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Inflammatory polyarthritis can be a self-limiting disease, develop into rheumatoid arthritis (RA) or differentiate into another form of chronic arthritis. It remains a clinical and scientific challenge to understand the relationship between these phenotypes, determine their aetiologies and predict the course and outcome for individual patients. Even patients labelled as having RA show a wide spectrum of clinical phenotypes. Disease definition is a major problem in studying the aetiology of RA as currently used classification criteria were derived using patients with established disease. RA is thought to result from the combination of genetic susceptibility and exposure to an appropriate environmental trigger. The genetic component is probably oligogenic. The association with HLA has been known for over 25 years. RA is now thought to be associated with a conserved sequence of amino acids in a number of HLA-DRB1 alleles, called the RA shared epitope. However, the shared epitope appears to be associated with RA chronicity and severity more than with susceptibility. Other potential RA susceptibility genes include IL-1, aromatase, corticotropin-releasing hormone and a region on the X chromosome. Hormonal and reproductive factors also influence RA susceptibility and severity. RA is more common in women than men, especially before the menopause. Men may be protected by hormonal factors and require a stronger genetic component to develop disease. Although infectious triggers of RA have long been suspected, no definitive evidence has been obtained. Previous blood transfusion, smoking and obesity are also possible risk factors. Chronicity and remission are important aspects of the natural history of early RA. Although we can identify patients at risk of adverse prognosis with some accuracy, we remain unable to predict remission. Functional disability and radiological damage are the most studied outcomes in RA. Radiological damage often occurs early in the course of RA, but patients may show erosion for the first time several years after symptom onset. Many studies have demonstrated a relationship between HLA and features of severe RA in established patients. This appears to be related to gene dosage.
Best Pract Res Clin Rheumatol 2001 Mar
PMID:What is the natural history of rheumatoid arthritis? 1135 13

Two isoforms of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert the active glucocorticoid, cortisol, and inactive cortisone. 11beta-HSD1 is believed to act in vivo predominantly as an oxo-reductase using NADP(H) as a cofactor to generate cortisol. In contrast, 11beta-HSD2 acts exclusively as an NAD-dependent dehydrogenase inactivating cortisol to cortisone, thereby protecting the mineralocorticoid receptor from occupation by cortisol. In peripheral tissues, both enzymes serve to control the availability of cortisol to bind to the corticosteroid receptors. Defective expression of 11beta-HSD2 is implicated in patients with hypertension and intra-uterine growth retardation, while 11beta-HSD1 appears to be intricately involved in the conditions of apparent cortisone reductase deficiency, insulin resistance and visceral obesity. The ability of peripheral tissues to regulate corticosteroid concentrations through 11beta-HSD isozymes is established as an important mechanism in the pathogenesis of diverse human diseases. Modulation of enzyme activity may offer a novel therapeutic approach to treating human disease while circumventing the consequences of systemic glucocorticoid excess or deficiency.
Best Pract Res Clin Endocrinol Metab 2001 Mar
PMID:Cortisol metabolism and the role of 11beta-hydroxysteroid dehydrogenase. 1146 11

Preceding chapters in this volume describe relatively rare conditions associated with qualitative rather than quantitative changes in enzymes involved in steroid synthesis and metabolism. In this chapter, several examples show how more subtle variations in activities of the same enzymes may be important in the pathophysiology of common diseases of complex aetiology. This chapter reviews evidence for deranged steroid metabolism in patients with the 'insulin resistance syndrome'. In summary, patients with essential hypertension may have subtle 11beta-hydroxylase or 11beta-hydroxysteroid dehydrogenase type 2 deficiency resulting in mild mineralocorticoid excess. Patients with obesity, and/or associated hirsutism or hyperglycaemia, have evidence of altered peripheral metabolism of androgens (increased 5alpha-reductase) and glucocorticoids (altered 11beta-hydroxysteroid dehydrogenase type 1, resulting in enhanced cortisol levels in adipose tissue). Some of these changes in steroid metabolism lend themselves to therapeutic manipulation which may provide novel strategies to reduce cardiovascular risk.
Best Pract Res Clin Endocrinol Metab 2001 Mar
PMID:Steroid metabolism in metabolic syndrome X. 1146 14

Endometrial cancer is the commonest gynaecological cancer mostly affecting women in the post-menopausal age group. Rates vary worldwide and are highest in white women in Western populations. Some risk factors are related to reproduction, such as early age at menarche, late age at menopause and nulliparity, while others are more directly oestrogen-related, for example, conditions such as the polycystic ovarian syndrome. Use of unopposed oestrogen replacement therapy is associated with an increased risk, and use of the combined oral contraceptive pill is associated with a decreased risk. The relationship between tamoxifen and endometrial cancer is not established. Obesity, diabetes and hypertension increase the risk of endometrial cancer while smoking, low-fat diets and physical exercise appear to decrease the risk; all of these possibly exert their effects by various indirect influences on oestrogen levels, thus influencing the level of stimulation of the target endometrial epithelium.
Best Pract Res Clin Obstet Gynaecol 2001 Jun
PMID:Epidemiology of endometrial cancer. 1147 57

Women suffering from type-2 diabetes mellitus (NIDDM) show a more android fat pattern than healthy females, but to date no exact determination of their fat distribution differences exists. Measurements at 15 specified body sites with an optical device, the LIPOMETER, provide a subcutaneous adipose tissue topography (SAT-Top) of the individual. SAT-Top of 20 female NIDDM patients and 122 healthy controls was measured. ROC curve analysis was applied to evaluate the discriminative power of each body site and to provide cutoff values. Then a classification tree by the CART algorithm was established, showing SAT-Top differences between the two groups. Best discriminating results were achieved by the neck site (ROC area index = 0.76, sensitivity = 61.3%, specificity = 77.8%), the four sites of the thigh (area indices from 0.71 to 0.76), and a linear combination of all body sites stemming from a previous factor analysis, which provides condensed information of the extremities SAT-Top (area index = 0.80, sensitivity = 80.4%, specificity = 64.6%). The results could be improved by a summary measure of "android fat pattern" (area index = 0.89, sensitivity = 73.6%, specificity =88.3%) and a proportional measure of SAT-distribution, the relative neck (area index = 0.84, sensitivity = 83.0%, specificity = 70.5%). Overall, 136 (95.8%) of the 142 subjects were correctly classified by the classification tree (sensitivity = 75%, specificity = 99.2%). Both methods show the expected increased upper trunk obesity and decreased lower body obesity of NIDDM women compared with healthy females. Am. J. Hum. Biol. 12:388-394, 2000. Copyright 2000 Wiley-Liss, Inc.
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PMID:ROC and CART analysis of subcutaneous adipose tissue topography (SAT-Top) in type-2 diabetic women and healthy females. 1153 29

Obesity is a multifactorial condition. Environmental risk factors related to a sedentary life-style and unlimited access to food apply constant pressure in subjects with a genetic predisposition to gain weight. The fact that genetic defects can result in human obesity has been unequivocally established over the past 3 years with the identification of the genetic defects responsible for different monogenic forms of human obesity: the leptin, leptin receptor, pro-opiomelanocortin, pro-hormone convertase-1 and melanocortin-4 receptor genes. The common forms of obesity are, however, polygenic. The examination of specific genes for involvement in the susceptibility to common obesity has not yet yielded convincing results. Approaches involving the candidate genes and the positional cloning of major obesity-linked regions (state-of-the-art future prospects) will be discussed.
Best Pract Res Clin Endocrinol Metab 2001 Sep
PMID:Genetics of human obesity. 1155 78

The aim of the study was to determine the influence of adiposity on the relationship between bioelectrical impedance (BIA) measurements of body segments and estimation of body composition by dual-energy X-ray absorptiometry (DXA). Multiple frequencies of whole body and segmental impedances were measured in 68 normal-weight and obese subjects (46 women and 22 men), mean age 37.2+/-14.8 years (range, 18-69). Total and appendicular lean body mass (LBM) assessed by DXA correlated significantly with total and segmental impedance values adjusted for stature in both obese and normal-weight subjects. Best fitting equations for the prediction of appendicular LBM from segmental impedance measurements were derived for the arm and leg with and without the inclusion of adiposity (the percentage of body fat measured by DXA) in the regression models. Best prediction was obtained at low frequency for the arm and high frequency for the leg. Adiposity appears to significantly influence the prediction of leg LBM by BIA. These preliminary observations need further validation to provide an accurate assessment of appendicular LBM assessment by BIA.
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PMID:Prediction of lean body mass from multifrequency segmental impedance: influence of adiposity. 1175 8

A continuum of increasing risk of adulthood diseases, such as cardiovascular disease, type 2 diabetes and hypertension, with decreasing size at birth is now well-reported and a number of different hypotheses have been proposed. Birthweight links with disease risk markers such as insulin resistance are apparent from childhood, particularly when low birthweight is followed by rapid postnatal weight gain and childhood obesity. Such growth patterns follow fetal growth restraint, associated with maternal-uterine factors such as primiparity, smoking, maternal genes or variations in maternal diet. The fetal metabolic and hormonal responses to intrauterine growth restraint and to rapid postnatal growth are likely to be key to the early pathogenesis of adulthood disease. Thrifty fetal genotypes may enhance these adaptations and improve perinatal survival but predispose to adulthood disease. Their historical selection could explain high prevalences of type 2 diabetes in some ethnic groups, and their identification could allow targeting of potential interventions.
Best Pract Res Clin Endocrinol Metab 2002 Jun
PMID:Perinatal growth failure: the road to obesity, insulin resistance and cardiovascular disease in adults. 1206 88

Polycystic ovary syndrome (PCOS) frequently presents during adolescence and is the commonest cause of menstrual irregularity and hirsutism. The characteristic endocrine abnormalities include hypersecretion of androgens and LH. Metabolic dysfunction is also a feature of many young women with PCOS. Hyperinsulinaemia and insulin resistance, which can be regarded as an exaggeration of the normal metabolic changes that occur during puberty, are further amplified by obesity. The aetiology of PCOS is uncertain but there is evidence for a primary abnormality of ovarian androgen production which is manifest at puberty but may have its origins in childhood or even during fetal development.
Best Pract Res Clin Endocrinol Metab 2002 Jun
PMID:Adult polycystic ovary syndrome begins in childhood. 1206 92

Somatostatin (SMS) is a potent inhibitory molecule. It inhibits both exocrine and endocrine secretory functions of the pancreas, suppresses growth hormone secretion and reduces the level of insulin-like growth factor-1. Long-acting somatostatin analogues were currently investigated for potential clinical benefits in two settings: (a) control of hyperinsulinaemia in obesity and (b) control of an excess of pro-angiogenic factors in diabetes-associated retinal complications. In two randomized, controlled trials the long-acting somatostatin analogue octreotide retarded progression of the microvascular complications in pre-proliferative and advanced stages of diabetic retinopathy. Inhibition of the early phase of insulin secretion by use of octreotide in patients with hypothalamic obesity resulted in weight loss and improved quality of life. Efficacy of octreotide correlated to residual beta-cell activity prior to the treatment. Obesity and diabetes mellitus are the most common chronic metabolic disorders in the world. The use of somatostatin analogues addressing the various hormonal imbalances of these disorders may provide a novel concept for their pharmacological treatment.
Best Pract Res Clin Gastroenterol 2002 Jun
PMID:Use of somatostatin receptor ligands in obesity and diabetic complications. 1207 71


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