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Aim: Hospitalization for heart failure amongst younger men has increased. The reason for this is unknown but it coincides with the obesity epidemic. The aim of this study was to evaluate the association between childhood BMI (Body Mass Index) and BMI change during puberty for risk of adult heart failure in men.Methods: Using the BMI Epidemiology Study (BEST), a population-based study in Gothenburg, Sweden, we collected information on childhood BMI at age 8 years and BMI change during puberty (BMI at age 20 - BMI at 8) for men born 1945-1961, followed until December 2013 (n = 37 670). BMI was collected from paediatric growth charts and mandatory military conscription tests. Information on heart failure was retrieved from high-quality national registers (342 first hospitalizations for heart failure).Results: BMI change during puberty was independently of childhood BMI associated with risk of heart failure in a nonlinear J-shaped manner. Subjects in the upper quartile of BMI change during puberty (Q4) had more than twofold increased risk of heart failure compared with subjects in Q1 [HR (Hazard Ratio) = 2.29, 95% CI (Confidence Interval) 1.68-3.12]. Childhood BMI was not independently associated with risk of heart failure. Boys developing overweight during puberty (HR 3.14; 95% CI 2.25-4.38) but not boys with childhood overweight that normalized during puberty (HR 1.12, 95% CI 0.63-2.00) had increased risk of heart failure compared with boys without childhood or young adult overweight.Conclusion: BMI change during puberty is a novel risk factor for adult heart failure in men. [ABSTRACT FROM AUTHOR]

Background: Bone loss at peripheral sites in the elderly is mainly cortical and involves increased cortical porosity. However, an association between bone loss at these sites and 25-hydroxyvitamin D has not been reported.Objective: To investigate the association between serum levels of 25-hydroxyvitamin D, bone microstructure and areal bone mineral density (BMD) in elderly men.Methods: A population-based cohort of 444 elderly men (mean ± SD age 80.2 ± 3.5 years) was investigated. Bone microstructure was measured by high-resolution peripheral quantitative computed tomography, areal BMD by dual-energy X-ray absorptiometry and serum 25-hydroxyvitamin D and parathyroid hormone levels by immunoassay.Results: Mean cortical porosity at the distal tibia was 14.7% higher (12.5 ± 4.3% vs. 10.9 ± 4.1%, P < 0.05) whilst cortical volumetric BMD, area, trabecular bone volume fraction and femoral neck areal BMD were lower in men in the lowest quartile of vitamin D levels compared to the highest. In men with vitamin D deficiency (<25 nmol L-1 ) or insufficiency [25-49 nmol L-1 , in combination with an elevated serum level of parathyroid hormone (>6.8 pmol L-1 )], cortical porosity was 17.2% higher than in vitamin D-sufficient men (P < 0.01). A linear regression model including age, weight, height, daily calcium intake, physical activity, smoking vitamin D supplementation and parathyroid hormone showed that 25-hydroxyvitamin D independently predicted cortical porosity (standardized β = -0.110, R2 = 1.1%, P = 0.024), area (β = 0.123, R2 = 1.4%, P = 0.007) and cortical volumetric BMD (β = 0.125, R2 = 1.4%, P = 0.007) of the tibia as well as areal BMD of the femoral neck (β = 0.102, R2 = 0.9%, P = 0.04).Conclusion: Serum vitamin D is associated with cortical porosity, area and density, indicating that bone fragility as a result of low vitamin D could be due to changes in cortical bone microstructure and geometry. [ABSTRACT FROM AUTHOR]

Background: It has been suggested that osteoblasts are involved in the regulation of haematopoietic stem cells. Whether osteocalcin, which is derived from osteoblasts and is metabolically active, influences blood haemoglobin (Hb) levels is not known.Objective: To determine whether plasma osteocalcin is a determinant of Hb in elderly men.Methods: A total of 993 men (mean age 75.3 ± 3.2 years) participated in the population-based MrOS (osteoporotic fractures in men) study. Plasma osteocalcin concentration was evaluated in relation to Hb and adjustments were made for potential confounders (i.e. age, body mass index, erythropoietin, total oestradiol, fasting insulin, adiponectin, ferritin and cystatin C).Results: Hb correlated (age adjusted) negatively with osteocalcin in the total study group (r = -0.12, P < 0.001) as well as in the subgroup of nondiabetic men (r = -0.16, P < 0.001). In nondiabetic men with higher osteocalcin levels, it was more likely that Hb would be in the lowest quartile (odds ratio per SD decrease in osteocalcin 1.32, 95% confidence interval 1.13-1.53). Quartiles of Hb were negatively associated (age adjusted) with osteocalcin (P < 0.001). Anaemic men (47/812) (Hb <130 g L(-1) ) had significantly higher mean osteocalcin levels than nonanaemic men (33.9 vs. 27.1 μg L(-1) , P < 0.001). In multiple stepwise linear regression analyses (adjusted for age, body mass index, total oestradiol, adiponectin, erythropoietin, fasting insulin, cystatin C, leptin, ferritin and holotranscobalamin), osteocalcin was an independent predictor of Hb concentration in nondiabetic men (P < 0.05).Conclusions: These data add further support to the evidence indicating that the bone-specific protein osteocalcin has several endocrine functions targeting the pancreas, testes, adipocytes, brain. An additional novel finding is that osteocalcin may also have a paracrine function as a regulator of haematopoiesis. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Blood haemoglobin (Hb) concentration declines in elderly men, whilst the level of the adipocyte-derived protein adiponectin increases with age. The association between erythropoiesis and adiponectin in elderly men is unclear. The aim of this study was to determine whether adipokines such as adiponectin and leptin are associated with anaemia and Hb concentration in elderly community-dwelling men. DESIGN AND SETTING: The Gothenburg part of the population-based Swedish Osteoporotic Fractures in Men (MrOS) cohort (n = 1010; median age 75.3 years, range 69-81). MAIN OUTCOME MEASURES: We investigated the associations between levels of adiponectin and Hb before and after adjusting for potential confounders [i.e. age, body composition, erythropoietin (EPO), total oestradiol, leptin, cystatin C and iron and B vitamin status]. RESULTS: In these elderly men, age was negatively associated with Hb (r = -0.12, P < 0.001) and positively associated with adiponectin level (r = 0.13, P < 0.001). In age-adjusted partial correlations, Hb and adiponectin levels were negatively correlated (r = -0.20, P < 0.001); this association remained significant after multivariable adjustment for age, body composition, EPO, fasting insulin, sex hormones, leptin and ferritin. Age-adjusted mean adiponectin concentrations were significantly higher in anaemic men (66/1005; Hb <130 g L(-1) ) compared to nonanaemic men (14.0 vs. 11.7 [mu]g mL(-1) , P < 0.05). In multivariate analysis, adiponectin together with EPO, total oestradiol, insulin, albumin, transferrin saturation, HDL cholesterol, cystatin C, total body fat mass and free thyroxine, but not leptin, explained 35% of the variation in Hb level. These results remained essentially unchanged after exclusion of men with diabetes. CONCLUSIONS: Serum adiponectin, but not leptin, was negatively and independently associated with Hb. This finding suggests a possible role of adiponectin in the age-related decline in Hb level observed in apparently healthy elderly men. [ABSTRACT FROM AUTHOR]

Objectives Blood haemoglobin (Hb) concentration declines in elderly men, whilst the level of the adipocyte-derived protein adiponectin increases with age. The association between erythropoiesis and adiponectin in elderly men is unclear. The aim of this study was to determine whether adipokines such as adiponectin and leptin are associated with anaemia and Hb concentration in elderly community-dwelling men. Design and setting The Gothenburg part of the population-based Swedish Osteoporotic Fractures in Men (Mr OS) cohort ( n = 1010; median age 75.3 years, range 69-81). Main outcome measures We investigated the associations between levels of adiponectin and Hb before and after adjusting for potential confounders [i.e. age, body composition, erythropoietin ( EPO), total oestradiol, leptin, cystatin C and iron and B vitamin status]. Results In these elderly men, age was negatively associated with Hb ( r = −0.12, P < 0.001) and positively associated with adiponectin level ( r = 0.13, P < 0.001). In age-adjusted partial correlations, Hb and adiponectin levels were negatively correlated ( r = −0.20, P < 0.001); this association remained significant after multivariable adjustment for age, body composition, EPO, fasting insulin, sex hormones, leptin and ferritin. Age-adjusted mean adiponectin concentrations were significantly higher in anaemic men (66/1005; Hb <130 g L−1) compared to nonanaemic men (14.0 vs. 11.7 μg mL−1, P < 0.05). In multivariate analysis, adiponectin together with EPO, total oestradiol, insulin, albumin, transferrin saturation, HDL cholesterol, cystatin C, total body fat mass and free thyroxine, but not leptin, explained 35% of the variation in Hb level. These results remained essentially unchanged after exclusion of men with diabetes. Conclusions Serum adiponectin, but not leptin, was negatively and independently associated with Hb. This finding suggests a possible role of adiponectin in the age-related decline in Hb level observed in apparently healthy elderly men. [ABSTRACT FROM AUTHOR]

WNTs are extracellular proteins that activate different cell surface receptors linked to canonical and noncanonical WNT signalling pathways. The Wnt genes were originally discovered as important for embryonic development of fruit flies and malignant transformation of mouse mammary cancers. More recently, WNTs have been implicated in a wide spectrum of biological phenomena and diseases. During the last decade, several lines of clinical and preclinical evidence have indicated that WNT signalling is critical for trabecular and cortical bone mass, and this pathway is currently an attractive target for drug development. Based on detailed knowledge of the different WNT signalling pathways, it appears that it might be possible to develop drugs that specifically target cortical and trabecular bone. Neutralization of a bone-specific WNT inhibitor is now being evaluated as a promising anabolic treatment for patients with osteoporosis. Here, we provide the historical background to the discoveries of WNTs, describe the different WNT signalling pathways and summarize the current understanding of how these proteins regulate bone mass by affecting bone formation and resorption. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The effects of estrogen may be exerted via the nuclear estrogen receptors (ERs) ERalpha or ERbeta or via the recently proposed transmembrane estrogen receptor G protein-coupled receptor 30 (GPR-30). The purpose of this study was to elucidate the ER specificity for the ameliorating effects of estrogen on arthritis and bone loss in a model of postmenopausal rheumatoid arthritis (RA). METHODS: Female DBA/1 mice underwent ovariectomy or sham operation, and type II collagen-induced arthritis was induced. Mice were treated subcutaneously 5 days/week with the specific agonists propylpyrazoletriol (PPT; for ERalpha), diarylpropionitrile (DPN; for ERbeta), G1 (for GPR-30), or with a physiologic dose of estradiol. Clinical arthritis scores were determined continuously. At termination of the study, bone mineral density (BMD) was analyzed, paws were collected for histologic assessment, serum was analyzed for cytokines and markers of bone and cartilage turnover, and bone marrow was subjected to fluorescence-activated cell sorting. RESULTS: Treatment with PPT as well as estradiol dramatically decreased the frequency and severity of arthritis. Furthermore, estradiol and PPT treatment resulted in preservation of bone and cartilage, as demonstrated by increased BMD and decreased serum levels of bone resorption markers and cartilage degradation markers, whereas no effect was seen after DPN or G1 treatment. CONCLUSION: In a well-established model of postmenopausal RA, ERalpha, but not ERbeta or GPR-30 signaling, was shown to ameliorate the disease and the associated development of osteoporosis. Since long-term treatment with estrogen has been associated with significant side effects, increased knowledge about the mechanisms behind the beneficial effects of estrogen is useful in the search for novel treatments of postmenopausal RA. [ABSTRACT FROM AUTHOR]

The objective of the present study was to examine if near infrared reflectance spectroscopy (NIRS) could be used to predict degradation parameters and effective degradation from scans of original forage samples. Degradability of dry matter (DM), crude protein (CP) and neutral detergent fibre (NDF) of 61 samples of perennial ryegrass ( Lolium perenne L.) and orchardgrass ( Dactylis glomerata L.) was tested by using the in situ technique. The grass samples were harvested at three different stages, early vegetative growth, early reproductive growth and late reproductive growth. Degradability was described in terms of immediately rumen soluble fraction ( a fraction, for DM and CP only as NDF does not contain a soluble fraction), the degradable but not soluble faction ( b fraction) and the rate of degradation of the b fraction ( c value). Overall effective degradability of DM, CP and NDF was also calculated. Near infrared reflectance spectroscopy was examined for its ability to predict degradation parameters and to make a direct prediction of effective degradation from scans of the original samples of perennial ryegrass and orchardgrass. Prediction of effective degradation of the different feed fractions showed different accuracy. The coefficients of determination ( R2) from regressions of predicted vs. measured effective degradation, using a cross-validation method, were 0.92 for DM, 0.78 for CP and 0.61 for NDF. The attempt to predict the degradation parameters ( a, b and c) by NIRS was less successful as the coefficients of determination for the degradation parameters were low. Concentrations of CP and NDF in the original samples were predicted by using NIRS and the validated R2 value was 0.98 for CP and 0.92 for NDF. It is concluded that using NIRS predictions from scans of original samples is a promising method to obtain values for the effective degradation of DM, CP and NDF in ruminant feeds, but that larger calibration sets are necessary for obtaining improved accuracy. [ABSTRACT FROM AUTHOR]

Erlandsson MC, Islander U, Moverare S, Ohlsson C, Carlsten H. Estrogenic agonism and antagonism of the soy isoflavone genistein in uterus, bone and lymphopoiesis in mice. APMIS 2005;113:317–23.The isoflavone genistein (Gen) is a naturally occurring phytoestrogen found in high concentrations in soy. The biological effects of Gen have been extensively studied. The immunomodulating properties of Gen are, however, less well investigated and the results are contradictory. Our aim was to study possible estrogen agonistic and antagonistic properties of Gen in uterus, bone, lymphopoiesis and B-cell function by comparing effects in castrated and intact female mice, respectively. Oophorectomized (OVX) and sham-operated mice were treated with s.c. doses of 17β-estradiol (E2) (0.16 mg/kg), Gen (50 mg/kg), or vehicle (olive oil) as control. Effects on bone mineral density (BMD) were studied using peripheral quantitative computerized tomography, uterine and thymus weights were examined, lymphopoiesis in thymus and bone marrow was analyzed using flow cytometry, and the frequency of immunoglobulin-producing B cells in bone marrow and spleen was studied using an ELISPOT assay. Gen was clearly antagonizing endogenous estrogen in sham-operated female mice as shown by inhibiting the uterine weight and by increasing the frequency of B lymphopoietic cells in bone marrow. The only agonistic effect of Gen was shown by increased BMD in OVX mice. Our results are discussed in the context of estrogen receptor biology. [ABSTRACT FROM AUTHOR]

Summary 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-α and ER-β in the aged immune system was investigated in 18 months old-wild type (WT), ER-α (ERKO), ER-β (BERKO) and double ER-α and ER-β (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-β-oestradiol (E2)-induced downregulation of B lymphopoietic cells in bone marrow of young ovariectomized mice can be mediated through both ER-α and ER-β. However, only ER-α 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-α and ER-β in the aged immune system. [ABSTRACT FROM AUTHOR]

Abstract Background In the construction of a Kock reservoir for continent urinary diversion, 70 cm of the distal ileum are used. Impaired absorption of bile acids in these patients might cause diarrhoea. Data on the absorption of bile acids in different parts of the human intestine are limited. Methods Biopsies were taken during endoscopy from the duodenum, the terminal ileum or the right colon, and during surgery 10, 50, 100 and 150 cm proximally to the ileo-caecal valve using standard endoscopy biopsy forceps. The biopsy specimens were incubated in vitro with radio-labelled taurocholic acid at 37 °C for 22 or 45 min The radioactivity was determined using the liquid scintillation technique. Results A linear increase in the uptake was observed, with increased concentrations of taurocholic acid between 100 and 500 µm in all specimens tested, that represented passive uptake or unspecific binding. The active uptake could be calculated from the intercept of the line representing passive uptake with the ordinate. The active uptake in the terminal ileum was 3–4 times greater than 100 cm proximal to the valve. Conclusions The active absorption of bile acids in humans can be determined in small biopsy specimens taken using standard biopsy forceps during endoscopy or surgery. This method is suitable for clinical studies of bile acid absorption. Active uptake of bile acids not only takes place in the very distal part of the ileum but also to a considerable degree 100 cm proximally to the ileo-colonic valve. This should be taken into account when selecting the ileal segment for continent urinary diversion. [ABSTRACT FROM AUTHOR]

Summary 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 α (ERα; ERKO mice), lacking ERβ (BERKO mice), lacking both receptors (DERKO mice) or wild-type (wt) littermates were castrated and treated for 2·5 weeks with 30 μg/kg 17β-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 ERα 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 ERα and ERβ are required for complete down-regulation of B lymphopoiesis while only ERα is needed to up-regulate immunoglobulin production in both bone marrow and spleen. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to present prevalence data for overweight and obesity across school age in a large, recent, population-based cohort of children in Gothenburg, Sweden., Methods: We included 66,807 children (48.5% girls) aged 5-18.9 years who had their height and weight measured in school health care 2015-2018. The BMI values were categorised according to the age-dependent cut-offs for overweight and obesity from the International Obesity Task Force (IOTF)., Results: Overall, the prevalence of overweight and obesity for girls and boys was 18.1% and 18.0%, respectively. We observed increasing proportions of overweight (girls 11.5-17.1% and boys 8.4-17.4%) and obesity (girls 3.0-4.2% and boys 2.7-6.1%) with increasing age (p < 0.001 for trend in both sexes). Moreover, girls had higher prevalence of overweight during ages 5.0 to 8.9 years compared with boys (p < 0.001), while boys had higher prevalence of obesity 15.0-18.9 years compared with girls (p < 0.001)., Conclusion: In conclusion, we demonstrate increasing prevalence of overweight and obesity across the entire school age range, as well as differences in prevalences between boys and girls, in a population-based sample of 67,000 children in Gothenburg city, Sweden. Continuous monitoring of schoolchildren, together with effective preventive measures, is crucial to curb the obesity epidemic and its consequences., (© 2021 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci., (© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Objective: Bone loss in arthritis is a complex process characterized by bone erosions and periarticular and generalized bone loss. The antigen-induced arthritis (AIA) model is mainly used to study synovitis and joint destruction, including bone erosions; however, periarticular bone loss has been less extensively investigated. The objectives of this study were to characterize and establish AIA as a model for periarticular bone loss, and to determine the importance of NADPH oxidase 2 (NOX-2)-derived reactive oxygen species (ROS) in periarticular bone loss., Methods: Arthritis was induced in mice by local injection of antigen in one knee; the other knee was used as a nonarthritis control. At study termination, the knees were collected for histologic assessment. Periarticular bone mineral density (BMD) was investigated by peripheral quantitative computed tomography. Flow cytometric analyses were performed using synovial and bone marrow cells., Results: AIA resulted in decreased periarticular trabecular BMD and increased frequencies of preosteoclasts, neutrophils, and monocytes in the arthritic synovial tissue. Arthritis induction resulted in an increased capability to produce ROS. However, induction of arthritis in Ncf1 / mice, which lack NOX-2-derived ROS, and control mice resulted in similar reductions in periarticular trabecular BMD., Conclusion: The initiation of AIA resulted in periarticular bone loss associated with local effects on inflammatory cells and osteoclasts. Furthermore, based on our observations using this model, we conclude that NOX-2-derived ROS production is not essential for inflammation-mediated periarticular bone loss. Thus, AIA can be used as a model to investigate the pathogenesis of local inflammation-mediated bone loss., (© 2013 The Authors. Arthritis & Rheumatism is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Gastrectomy (Gsx) is associated with altered emotional function and a predisposition to depression/anxiety disorders. Here we investigated the effects of Gsx on emotional reactivity in rats and explored the underlying neurobiological mechanisms. Gsx- and sham-operated rats were exposed to behavioural tests that explore anxiety- and depression-like behaviour (open field, black and white box, elevated plus maze, social interaction, forced swim) as well as memory (object recognition). The potential neurobiological mechanisms underlying these differences were explored by measuring (i) turnover of candidate neurotransmitter systems in the nucleus accumbens, (ii) hippocampal neurogenesis by BrdU labelling or by analysis of candidate genes involved in neuronal growth and (iii) changes in mRNA expression of candidate genes in dissected hippocampal and amygdala tissue. Data from individual behavioural tests as well as from multivariate analysis revealed differing emotional reactivity between Gsx- and sham-operated rats. Gsx rats showed reduced emotional reactivity in a new environment and decreased depression-like behaviour. Accumbal serotonin and dopamine turnover were both reduced in Gsx rats. Gsx also led to a memory deficit, although hippocampal neurogenesis was unaffected. Of the many candidate genes studied by real-time RT-PCR, we highlight a Gsx-associated decrease in expression of Egr-1, a transcription factor linked to neural plasticity and cognition, in the hippocampus and amygdala. Thus, Gsx induces an alteration of emotional reactivity and a memory/cognitive deficit that is associated with reduced turnover of serotonin and dopamine in the nucleus accumbens and decreased expression of Egr-1 in the hippocampus and amygdala., (© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Objective: In postmenopausal rheumatoid arthritis (RA), both estrogen deficiency and the inflammatory disease contribute to the development of generalized osteoporosis. Hormone replacement therapy (HRT) with estradiol preserves bone mineral density (BMD) and ameliorates arthritis, but long-term therapy is no longer an option due to significant side effects. We therefore used a mouse model of human RA to test the hypothesis that a selective estrogen receptor modulator (SERM), the raloxifene analog LY117018, could be beneficial in the treatment of both arthritis and osteoporosis., Methods: Female DBA/1 mice were ovariectomized and arthritis was induced with collagen immunization. Mice received an injection of raloxifene, estradiol, or vehicle control, administered prophylactically or therapeutically, and thereafter the clinical arthritis score was evaluated continuously. At termination, BMD was analyzed with peripheral quantitative computed tomography. Paws were collected for histology, and sera were analyzed for cytokines and markers of bone and cartilage turnover. Levels of cytokine messenger RNA (mRNA) were investigated with real-time polymerase chain reaction., Results: Treatment with raloxifene dramatically decreased the frequency and severity of arthritis. Effective preservation of bone and cartilage was seen in raloxifene-exposed mice, as demonstrated by increased BMD and decreased serum levels of cartilage oligomeric matrix protein in the raloxifene-treated mice compared with controls. Decreased levels of mRNA for both tumor necrosis factor alpha and RANKL in spleen cells from raloxifene-treated arthritic mice indicated an immunosuppressive action of this SERM., Conclusion: In a well-established model of postmenopausal RA, the raloxifene analog LY117018 potently inhibits the progression of arthritis and the associated development of osteoporosis, both in a prophylactic and in a therapeutic regimen. Since long-term HRT has been associated with significant side effects, raloxifene may be a useful adjuvant treatment for postmenopausal RA.

Aim: To investigate if postoperative treatment with dexamethasone eye drops has the capacity to affect longitudinal growth in newborn rabbits., Methods: Thirty-four male and female rabbits had clear lens extraction performed in one eye at 3 wk of age and were then treated either intensively (group 1) or less intensively (group 2) with de-escalating doses of dexamethasone eye drops for 8 wk (average doses 0.27 and 0.10 mg/kg body weight/day, respectively). The control group (group 3) received vehicle eye drops only. Body weight and crown-rump length were recorded every week. After 8 wk of treatment, all rabbits were killed and the left femur was measured., Results: Rabbits treated with dexamethasone eye drops gained weight slower (711+/-42 and 989+/-153 g weight increase for groups 1 and 2, respectively) than control animals (group 3; 1224+/-87 g weight increase; p<0.001 vs group 1, p<0.01 vs group 2). Longitudinal growth, determined as increase in crown-rump and femur lengths, was impaired by dexamethasone eye drops in a dose-dependent way. Crown-rump length increased by 8.25+/-0.86, 10.90+/-1.19 and 15.35+/-1.31 cm in groups 1, 2 and 3, respectively (p<0.001 for all comparisons). At endpoint, i.e. after 8 wk of treatment, the average femur length was 6.36+/-0.21, 7.39+/-0.27 and 8.37+/-0.28 cm in groups 1, 2 and 3, respectively (p<0.001 for all comparisons)., Conclusion: Dexamethasone, administered topically as eye drops, has systemic effects and impairs longitudinal growth in young rabbits. Therefore, we propose that growth should be closely monitored in all children intensively treated with glucocorticoid eye drops.