Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Joint damage occurs when structures protecting the joint fail. Because osteoarthritis consists of end-stage joint damage, I propose that risk factors for disease can be best understood as either impairments of joint protectors, increasing joint vulnerability, or as factors that excessively load the joint, leading to injury. I review current knowledge using this paradigm, separating factors into those increasing joint vulnerability (malalignment, muscle weakness, genetic and ethnic predispositions, aging) and those that cause excessive loading (obesity; certain physical activities). Osteoarthritis and cartilage loss can occur without pain. This review focuses separately on factors associated with pain in those with osteoarthritis. To identify sources of pain in osteoarthritis, recent studies have compared magnetic resonance imaging findings of people with osteoarthritis with and without pain, focusing on structures known to have nociceptive innervations. Those with pain are more likely to have effusions, bone marrow lesions, synovial hypertrophy, and tendinitis and bursitis around the joint. This review creates a new paradigm for understanding risk factors for osteoarthritis, using joint vulnerability and loading as a framework and focuses separately on the emerging investigative area of sources of pain.
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PMID:Risk factors for osteoarthritis: understanding joint vulnerability. 1548 60

Regardless of etiology, all cases of endogenous Cushing's syndrome are due to increased production of cortisol by the adrenal gland. Most are caused by adrenocorticotrophic hormone (ACTH)-secreting pituitary adenomas. Alternatively, the glucocorticoid excess may be due to adrenal neoplasia or to ectopic ACTH-secreting tumors. Cushing's syndrome is characterized by endocrine and metabolic alterations such as truncal obesity, hypertension, weakness, amenorrhea, hyperglycemia, osteoporosis and depression. Unless treated, the disease is associated with high morbidity, and ultimately, mortality. Depending on the etiology of Cushing's syndrome two different treatment modalities are possible: reduction of pituitary ACTH production or reduction of adrenocortical cortisol secretion. In the absence of efficient drug therapy, transsphenoidal resection of the pituitary adenoma is the primary treatment of choice for the reduction of ACTH secretion. In the last years there was much progress in understanding the molecular mechanisms that control the function of the hypothalamic-pituitary-adrenal axis. Thus, new insights made it possible to identify potential drug targets for the treatment of Cushing's syndrome. The present article reviews different drug targets and therapeutic options including drugs that control the central ACTH regulation, e.g. by modulating signaling pathways and transcriptional regulation of ACTH biosynthesis, corticotrophin releasing hormone (CRH) or glucocorticoid receptor antagonists, inhibitors of glucocorticoid synthesis, ketoconazole, somatostatin and dopamine analogs. Some of these substances might be useful for the treatment of Cushing's syndrome.
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PMID:New perspectives in the treatment of Cushing's syndrome. 1557 85

The TSOD mouse has been established as an inbred strain with spontaneous development of diabetes mellitus as the first clinical signs of diabetes. Polydipsia and polyuria are observed at about 2 months old only in male mice, after which hyperglycemia and hyperinsulinemia are detected. Following these symptoms obesity gradually develops until about 12 months old. In histopathological examination of the pancreas, severe hypertrophy of pancreatic islets was observed due to proliferation and swelling of B cells. In the kidney, thickening of the basement membrane in glomeruli and an increase of the mesangial area were observed at 18 months old. Motor neuropathy in TSOD mice began to appear at 14 months old and most male mice at 17 months old showed weakness of front and hind paws caused by neuron degeneration in the peripheral nerve. In sensory neuropathy, the threshold in the tail pressure test decreased significantly at 12 months old. Light microscopic and electron microscopic examination of sciatic nerves showed a decrease in the density of nerve fibers by the endoneural fibrosis and loss of these fibers. Degenerative changes of myelinated fibers, separation of myelin sheaths with intralamellar edema and remyelination were frequently observed. In the severely affected nerve fibers, the lamellar structure was completely destroyed and macrophages migrated around the myelin sheath or invaded the intramyelin space. Considering these findings similar to non-insulin dependent diabetes mellitus (NIDDM) in humans, the TSOD mouse should be a useful model for the pathogenic study of diabetic complications, especially of peripheral neuropathy.
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PMID:Diabetic complications in a new animal model (TSOD mouse) of spontaneous NIDDM with obesity. 1572 83

Osteoarthritis is the most common joint disease, which is associated with considerable morbidity and mortality. It is complex disease whose etiology bridges biomechanics and biochemistry. It is unclear whether osteoarthritis is a single disease or many disorders with a similar final common pathway. We need to clarify the genetics of osteoarthritis and identify risk factors for progression. Until now, there is some evidence growing for the role of systemic factors and of local factors. Systemic factors are thought such as genetics, hormone, and bone density, and local factors are thought such as obesity, injury, sports, occupation, and muscle weakness. However, the impacts of such risk factors in different joints vary. Effective outcome measures are needed to accelerate testing of new treatments.
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PMID:[Pathogenesis and risk factors of osteoarthritis]. 1577 71

Leptin plays a central role in the homeostasis of body weight through its regulatory effects on appetite and energy expenditure, yet in trials as a therapeutic agent for the treatment of obesity in humans it has been disappointing. The poor clinical efficacy of leptin results from its short circulating half-life, low potency and poor solubility, necessitating large and frequent doses to obtain even modest clinical benefit. Engineered Fc-leptin immunofusins, consisting of the Fc fragment of an immunoglobulin gamma chain followed by leptin, exhibit improved pharmacological properties with very consistent and potent biological activities. Furthermore, in extending the circulating half-life of the protein in vivo from a few minutes for leptin to many hours for Fc-leptin, these proteins have the potential to reduce drastically the dosage and frequency of administration required to obtain clinical benefit. The results of this study show that the engineered leptin immunofusins described here have significantly enhanced pharmacological properties in comparison with the recombinant leptin that was used in clinical trials. As such, they could represent an important step towards a therapeutically superior form of leptin if the disappointing performance of leptin in early clinical trials was due to its poor pharmacological properties rather than any conceptual weakness in the strategy of using leptin for the treatment of obesity and its related disorders.
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PMID:Engineering a pharmacologically superior form of leptin for the treatment of obesity. 1579 May 75

Hyperadrenocorticism is a common endocrinopathy which results from the excessive production of cortisol by the adrenal cortex. In the majority of cases, this increased secretion of cortisol results from stimulation of the adrenal cortex by adrenocorticotrophic hormone secreted from the pituitary gland. In a smaller number of cases adrenal tumours are present. Clinical signs are variable but commonly include polydipsia and polyuria, polyphagia, obesity, a pendulous abdomen, hepatomegaly, alopecia, lethargy, weakness and anoestrus. Haematology, serum chemistry analysis and urinalysis should be performed on a dog with suspected hyperadrenocorticism. Finding a significant number of changes that are consistent with hyperadrenocorticism often allows a presumptive diagnosis to be made. Other tests can then be used to confirm the diagnosis and to help localise the cause, including liver biopsy, radiology, ultrasonography, gamma camera imaging, computed tomography, and measurement of blood and urine hormone levels. The ACTH stimulation test, low dose dexamethasone suppression test and measurement of the urine cortisol:creatinine ratio are used to assess whether hyperadrenocorticism is present. The high dose dexamethasone suppression test, measurement of plasma ACTH, corticotropin-releasing hormone stimulation test, and a modification of the urinary cortisol:creatinine ratio test are then implemented to determine the aetiology. The treatment of choice for adrenal neoplasia is surgical removal of the affected adrenal. On the other hand, pituitary hyperplasia or neoplasia may be treated either surgically, by bilateral adrenalectomy or hypophysectomy, or medically. The drug which is chosen most commonly for medical management is 1,1-dichloro-2(O-chlorophenyl)-2-(P-chlorophenyl) ethane (op'-DDD), which can be used to suppress adrenal function or to completely destroy the adrenal cortex. The antifungal agent ketoconazole also suppresses adrenal steroid synthesis and provides an alternative form of medical treatment for hyperadrenocorticoid dogs.
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PMID:Canine hyperadrenocorticism. 1603 96

The development of respiratory failure is common in patients with neuromuscular disorders that involve the respiratory muscles. However, the high incidence of sleep-related breathing problems in this population is less well known. In patients with neuromuscular disease, nocturnal breathing abnormalities frequently precede respiratory failure during wakefulness by months or even years. These nocturnal breathing problems are caused by multiple factors, including diaphragm and upper airway muscle weakness, scoliosis, obesity, and central respiratory control problems. Advances in the understanding of the links between sleep-disordered breathing and the development of daytime dysfunction and respiratory failure has revolutionized the management of these individuals. Mask positive pressure therapy is now available to improve both quality of life and longevity for these individuals. The lack of correlation between daytime testing and the severity of nocturnal breathing abnormalities makes it difficult to predict the presence of sleep-disordered breathing. Further, patients may not always be aware of symptoms associated with sleep-disordered breathing, even if specifically questioned. However, simple bedside measurements of vital capacity and inspiratory muscle strength can provide useful guides for when nocturnal respiratory monitoring is indicated.
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PMID:Sleep abnormalities associated with neuromuscular disease: pathophysiology and evaluation. 1608 13

The aim of the study was to determine relationship between the tempo of maturation and stature, body weight and body mass index (BMI) in young adulthood. The study comprised 2660 girls, aged 15 to 18 years. The weakness correlation was found between menarcheal age and body height. Analysis of a relationship between those variables shows that girls who matured later were the tallest, and those maturing earlier were the shortest, however, the differences were not statistically significant. With regard to body weight, a clear regularity could be noticed; viz. girls in whom the first menstruation occurred in the earliest were the heaviest, whereas the lowest body weight was a characteristic of those with the latest onset of menstruation. This relationship was confirmed by correlation between menarcheal age and BMI. The present study indicates that the tempo of maturation showed strong dependence on body adiposity. It corroborates suggestions of other authors indicating that early menarcheal age can be considered as one of the basic risk factors of obesity in adulthood.
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PMID:[Relationship between the tempo of maturation and the body/height proportions in adulthood]. 1652 61

Despite enormous medical progress during the past few decades, the last years of life are still accompanied by increasing ill health and disability. The ability to maintain active and independent living for as long as possible is a crucial factor for ageing healthily and with dignity. The most important and drastic gender differences in aging are related to the reproductive organs. In distinction to the course of reproductive ageing in women, with the rapid decline in sex hormones expressed by the cessation of menses, men experience a slow and continuous decline. This decline in endocrine function involves: a decrease of testosterone, dehydro epiandrosterone (DHEA), oestrogens, thyroid stimulating hormone (TSH), growth hormone (GH), IGF1, and melatonin. The decrease of sex hormones is concomitant with a temporary increase of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In addition sex hormone binding globulins (SHBG) increase with age resulting in further lowering the concentrations of free biologically active androgens. These hormonal changes are directly or indirectly associated with changes in body constitution, fat distribution (visceral obesity), muscle weakness, osteopenia, osteoporosis, urinary incontinence, loss of cognitive functioning, reduction in well being, depression, as well as sexual dysfunction. The laboratory and clinical findings of partial endocrine deficiencies in the aging male will be described and discussed in detail. With the prolongation of life expectancy both women and men today live 1/3 of their life with endocrine deficiencies. Interventions such as hormone replacement therapy may alleviate the debilitating conditions of secondary partial endocrine deficiencies by preventing the preventable and delaying the inevitable.
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PMID:Endocrinology of the aging male. 1658 70

Osteoarthritis (OA) can be a progressive, disabling disease, leading to diminished quality of life, and, for over 500,000 individuals annually in the US, total joint replacement. The etiology of OA will vary among individuals, with potential roles for systemic factors (such as genetics and obesity) as well as for local biomechanical factors (such as muscle weakness, joint laxity and traumatic injury). Joint deterioration occurs over extended periods of time, and the diverse molecular mechanisms that mediate pathogenic events of early, mid and late disease are not yet fully understood. The success of biologic therapies in the treatment of rheumatoid arthritis has demonstrated that the blockade of a single dominant cytokine or regulatory molecule can prevent cartilage destruction in a complex disease, and has raised expectations that mechanism-based treatments could also be developed for patients with OA. In this review, we will address the biological mechanisms that mediate structural damage in OA and examine current targets that are candidates for disease modification. The challenges to drug development and the obstacles to disease modification strategies will also be addressed.
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PMID:Prospects for disease modification in osteoarthritis. 1693 9


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