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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-five patients with metastatic malignant melanoma were treated with isotretinoin (13-cis-retinoic acid) orally at 1 mg/kg daily and recombinant interferon alfa-2a (INF-alpha) subcutaneously at 3 million units daily for 16-48 weeks. Therapy was well tolerated; fatigue and hyperlipidemia were the most frequent dose-limiting toxicity and necessitated dose reductions in 14 patients. Two patients achieved a complete response, and 3 responded partially for a total response rate of 20% (95% confidence interval: 4-36%). Responses occurred primarily in patients with limited tumor burden and disease confined to the skin and lymph nodes. Significant elevations in peripheral blood 2'-5'-oligoadenylate synthetase activity and natural killer activity were observed with therapy. The magnitude of these changes, however, was not predictive of response. Biopsy specimens of two responding lesions showed extensive necrosis of tumor. One specimen showed large aggregates of melanophages in association with tumor. The combination of isotretinoin and IFN-alpha is an active, easily administered regimen with acceptable toxicity for metastatic malignant melanoma.
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PMID:Isotretinoin and recombinant interferon alfa-2a therapy of metastatic malignant melanoma. 868 22

Dexfenfluramine increases serotonergic activity by stimulating serotonin (5-hydroxytryptamine; 5-HT) release into brain synapses, inhibiting its reuptake into presynaptic neurons and by directly stimulating postsynaptic serotonin receptors. On the basis of the serotonin hypothesis of appetite control, these actions would be expected to reduce appetite and, consequently, bodyweight. Studies conducted in animals and in overweight patients with and without associated disorders have confirmed the weight-reducing efficacy and good tolerability of dexfenfluramine. In 3-month clinical studies in obese patients, weight reductions with dexfenfluramine 15mg twice daily combined with dietary support were significantly higher than those achieved with placebo and similar to those with ephedrine/caffeine 20/20mg 3 times daily, sibutramine 10mg once daily and fluoxetine 60 mg/day. Furthermore, dexfenfluramine recipients with non-insulin-dependent diabetes mellitus, hyperlipidaemia or hypertension consistently show improvements in glycaemic control, blood lipid profiles and blood pressure. 12-month trial results indicate that most weight loss occurs in the initial 6 months and appears to be maintained for a further 6 months. Weight regain after withdrawal of treatment in 12-month studies demonstrates that dexfenfluramine is effective in maintaining a stable bodyweight at a lower level than placebo and in limiting food intake over this time period. Commonly reported adverse events with dexfenfluramine include diarrhoea, tiredness, dry mouth and somnolence; these symptoms are generally mild and transient. Approximately 7 and 10% of dexfenfluramine recipients in short and long term studies withdrew because of adverse events. Dexfenfluramine was better tolerated than ephedrine/caffeine and fluoxetine in short term studies. Obesity is a chronic condition that is accompanied by a number of metabolic complications. It is a significant health problem in developed countries, and as a major risk factor for many chronic diseases, including diabetes and cardiovascular disease, the economic burden of this condition is considerable. As with other chronic conditions, there is a role for pharmacological intervention in patients with severe obesity. However, drugs should be considered as only one component of a weight-control programme, since additional lifestyle modification is required to maintain weight loss. The promising data on the long term efficacy and tolerability of dexfenfluramine as well as its favourable effects on risk factors associated with obesity requires confirmation in long term studies. In the meantime, dexfenfluramine should be considered a valuable adjunct to a reduced-calorie diet in the management of severe obesity, particularly in patients with associated disorders and those unsuccessful with conventional weight loss measures. Available data support the use of the drug for up to 1 year to maintain weight loss and thus dexfenfluramine should be considered for long term administration.
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PMID:Dexfenfluramine. An updated review of its therapeutic use in the management of obesity. 911 19

Brown adipose tissue (BAT) has the capacity for uncoupled mitochondrial respiration and is proposed to be a key site for regulating energy expenditure in rodents. To better define the role of BAT in energy homeostasis, we previously created a line of transgenic mice with deficiency of BAT (UCP promoter-driven diphtheria toxin A transgenic mice [UCP-DTA]) mice. These mice develop obesity that initially is due to decreased energy expenditure and later accompanied by hyperphagia despite increased levels of circulating leptin. In addition, the obesity of these mice is accompanied by severe insulin-resistant diabetes and hyperlipidemia. To better define the basis for leptin resistance in this model, we treated UCP-DTA mice with leptin (300 microg i.p., b.i.d.) and compared their response with that of leptin-treated ob/ob and FVB control mice (30 microg i.p., b.i.d.). Leptin treatment of FVB and ob/ob mice decreased their body weight and food intake and improved their glucose homeostasis. In contrast, tenfold higher dosages of leptin had no effect on body weight, food intake, or circulating insulin or glucose concentrations of UCP-DTA mice. Hypothalamic neuropeptide Y (NPY) mRNA expression was lower in UCP-DTA mice than in littermate control FVB mice in the fed state, and increased progressively in response to food restriction as leptin levels fell. In parallel to the levels of hypothalamic NPY, corticosterone levels were initially suppressed and rose with food restriction. Thus food intake, body weight, and insulin and glucose homeostasis of UCP-DTA mice are all extraordinarily resistant to leptin, whereas hypothalamic NPY and the hypothalamopituitary adrenal (HPA) axis may remain under leptin control. Further elucidation of the mechanisms underlying leptin resistance in UCP-DTA mice may provide valuable insights into the basis for leptin resistance in human obesity.
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PMID:Severe leptin resistance in brown fat-deficient uncoupling protein promoter-driven diphtheria toxin A mice despite suppression of hypothalamic neuropeptide Y and circulating corticosterone concentrations. 951 18

Unsafe and potentially safe herbal therapies are discussed. The use of herbal therapies is on the rise in the United States, but most pharmacists are not adequately prepared educationally to meet patients' requests for information on herbal products. Pharmacists must also cope with an environment in which there is relatively little regulation of herbal therapies by FDA. Many herbs have been identified as unsafe, including borage, calamus, coltsfoot, comfrey, life root, sassafras, chaparral, germander, licorice, and ma huang. Potentially safe herbs include feverfew, garlic, ginkgo, Asian ginseng, saw palmetto, St. John's wort, and valerian. Clinical trials have been used to evaluate feverfew for migraine prevention and rheumatoid arthritis; garlic for hypertension, hyperlipidemia, and infections; ginkgo for circulatory disturbances and dementia; ginseng for fatigue and cancer prevention; and saw palmetto for benign prostatic hyperplasia. Also studied in formal trials have been St. John's wort for depression and valerian for insomnia. The clinical trial results are suggestive of efficacy of some herbal therapies for some conditions. German Commission E, a regulatory body that evaluates the safety and efficacy of herbs on the basis of clinical trials, cases, and other scientific literature, has established indications and dosage recommendations for many herbal therapies. Pharmacists have a responsibility to educate themselves about herbal therapies in order to help patients discern the facts from the fiction, avoid harm, and gain what benefits may be available.
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PMID:Unsafe and potentially safe herbal therapies. 1003 May 29

The rapidly rising prevalence of obesity, worldwide, has prompted re-evaluations of the definitions and diagnostic criteria, and of the extent of the burden it contributes to health care services. Although categorized arbitrarily for epidemiological purposes according to BMI > 25 kg/m2 ('overweight') and BMI > 30 kg/m2 ('obese'), the disease itself (ICD code E.66) is the process of excess fat accumulation. It leads to multiple organ-specific pathological consequences, particularly if there is a tendency to intra-abdominal fat accumulation. The simplest field method to identify obesity and risk of medical problems is the waist circumference, and this method has found a special role in health promotion. Risks begin with waist > 80 cm (women) or > 94 cm (men). As a broad generalization, obesity produces few symptoms below the age of 40 years, but then several symptoms often develop; tiredness, breathlessness, back pain, arthritis, sweatiness, poor sleeping, depression and menstrual disorders all being common. The symptoms are often attributed to diseases in other body systems. Metabolic diseases like diabetes, hyperlipidaemia and, hypertension develop later, but the mean BMI at diagnosis of diabetes is 28 kg/m2. Ultimately, obesity increases the likelihood of myocardial infarction, stroke and several major cancers, but its biggest impact on health, especially in the elderly, is probably the multiplicity of effects on other body systems. The greatest challenge for public health is to develop effective preventive measures, recognizing that BMI > 25 kg/m2 before the age of 20 years is a very strong predictor of obesity and ill health in adulthood.
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PMID:Pathophysiology of obesity. 1099 48

Diabetes mellitus, caused by the malfunction of insulin-dependent glucose and lipid metabolism, presents with the classical triad of symptoms: polydypsia, polyuria, and polyphagia which are often accompanied by chronic fatigue and loss of weight. Complications of diabetes mellitus include retinopathy, nephropathy, neuropathy, and cardiovascular disease. Periodontal diseases are infections affecting the periodontium and resulting in the loss of tooth support. The association between diabetes mellitus and periodontitis has long been discussed with conflicting conclusions. Both of these diseases have a relatively high incidence in the general population (diabetes 1% to 6% and periodontitis 14%) as well as a number of common pathways in their pathogenesis (both diseases are polygenic disorders with some degree of immunoregulatory dysfunction). On the one hand, numerous reports indicate a higher incidence of periodontitis in diabetics compared to healthy controls, while other reports fail to show such a relationship. Clarification of this dilemma is occurring as the diagnostic criteria for periodontitis and diabetes mellitus improve, controlled studies with increased sample sizes are carried out, and the studies take into account major confounding variables that impact on the pathogenesis of both diseases. Current studies tend to support a higher incidence and severity of periodontitis in patients with diabetes mellitus. The overview looks at the bidirectional relationship between periodontitis and diabetes. An analysis of the National Health and Nutrition Examination Survey (NHANES) III data set confirms the previously reported significantly higher prevalence of periodontitis in diabetics than in non-diabetics (17.3% versus 9%). The analysis of the data also shows that the prevalence of diabetes in patients with periodontitis is double that seen in the non-periodontitis patients (12.5% versus 6.3%) and that this difference is also statistically significant. The pathogenesis of the 2 diseases is reviewed with an emphasis on common genetic and immune mechanisms. On the basis of the overview, 2 hypotheses for testing the relationship between periodontitis and diabetes are discussed. The first proposes a direct causal or modifying relationship in which the hyperglycemia and hyperlipidemia of diabetes result in metabolic alterations that may then exacerbate bacteria-induced inflammatory periodontitis. The second hypothesis proposes that a fortuitous combination of genes (gene sets) could result in a host who, under the influence of a variety of environmental stressors, could develop either periodontitis or diabetes or both.
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PMID:The relationship between periodontal diseases and diabetes: an overview. 1188 77

Nonalcoholic fatty liver disease is a condition gaining increasing recognition as a cause of cirrhosis and end-stage liver disease. The condition appears identical to alcoholic liver disease histologically, yet occurs in patients with negligible alcohol intake. Nonalcoholic fatty liver disease covers a spectrum of diseases ranging from simple fatty deposition in the liver to fat and inflammation and finally to fibrosis and cirrhosis. Conditions most frequently found in association with nonalcoholic fatty liver disease include obesity, Type 2 diabetes, and hyperlipidemia. Although the exact etiology of nonalcoholic fatty liver disease is not clear, insulin resistance is thought to play an important factor. Patients typically present with asymptomatic serum aminotransferase elevations of 2-3 times normal. Symptoms may include fatigue and abdominal pain. The clinical course is difficult to predict due to a lack of research in the natural history of the disease. It is known a percentage of patients progress to end-stage liver disease and may require liver transplantation. No medical treatment has been found to be totally effective. Patients who are overweight or obese should be encouraged in gradual weight reduction that has been associated with improvement in liver test abnormalities.
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PMID:Nonalcoholic Fatty liver disease. 1292 Apr 29

Mitochondriopathies (MCPs) are either due to sporadic or inherited mutations in nuclear or mitochondrial DNA located genes (primary MCPs), or due to exogenous factors (secondary MCPs). MCPs usually show a chronic, slowly progressive course and present with multiorgan involvement with varying onset between birth and late adulthood. Although several proteins with signalling, assembling, transport, enzymatic function can be impaired in MCP, most frequently the activity of the respiratory chain (RC) protein complexes is primarily or secondarily affected, leading to impaired oxygen utilization and reduced energy production. MCPs represent a diagnostic challenge because of their wide variation in presentation and course. Systems frequently affected in MCP are the peripheral nervous system (myopathy, polyneuropathy, lactacidosis), brain (leucencephalopathy, calcifications, stroke-like episodes, atrophy with dementia, epilepsy, upper motor neuron signs, ataxia, extrapyramidal manifestations, fatigue), endocrinium (short stature, hyperhidrosis, diabetes, hyperlipidaemia, hypogonadism, amenorrhoea, delayed puberty), heart (impulse generation or conduction defects, cardiomyopathy, left ventricular non-compaction heart failure), eyes (cataract, glaucoma, pigmentary retinopathy, optic atrophy), ears (deafness, tinnitus, peripheral vertigo), guts (dysphagia, vomiting, diarrhoea, hepatopathy, pseudo-obstruction, pancreatitis, pancreas insufficiency), kidney (renal failure, cysts) and bone marrow (sideroblastic anaemia). Apart from well-recognized syndromes, MCP should be considered in any patient with unexplained progressive multisystem disorder. Although there is actually no specific therapy and cure for MCP, many secondary problems require specific treatment. The rapidly increasing understanding of the pathophysiological background of MCPs may further facilitate the diagnostic approach and open perspectives to future, possibly causative therapies.
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PMID:Mitochondriopathies. 1500 63

A 73-year-old woman with a history of hypertension and hyperlipidemia presented with a sharp pain ranging from the right shoulder to the upper limb. She had suffered a sharp pain at rest accompanied by general fatigue and nausea for about ten months prior to admission. Her white blood cell count was 12,800/microl, and her serum C-reactive protein was 17.5 mg/dl. A chest computed tomography scan revealed an aneurysmal change of the origin of the brachiocephalic artery. Pseudoaneurysm due to infection and aortic dissection was considered as a preoperative diagnosis. A total arch replacement was performed under cardiopulmonary bypass, deep hypothermia, and selective cerebral perfusion. Postoperatively, a bacteriologic culture of the contents of the aneurysm revealed Staphylococcus aureus. Perioperative administration of antibiotics was effective and the postoperative course was uneventful.
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PMID:Mycotic pseudoaneurysm of the brachiocephalic artery. 1507 52

Non-alcoholic steatohepatitis (NASH) is one of the most common liver disorders. This is highly prevalent in obese and diabetic subjects. Persons with central obesity are at particular risk. Other clinical predictors are age more than 40-50 years and hyperlipidemias, but none of these factors is invariable for causation of NASH. Other reported associations are, celiac disease, Wilson's Disease and few other metabolic diseases. Drugs, particularly amiodarone, tamoxifen, nucleoside analogues and methotrxate have also been linked to NASH. The disease is evenly distributed in both sexes but advanced disease is more common in women. Ethnic variation exists and African Americans are less affected than Hispanic Americans. Specific clinical features of NASH are infrequent. Patients usually come to clinical attention by elevated liver enzymes found on routine evaluation but on history, about two third of patients will admit to have mild fatigue and about half will report right upper quadrant pain. Rarely, patient may present with a complication of cirrhosis. Physical examination may reveal hepatomegaly and splenomegaly. Research in last few years has stressed that development of steatosis, stetohepatitis, fibrosis with subsequent cirrhosis are most probably the result of insulin resistance. Therefore, clinical features may reflect existence of insulin resistance. Obesity, particularly central obesity is most important of these. Patients may have sleep apnea syndrome. Hypertension and manifestations of diabetes mellitus like polyuria, polydypsia, and neurological deficits may occur. Patients may have varying combination of obesity, diabetes, hyperlipidemia, hypertension and impaired fibrinolysis (syndrome X). Children with insulin resistance may show acanthosis nigricance. Patients with polycystic ovary syndrome, which consists of insulin resistance, diabetes, obesity, hirsutism, oligo or polymenorrha and hyperlipidemia may have NASH. Other rare manifestations of insulin resistance, which can be seen in patients of NASH are lipomatosis, lipoatrophy/lipodystrophy and panniculitis. Most other rare conditions known to cause NASH like peroxisomal diseases, mitochondialpathies, Weber-Christian disease, Mauriac syndrome, Madelung's lipomatosis and abetaliopprotenemia also have insulin resistance. This is believed that primary defect underlying insulin resistance is impairment in postreceptor pathways (through tyrosine kinase activity) of insulin action. Primary defect in insulin receptors appear uncommon. This results in down regulation of insulin receptor substance 1 (IRS-1) signaling by excess free fatty acids. In muscle, activated IRS-1 promotes translocation of glucose transporter protein 4 (GLUT4) to cell membrane. As a result, monocyte glucose uptake by GLUT4 increases glucose disposal from blood and reduced need for insulin. PKC-0 is a likely candidate as serine kinase in muscle regulated by fatty acids that can impair the activation of IRS-1. Insulin resistance is usually evaluated by fasting insulin levels, Quantitative Insulin Check Index (QUICKI) and Homeostasis Model Assessment of Insulin Resistance (HOMA), C-peptid/insulin ratio oral glucose tolerance test and hyper insulinemic euglycemic clamp. The clamp technique is considered the gold standard.
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PMID:Insulin resistance and clinical aspects of non-alcoholic steatohepatitis (NASH). 1619 20


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