HEPARIN
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84051855
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Ger
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A subtractive library screening was performed to identify changes in gene expression that occur during the process of neoplastic transformation of thyroid cells. A cDNA library was constructed from a human thyroid papillary carcinoma cell line (NPA) subtracted with cDNAs from normal thyroid cells (HTC 2). The differential screening of this library lead to the isolation of 39 cDNA clones; six of them showed homology with a recently isolated gene, named HIP, that codes for a protein belonging to a novel class of heparin/heparan sulfate-binding proteins. Northern blot analysis revealed HIP gene overexpression in all of the human thyroid carcinoma cell lines analyzed, as compared to the HTC 2 cells. HIP expression was particularly abundant in the anaplastic carcinoma-derived cell lines. The analysis of surgically removed thyroid tumors showed overexpression of HIP gene in all of the carcinomas, independent of the histotype, although the largest increase in HIP expression was observed in the undifferentiated forms. In contrast, none of the benign adenomas or normal thyroid tissues showed HIP overexpression. To establish the role of HIP overexpression in cell transformation, the NPA cell line was transfected with an eukaryotic expression vector carrying the HIP gene in the antisense orientation. Stable transfectants expressed reduced HIP mRNA levels and showed morphological changes, such as becoming spindle-shaped and growing scattered. The growth rate of the antisense clones was greatly reduced compared to the NPA cells transfected with the backbone vector. Taken together, these results indicate that HIP gene overexpression is associated with thyroid carcinogenesis and strongly suggest its involvement in thyroid cell growth regulation.
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Generalized osteoporosis currently represents a heterogeneous group of conditions with many different causes and pathogenetic mechanisms, that often are variably associated. The term "secondary" is applied to all patients with osteoporosis in whom the identifiable causal factors are other than menopause and aging. In this heterogeneous group of conditions, produced by many different pathogenetic mechanisms, a negative bone balance may be variably associated with low, normal or increased bone remodeling states. A consistent group of secondary osteoporosis is related to endocrinological or iatrogenic causes. Exogenous hypercortisolism may be considered an important risk factor for secondary osteoporosis in the community, and probably glucocorticoid-induced osteoporosis is the most common type of secondary osteoporosis. Supraphysiological doses of corticosteroids cause two abnormalities in bone metabolism: a relative increase in bone resorption, and a relative reduction in bone formation. Bone loss, mostly of trabecular bone, with its resultant fractures is the most incapacitating consequence of osteoporosis. The estimated incidence of fractures in patients prescribed corticosteroid is 30% to 50%. Osteoporosis is considered one of the potentially serious side effects of heparin therapy. The occurrence of heparin-induced osteoporosis appeared to be strictly related to the length of treatment (over 4-5 months), and the dosage (15,000 U or more daily), but the pathogenesis is poorly understood. It has been suggested that heparin could cause an increase in bone resorption by increasing the number of differentiated osteoclasts, and by enhancing the activity of individual osteoclasts. Hyperthyroidism is frequently associated with loss of trabecular and cortical bone; the enhanced bone turnover that develops in thyrotoxicosis is characterized by an increase in the number of osteoclasts and resorption sites, and an increase in the ratio of resorptive to formative bone surfaces, with the net result of bone loss. Despite these findings, the occurrence of pathological fractures in patients with hyperthyroidism is relatively low, and probably due to the fact that deficiencies in bone mass may be reversed by treatment of the thyroid disease. Most, but not all, studies on insulin-dependent diabetes mellitus (IDDM) report an association with osteopenia. In IDDM, the extent of bone loss is usually slight, which helps explain the discrepancy between the frequency of decreased bone mineral density, and the frequency of osteoporotic fractures in long-standing diabetes. Contradictory results have been obtained in non-insulin-dependent diabetes mellitus (NIDDM) patients. Increased rates of bone loss at the radius and lumbar spine were demonstrated either in patients with two-thirds gastric resection and Billroth II reconstruction, or in those with one-third resection and Billroth I anastomosis, and the metabolic bone disease following gastrectomy may consist also of osteomalacia or mixed pattern of osteoporosis-osteomalacia, with secondary hyperparathyroidism. Miscellaneous causes of secondary osteoporosis are also immobilization, pregnancy and lactation, and alcohol abuse.
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Link Discovered Between Diabetes And Heart Disease |
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June 30, 2000 NEW YORK (Reuters Health) - Diabetics have an elevated risk of developing heart disease, and now researchers believe they have found one reason why. It appears that a class of proteins that are responsible for clearing fat from the blood may not work as well in the presence of high blood sugar levels seen in uncontrolled diabetes, according to Dr. Neil S. Shachter, assistant professor of medicine at Columbia University College of Physicians and Surgeons in New York. "Clearance is the problem," said Shachter, who conducted a study in mice looking at the problem. This excess fat may build up in the arteries of diabetics, making them more prone to atherosclerotic heart disease and a number of other complications of diabetes, he explained. Shachter and colleagues noted that after diabetics eat a meal, the fat in their blood tends to remain elevated longer than it does in people without diabetes. To take a closer look at the problem, the researchers fed mice with a diabetes-like illness a high fat diet. They found that blood-fat levels did stay elevated for longer after a meal than the levels seen in normal mice. Since the mice were not producing more fats after a meal, they concluded that there must be another reason for the abnormally high levels of fat in the body after feeding. It made sense to assume that "if they were not making more, they must be clearing it worse," Shachter said. They found that a class of proteins found in the liver known as heparan sulfate proteoglycans (HSPGs), which are responsible for transporting fats, did not work as well as usual in the high-sugar environment present in the mice. HSPGs are comprised of protein and sugar chains, and it appears that in the diabetic mice, not as many HSPGs are createdso less fat is being cleared. These results convinced the researchers, who report their findings in the June issue of The Journal of Clinical Investigation, that HSPG is responsible for more than just heart disease. "We've connected every major complication of diabetes with a low production of HSPGs," Shachter said. The next step is to determine what causes the HSPGs to be produced at such low levels, and to see if there is a way to stimulate production of these proteins and therefore decrease or stop many of the complications related to diabetes, including heart disease, he noted. "We might see therapy as a result," Shachter told Reuters Health. "All we know is that a low production of HSPG is now important for this side effect (heart disease). No drugs will come out just around the corner but we hope one day we can treat it (the problem of low HSPG production) directly." SOURCE: The Journal of Clinical Investigation 2000; 105: 1807-1818. |
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