity for the effects of estrogen in ovariectomized mice.
- 2002
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Ingår i: The Journal of endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 174:2, s. 167-78
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen exerts a variety of important physiological effects, which have been suggested to be mediated via the two known estrogen receptors (ERs), alpha and beta. Three-month-old ovariectomized mice, lacking one or both of the two estrogen receptors, were given estrogen subcutaneously (2.3 micro g/mouse per day) and the effects on different estrogen-responsive parameters, including skeletal effects, were studied. We found that estrogen increased the cortical bone dimensions in both wild-type (WT) and double ER knockout (DERKO) mice. DNA microarray analysis was performed to characterize this effect on cortical bone and it identified four genes that were regulated by estrogen in both WT and DERKO mice. The effect of estrogen on cortical bone in DERKO mice might either be due to remaining ERalpha activity or represent an ERalpha/ERbeta-independent effect. Other effects of estrogen, such as increased trabecular bone mineral density, thymic atrophy, fat reduction and increased uterine weight, were mainly ERalpha mediated.
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