Educational level and use of osteoporosis drugs in elderly men and women: a Swedish nationwide register-based study.

SUMMARY: We examined educational disparities in use of osteoporosis drugs in a nationwide population of Swedes aged 75-89 years old. Individuals with high education were more likely to receive osteoporosis drug treatment than lower educated individuals, particularly among women. INTRODUCTION: This study aims to investigate whether educational level is associated with use of osteoporosis drugs in the general population of older men and women in Sweden, also after adjustment for fractures. METHODS: By record linkage of The Swedish Prescribed Drug Register, The Swedish Patient Register, and The Swedish Education Register, we obtained information on filling of prescriptions for osteoporosis drugs (bisphosphonates, calcium/vitamin D combinations, and selective estrogen receptor modulators) from July to October 2005, osteoporotic fractures from 1998 to 2004, and educational level for 645,429 people aged 75-89 years. Multivariate logistic regression analysis was used to investigate whether education was associated with use of osteoporosis drug therapy. RESULTS: Higher education was associated with use of osteoporosis drugs for both men [odds ratio (OR)(high education vs low), 1.27; 95% confidence interval (CI), 1.19-1.35] and women (OR(high education vs low), 1.57; 95% CI, 1.52-1.61), after adjustment for age, osteoporotic fractures, and comorbidity (i.e., number of other drugs). Among those who had sustained a fracture (n = 57,613), the educational differences in osteoporosis drug treatment were more pronounced in women than men. Further, women were more likely to receive osteoporosis drug treatment after osteoporotic fracture. CONCLUSION: Uptake of osteoporosis drug therapy seems to be unequally distributed in the elderly population, even in a country with presumably equal access to health care.

Cognitive impairments in adult mice with constitutive inactivation of RIP140 gene expression.

Receptor-interacting protein 140 (RIP140) is a negative transcriptional coregulator of nuclear receptors such as estrogen, retinoic acid or glucocorticoid receptors. Recruitment of RIP140 results in an inhibition of target gene expression through different repressive domains interacting with histone deacetylases or C-terminal binding proteins. In this study, we analyzed the role of RIP140 activity in memory processes using RIP140-deficient transgenic mice. Although the RIP140 protein was clearly expressed in the brain (cortical and hippocampus areas), the morphological examination of RIP140(-/-) mouse brain failed to show grossly observable alterations. Using male 2-month-old RIP140(-/-) , RIP140(+/-) or RIP140(+/+) mice, we did not observe any significant differences in the open-field test, rotarod test and in terms of spontaneous alternation in the Y-maze. By contrast, RIP140(-/-) mice showed long-term memory deficits, with an absence of decrease in escape latencies when animals were tested using a fixed platform position procedure in the water maze and in the passive avoidance test. Noteworthy, RIP140(-/-) mice showed decreased swimming speed, suggesting swimming alterations that may in part account for the marked alterations measured in the water maze. Moreover, RIP140(+/-) and RIP140(-/-) mice showed a significant increase in immobility time in the forced swimming test as compared with wild-type animals. These observations showed that RIP140 gene depletion results in learning and memory deficits as well as stress response, bringing to light a major role for this transcriptional coregulator in the neurophysiological developmental mechanisms underlying cognitive functions.

Kidney allograft biopsy: timing to complications.

BACKGROUND: Clinical Practice guidelines recommend that patients be observed overnight after kidney biopsy based upon data that 1/3 of bleeding complications occur 12 hours post-procedure. Retrospective studies of same day discharge after kidney allograft biopsy suggest this practice may be safe, but no prospective studies to date have examined time to bleeding complications. METHODS: We conducted a single center, prospective, observational study of adult outpatient kidney allograft recipients undergoing elective percutaneous allograft biopsy who were observed for 8 hours post-procedure before discharge home. Bleeding complications were characterized as minor or major and tracked by time post-biopsy. Baseline demographics were assessed for correlation with complications. RESULTS: 8/124 (6.4%) of patients had a bleeding complication and 7/8 (87.5%) of complications occurred within the observation window. 3.2 % were minor and 3.2% were major complications with one major complication occurring after the 8-hour period. Neither the baseline demographics nor drop in serum hemoglobin of > 1 g/dl 6 hours after biopsy predicted a bleeding complication. However, a drop of > 1.5 g/dl correlated with a significant bleeding event (p = 0.006). CONCLUSIONS: An 8-hour observation window captures the majority of bleeding complications after adult kidney transplant biopsy.

A premature infant with fetal myocardial and abdominal calcifications and factor V Leiden homozygosity.

We present a premature male neonate with confirmed factor V Leiden deficiency diagnosed prenatally with cardiac and abdominal calcifications. Our patient's findings suggest that clinicians consider thromboembolic conditions when multiple fetal calcifications are visualized.

Conditionally immortalized white preadipocytes: a novel adipocyte model.

This study describes a novel approach to generate conditionally immortalized preadipocyte cell lines from white adipose tissue (IMWAT) that can be induced to differentiate into white adipocytes even after expansion in culture. Such adipocytes express markers of white fat such as peroxisome proliferator-activated receptor gamma and aP2 but not brown fat markers, have an intact insulin signaling pathway, and express proinflammatory cytokines. They can be readily transduced with adenoviral vectors, allowing them to be used to investigate the consequences of the depletion of specific adipocyte factors using short hairpin RNA. This approach has been used to study the effect of reduced expression of the nuclear receptor corepressor receptor interacting protein 140 (RIP140), a regulator of adipocyte function. The depletion of RIP140 results in changes in metabolic gene expression that resemble those in adipose tissue of the RIP140 null mouse. Thus, IMWAT cells provide a novel model for adipocytes that are derived from preadipocytes rather than fibroblasts and provide an alternative system to primary preadipocytes for the investigation of adipocyte function.

Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression.

Prostate tumour growth depends on androgens; hence treatment includes androgen ablation and anti-androgens. Eventually tumours progress and in approximately 30% of patients this is associated with mutation of the androgen receptor. Several receptor variants associated with advanced disease show promiscuous activation by other hormones and anti-androgens. Such loss of specificity could promote receptor activation, hence tumour growth, in the absence of conventional ligands, explaining therapy failure. We aimed to elucidate mechanisms by which alternative ligands promote receptor activation. The three most commonly identified variants in tumours (with amino-acid substitutions H874Y, T877A and T877S) and wild-type receptor showed differences in co-activator recruitment dependent upon ligand and the interaction motif utilized. Co-expression and knockdown of co-activators that bind via leucine or phenylalanine motifs, combined with chromatin immunoprecipitation and quantitative PCR, revealed these preferences extend to co-activator recruitment in vivo and affect receptor activity at the transcriptional level, with subsequent effects on target gene regulation. The findings suggest that mutant receptors, activated by alternative ligands, drive growth via different mechanisms to androgen-activated wild-type receptor. Tumours may hence behave differently dependent upon any androgen receptor mutation present and what ligand is driving growth, as distinct subsets of genes may be regulated.

The nuclear receptor co-repressor RIP140 controls the expression of metabolic gene networks.

NRs (nuclear receptors) regulate the expression of specific gene networks in target cells by recruiting cofactor complexes involved in chromatin remodelling and in the assembly of transcription complexes. The importance of activating gene expression, in metabolic tissues, is well established, but the contribution of transcriptional inhibition is less well defined. In this review, we highlight a crucial role for RIP140 (receptor-interacting protein 140), a transcriptional co-repressor for NR, in the regulation of metabolic gene expression. Many genes involved in lipid and carbohydrate metabolism are repressed by RIP140 in adipose and muscle. The repressive function of RIP140 results from its ability to bridge NRs to repressive enzyme complexes that modify DNA and histones. In the absence of RIP140, expression from many metabolic genes is increased so that mice exhibit a lean phenotype and resistance to high-fat-diet-induced obesity and display increased glucose tolerance and insulin sensitivity. We propose that a functional interplay between transcriptional activators and the co-repressor RIP140 is an essential process in metabolic regulation.

Identification of novel oestrogen receptor target genes in human ZR75-1 breast cancer cells by expression profiling.

Oligonucleotide microarrays were used to analyse gene expression profiles in human ZR75-1 breast cancer cells in the presence of 17beta-oestradiol and oestrogen antagonists. Differential gene expression of a number of genes was confirmed by quantitative RNA analysis. In addition to known oestrogen-responsive genes, an appreciable number of novel targets were identified, including growth factors and components of the cell cycle, adhesion molecules, enzymes, signalling molecules and transcription factors. The most pronounced oestrogen-sensitive gene was that for the cytochrome P450-IIB enzyme, involved in metabolising steroids and xenobiotics, which was increased 100-fold over a 24 h period. It is a direct target gene for oestrogens, because its expression was increased in the presence of cyclohexamide. In contrast, expression of cytochrome P450-IIB was not detected in human MCF7 breast cancer cells. Expressions of the cationic amino acid transporter E16, gap junction protein and insulin-like growth factor binding protein 4 were also markedly increased by oestrogens, but the kinetics of induction varied according to the target gene. With the exception of the cationic amino acid transporter E16 and the insulin-like growth factor binding protein 4, the expression of the majority of the genes was unaffected by antioestrogen treatment. Further analysis of this set of markers will provide alternative approaches to the investigation of the mitogenicity of oestrogens in breast cancer cells.

Cross-talk between Stat5b and estrogen receptor-alpha and -beta in mammary epithelial cells.

Both 17beta-estradiol and prolactin play important roles in the mammary gland, raising the possibility of functional cross-talk between the two signaling pathways. Here, we demonstrate that estrogen receptor-alpha (ERalpha) and -beta (ERbeta) are both able to potentiate transcription from a Stat5-responsive promoter when activated by prolactin. Potentiation was observed not only in the presence of 17beta-estradiol, but also in the presence of anti-estrogens such as tamoxifen and ICI 182,780. The magnitude of the response was dependent on cell-type: in the HC11 mouse mammary epithelial cell line ERbeta potentiates transcription efficiently whereas ERalpha showed low activity. Conversely, in COS-7 cells, both estrogen receptors were active. We show that activation domains in the N-terminus (AF-1) and the C-terminus (AF-2) of the ERs are dispensable for potentiation. The effects are dependent on the presence of an intact DNA-binding/hinge domain, which we show is capable of interacting with Stat5b in vitro and in HC11 cell extracts. We conclude that ERalpha and ERbeta act as coactivators for Stat5b through a mechanism which is independent of AF-1 and AF-2.

Use of suppressor mutants to probe the function of estrogen receptor-p160 coactivator interactions.

Estrogen-dependent recruitment of coactivators by estrogen receptor alpha (ERalpha) represents a crucial step in the transcriptional activation of target genes. However, studies of the function of individual coactivators has been hindered by the presence of endogenous coactivators, many of which are potentially recruited in the presence of agonist via a common mechanism. To circumvent this problem, we have generated second-site suppressor mutations in the nuclear receptor interaction domain of p160 coactivators which rescue their binding to a transcriptionally defective ERalpha that is refractory to wild-type coactivators. Analysis of these altered-specificity receptor-coactivator combinations, in the absence of interference from endogenous coregulators, indicated that estrogen-dependent transcription from reporter genes is critically dependent on direct recruitment of a p160 coactivator in mammalian cells and that the three p160 family members serve functionally redundant roles. Furthermore, our results suggest that such a change-of-specificity mutation may act as a transposable protein-protein interaction module which provides a novel tool with which to dissect the functional roles of other nuclear receptor coregulators at the cellular level.

An outcomes analysis and satisfaction survey of 199 consecutive abdominoplasties.

Abdominoplasty is a popular body-contouring procedure. In this study the authors review retrospectively 199 abdominoplasty patients during a 15-year period to identify factors that affect overall outcome. Patients included 190 women and 9 men. The complication rate was 32% with few major complications (1.4%). The revision rate was 43%, and was related to fine-tuning the aesthetic appearance. Patients were divided into four groups based on tobacco use and history of diabetes and hypertension. There was no significant difference in revision rates or major complications between the subgroups. Minor complication rates, however, were significantly higher in smokers and patients with diabetes and/or hypertension. Complication and revision rates in patients undergoing intra-abdominal procedures combined with abdominoplasty were not significantly different from those patients undergoing abdominoplasty alone. A patient survey revealed symptom improvement in 95% of patients. Eighty-six percent of patients were satisfied with their result, and 86% would recommend abdominoplasty to a friend. The authors conclude that abdominoplasty is a safe and satisfying procedure, whether performed alone or in conjunction with another procedure. Patients are pleased with the outcome and have improvement in their symptoms, with minimal health risk. There is, however, a significant incidence of minor complications, related primarily to wound healing. These complications are increased significantly in smokers and patients with diabetes and/or hypertension. Revision rates are not different significantly between the subgroups. When complications do occur or revisions are required, they are minor and managed easily in an office setting.

Core LXXLL motif sequences in CREB-binding protein, SRC1, and RIP140 define affinity and selectivity for steroid and retinoid receptors.

An alpha-helical motif containing the sequence LXXLL is required for the ligand-dependent binding of transcriptional co-activators to nuclear receptors. By using a peptide inhibition assay, we have defined the minimal "core" LXXLL motif as an 8-amino acid sequence spanning positions -2 to +6 relative to the primary conserved leucine residue. In yeast two-hybrid assays, core LXXLL motif sequences derived from steroid receptor co-activator (SRC1), the 140-kDa receptor interacting protein (RIP140), and CREB-binding protein (CBP) displayed differences in selectivity and affinity for nuclear receptor ligand binding domains. Although core LXXLL motifs from SRC1 and RIP140 mediated strong interactions with steroid and retinoid receptors, three LXXLL motifs present in the global co-activator CBP were found to have very weak affinity for these proteins. Core motifs with high affinity for steroid and retinoid receptors were generally found to contain a hydrophobic residue at position -1 relative to the first conserved leucine and a nonhydrophobic residue at position +2. Our results indicate that variant residues in LXXLL core motifs influence the affinity and selectivity of co-activators for nuclear receptors.

Influence of sociocultural and structural factors on functional ability: the case of elderly people in Bangladesh.

OBJECTIVE: To describe and contextualize functional status of elderly people (greater or lesser than 60 years) in Bangladesh by relating it to gender, region, and socioeconomic status. METHODS: In this community-based study (N = 696), functional status was described through assessment of activities of daily living (ADL) and instrumental activities of daily living (IADL). Information was obtained on type of help used for ADLs and IADLs and reason for nonperformance of IADLs. RESULTS: Findings indicate differential performance in ADLs and IADLs by gender and region. Socioeconomic status is found to influence IADLs only. Empirical evidence regarding type of help used and reason for not performing a task enables understanding of sociocultural and structural influence on functional ability. DISCUSSION: The underlying assumption of ADL and IADL instruments that an individual will perform an activity given physical or cognitive ability is questioned. It is suggested that sociocultural and structural factors are strong determinants of task performance.

Priorities in care and services for elderly people: a path without guidelines?

The growing gap between demands and resources is putting immense pressure on all government spending in Sweden. The gap is especially apparent in care and services for elderly people in light of the rapid aging of the population. The article considers the decisions and priorities concerning resource allocation in the welfare sector in general and in elderly care in particular. The aim is to describe the political and administrative setting and to provide a conceptual structure that outlines the nature of the problem. Various levels of decision making are identified and discussed in the context of political accountability. Current transitions in elderly care are described with respect to service provision, marketisation, coverage rates, and eligibility standards. Basic principles of distribution are highlighted in order to clarify some central concepts of efficiency and justice, and a number of strategies for actual prioritising are identified. The article concludes with an endorsement of more conscious decisions in resource allocation. Existing knowledge and information concerning the effects of various strategies must be utilised, and the values and assumptions used for setting priorities must be made explicit.

Differential effects of xenoestrogens on coactivator recruitment by estrogen receptor (ER) alpha and ERbeta.

It has been proposed that tissue-specific estrogenic and/or antiestrogenic actions of certain xenoestrogens may be associated with alterations in the tertiary structure of estrogen receptor (ER) alpha and/or ERbeta following ligand binding; changes which are sensed by cellular factors (coactivators) required for normal gene expression. However, it is still unclear whether xenoestrogens affect the normal behavior of ERalpha and/or ERbeta subsequent to receptor binding. In view of the wide range of structural forms now recognized to mimic the actions of the natural estrogens, we have assessed the ability of ERalpha and ERbeta to recruit TIF2 and SRC-1a in the presence of 17beta-estradiol, genistein, diethylstilbestrol, 4-tert-octylphenol, 2',3',4', 5'-tetrachlorobiphenyl-ol, and bisphenol A. We show that ligand-dependent differences exist in the ability of ERalpha and ERbeta to bind coactivator proteins in vitro, despite the similarity in binding affinity of the various ligands for both ER subtypes. The enhanced ability of ERbeta (over ERalpha) to recruit coactivators in the presence of xenoestrogens was consistent with a greater ability of ERbeta to potentiate reporter gene activity in transiently transfected HeLa cells expressing SRC-1e and TIF2. We conclude that ligand-dependent differences in the ability of ERalpha and ERbeta to recruit coactivator proteins may contribute to the complex tissue-dependent agonistic/antagonistic responses observed with certain xenoestrogens.

Mobility limitations in the Swedish population from 1968 to 1992: age, gender and social class differences.

Mobility limitations are closely related to disability in old age. The study of mobility limitations in the population may improve the understanding of the development of disability, as well as gender and class patterns in disability in old age. Representative samples of the Swedish population between the ages of 18 and 75 years were interviewed in 1968, 1974, 1981, and 1991. A further sample of people aged 76+ years was interviewed in 1992. The questionnaire included the ability to walk 100 meters, to walk up and down stairs, and to run 100 meters. Mobility limitations begin to appear around age 40 years, and increase with age. In 1992 nearly none in the oldest age group (85+) could run 100 meters, and less than half could walk 100 meters, or go up and down stairs without difficulty. Between 1968 and 1991, the proportion of people with mobility limitations was reduced by one third, with the most prominent reduction among the oldest age groups. Women were more likely to report mobility limitations compared to men at all waves; however, the gender difference decreased between 1968 and 1991. Blue-collar workers had more mobility limitations than white-collar workers, and this discrepancy did not decrease over time. Mobility limitations often begin early in life, and differences between cohorts, men and women, and social classes can be seen well before the age of 50. The results suggest that gender differences in functional limitations among elderly people may decrease in the future, while social class inequalities are likely to persist.

Functional interaction between the p160 coactivator proteins and the transcriptional enhancer factor family of transcription factors.

SRC1, initially identified as a nuclear receptor coactivator, was found to interact with a member of the transcriptional enhancer factor (TEF) family of transcription factors, TEF-4. The interaction, which occurs in both intact cells and in a cell-free system, is mediated by the highly conserved basic helix-loop-helix/Per-Arnt-Sim (bHLH-PAS) domain present in the N-terminal region of SRC1. Moreover, all three members of the p160 family of nuclear receptor coactivators, SRC1, TIF2, and RAC3, are able to potentiate transcription from a TEF response element in transient transfection experiments, and this activation requires the presence of the bHLH-PAS domain. These results suggest that the p160 proteins could be bona fide coactivators of the TEF family of transcription factors.

Mutations in the estrogen receptor ligand binding domain discriminate between hormone-dependent transactivation and transrepression.

The estrogen receptor (ER) suppresses transcriptional activity of the RelA subunit of nuclear factor-kappaB in a hormone-dependent manner by a mechanism involving both the receptor DNA binding domain and ligand binding domain (LBD). In this study we examine the role of the ER LBD in mediating ligand-dependent RelA transrepression. Both ERalpha and ERbeta inhibit RelA in response to 17beta-estradiol but not in the presence of antihormones. We have identified residues within the ERalpha LBD that are responsible for receptor dimerization and show that dimerization is necessary for transactivation and transrepression. Moreover we have generated mutant receptors that have lost their ability to inhibit RelA but retain their capacity to stimulate transcription and conversely mutants that are transcriptionally defective but capable of antagonizing RelA. Overexpression of p160 and cAMP-response element-binding protein-binding protein/p300 co-activators failed to relieve repression of RelA, which is consistent with the demonstration that RelA inhibition can occur independently of these co-activators. These findings suggest it is unlikely that sequestration of these cofactors required for ER transcriptional activation can account for hormone-dependent antagonism of RelA. The identification of ER mutants that discriminate between transactivation and transrepression implies that distinct surfaces within the LBD are involved in mediating these two receptor functions.

Panniculectomy at the time of gynecologic surgery in morbidly obese patients.

OBJECTIVE: Our goal was to demonstrate that panniculectomy performed at the time of gynecologic surgery aids in reducing the operative time and exposure and does not increase the wound infection rate in morbidly obese patients. STUDY DESIGN: A retrospective survey was performed of massively obese patients who underwent panniculectomy at the time of gynecologic surgery at Northeastern Ohio Universities College of Medicine consortium hospitals from 1990-1999. Data collected during surgery included the patient's weight, operative opening and closing times, blood loss, and weight of the removed panniculus adiposus. Postoperative wound infection rates were monitored, and patients were followed up for 6 months. RESULTS: Seventy-eight patients underwent the following operations: radical hysterectomy (n = 19), extrafascial hysterectomy (n = 18), standard hysterectomy (n = 32), or other gynecologic surgery (n = 9). The average blood loss was 71 mL. Opening and closing times were 27 and 33 minutes, respectively, adding a minimal amount of operative time to the required gynecologic surgery. The average removed panniculus adiposus weighed 4745 g. Efficiency in obtaining exposure to the operative site was noted. A total of 2 wound infections were recorded in the postoperative period. In 1 case debridement was required, and in the other healing occurred by secondary intention. Minimal separation occurred in 4 other cases and required no intervention. CONCLUSION: Massively obese patients can safely undergo panniculectomy simultaneously with a gynecologic procedure. The difficulty with operative exposure is reduced, and these patients are better served intraoperatively. Postoperatively, the wound infection rates quoted for this population were markedly improved from prior studies and involved a larger group of patients.

Cofactor competition between the ligand-bound oestrogen receptor and an intron 1 enhancer leads to oestrogen repression of ERBB2 expression in breast cancer.

Overexpression of the ERBB2 proto-oncogene in breast tumours, which occurs in 25-30% of patients, correlates with poor prognosis. In oestrogen receptor (ER) positive breast epithelial cells oestrogens reduce ERBB2 mRNA and protein levels, an effect that is reversed in the presence of anti-oestrogens such as tamoxifen and ICI 182780. Our previous studies have shown that the major effect of oestrogen on ERBB2 expression is at the level of transcription and that this is mediated through a region within the ERBB2 first intron which can act as an oestrogen-suppressible enhancer in ER positive breast cells. In vitro footprinting of the smallest DNA fragment that retained full activity revealed four transcription factor binding sites. We report here that two of these sites are recognized by AP-2 proteins and the other two are bound by a variety of bZIP factors, including CREB and ATFI, with a major complex containing ATFa/ JunD. However, by using ER mutants it is clear that repression occurs essentially off the DNA. Indeed, the essential domain of the ER responsible for repression of the ERBB2 enhancer is a region termed AF2 which is required for the ligand-dependent association of non-DNA binding cofactors. We further demonstrate that one of these ER cofactors, SRC-1, can relieve oestrogen repression of the ERBB2 enhancer and conclude that these data fit with a model whereby the ER and the ERBB2 enhancer compete for this limiting, non-DNA binding cofactor. Thus, in oestrogenic conditions SRC-1 preferentially binds to the ER which effectively sequesters it thereby reducing enhancer activity, but in antioestrogenic media the cofactor is released from the ER and is therefore available to activate the ERBB2 enhancer.