Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

My purpose in this article is to restore the histologic appraisal of renal bone disease to the mainstream of bone and mineral metabolism from which it has been separated for many years. Historically, both the two major components were found in varying degrees in most patients, although one or other of them often predominated. For more than 15 years bone biopsy has been used almost exclusively to classify individual patients into hyperparathyroid, osteomalacic, mixed and adynamic categories according to rigid non-overlapping criteria, and remarkably few histologic data have been reported. All metabolic bone diseases result from disordered bone remodeling, the physiologic mechanism for replacing bone that has become too old to carry out its mechanical or metabolic functions. Bone remodeling is not directly concerned with the regulation of plasma calcium, which reflects the level of equilibration at quiescent bone surfaces between systemic and bone extracellular fluid set by parathyroid hormone. The separation of remodeling from homeostasis explains the concurrence of increased turnover and decreased plasma calcium in chronic renal failure; it is the homeostatic system, rather than the remodeling system, which is resistant to parathyroid hormone. The effect of mild hyperparathyroidism is a nonspecific increase in bone turnover, of which the best index is the bone formation rate measured by double tetracycline labeling expressed per unit of bone surface. Increased turnover is always accompanied by increased reversible mineral deficit. In prolonged hyperparathyroidism there is also accelerated irreversible bone loss manifested mainly as thinning of cortical bone, detectable in chronic renal failure before any symptoms, due to increased resorption depth on the endocortical surface. In severe hyperparathyroidism resorbed bone is replaced, not by a lesser quantity of normal bone, but by a mixture of vascular fibrous tissue and woven bone, referred to as osteitis fibrosa. In osteomalacia there is increased accumulation of osteoid, due not to increased turnover, but to prolongation of mineralization lag time, which in conjunction with increased thickness, surface and volume of osteoid is diagnostic. Converting histomorphometric data into category assignment discards most of the useful information, which can be retained by two-dimensional representation of severity. For the hyperparathyroid dimension, bone formation rate measured by double tetracycline labeling expressed per unit of bone surface is the most useful although not ideal. For the osteomalacic dimension a mineralization index was constructed that is unaffected by age or race. In patients with osteitis fibrosa, bone formation rate per unit of bone surface and mineralization index were inversely correlated. For the third dimension a structure/formation index was constructed which increases with age in healthy women and shows weak inverse correlation with bone formation rate. The structure/formation index is lower than normal in patients with osteitis fibrosa, and should be useful in the study of osteopenia in chronic renal failure. Bone formation rate is low in osteomalacia, but some patients have subnormal rates through quite a different mechanism. The frequency of this finding has been overestimated for several reasons: failure to exclude atypical osteomalacia (increased surface and volume but not thickness of osteoid), use of inappropriate reference values, and failure to measure the bone formation rate on endocortical and intracortical surfaces. In healthy women bone formation rate can be zero on the cancellous surface alone. Low bone formation rate is sometimes due to diabetes but most often is the expected response to subnormal parathyroid hormone secretion accompanying an excess of calcium, a situation recognized only recently because of improvement in parathyroid hormone assay methodology. Low cancellous bone formation rate should not increase fracture risk because turnover is much lower in the peripheral than in the central skeleton, and all reports of increased fracture risk are flawed or open to different interpretation. Low bone formation rate is associated with reduced skeletal buffering of calcium and increased soft tissue calcification. This is not a new disease needing its own treatment, however, but represents the final stage of skeletal adaptation to a surfeit of calcium. The concept of adynamic bone disease has been harmful by directing attention away from the most important consequence of over-treatment of hyperparathyroidism.
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PMID:Renal bone disease: a new conceptual framework for the interpretation of bone histomorphometry. 1281 35

Aging of skin is a continuous process that may be enhanced by sun exposure. Photoaging may provoke changes different from aging. Epidermal changes involve thinning of stratum spinosum and flattening of the dermo-epidermal junction. The senescent keratinocytes becomes resistant to apoptosis and may survive for a long time giving time for DNA and protein damage to accumulate with possible implication for carcinogenesis. The numbers of melanocytes decrease with age with dysregulation of melanocyte density resulting in freckles, guttate hypo-melanosis, lentigines and nevi. The number of dendritic Langerhans cells also decreases with age and the cells get less dendrites and have reduced antigen-trapping capacity. Aging involves dermal changes such as damage to elastic and collagen fibers giving thickened, tangled, and degraded non-functional fibers. Collagen intermolecular cross-links are stable and essential for stability and tensile strength. Cross-links increase with age converting divalent cross-links into mature trivalent cross-links of, e.g. histidinohydroxylysinonorleucine. Two mechanisms are involved; an enzyme-controlled process of maturation and a non-enzymatic glycosylation, the Maillard reaction leading to cross-links in proteins such as in collagen between arginine and lysine. Such may be seen with age and in diabetes mellitus. However, autofluorescence studies have shown that UVR reduces collagen cross-links. Natural photoprotection involves thickening of stratum corneum by sunlight and increased pigmentation. This leads to a factor 2 increase in photoprotection from spring until after-summer. The constitutive pigmentation is independent of age and thickness of stratum corneum is likewise independent of age. The minimal erythema dose is thus the same through life, when corrected for pigmentation or measured in areas with constitutive pigmentation.
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PMID:Skin aging and natural photoprotection. 1503 73

Enamel hypoplasia is the most common developmental defect of human teeth that may be seen in deciduous teeth of babies born to diabetic women. In the present experimental study, we analyzed the enamel organ of the mandibular incisors of the offspring of rats with alloxan-induced diabetes. By light microscopy, no alterations could be found in the enamel organ of rats born to diabetic mothers compared to normal ones, except in one case. In contrast, significant differences were detected with computer-aided morphometry. In the rats born to treated and untreated diabetic mothers, there was thinning of the enamel matrix and of the ameloblasts and the nuclear area of the latter was smaller. In the rats born to treated diabetic mothers, the nuclei of the ameloblasts were more elliptical and there was enlargement of the interstitial area of the stellate reticulum. These results indicate that there are structural defects in the enamel organ of rats born to mothers with alloxan-induced diabetes which could induce the enamel hypoplasia observed by scanning electron microscopy and which may reflect the metabolic alterations seen in this condition. Future studies are needed to determine whether these effects are transitory or permanent.
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PMID:Are there structural alterations in the enamel organ of offspring of rats with alloxan-induced diabetes mellitus? 1505 90

The clinical features and course of cardiac involvement in a patient with maternally inherited diabetes and deafness associated with the mitochondrial DNA 3243 mutation are reported. A 45-year-old woman with maternally transmitted diabetes mellitus and deafness presented with congestive heart failure. The patient showed a short P-R interval on electrocardiogram (ECG) and had developed progression from left ventricular hypertrophy to a hypokinetic cardiomyopathy pattern over the course of 10 months. Rapid cardiac change was accompanied by left ventricular remodeling, as shown by wall thinning on echocardiogram and decrease in QRS voltages on ECG. Coronary arteriography revealed no significant stenosis. In the endomyocardial biopsy specimens, light microscopy showed nonspecific cardiomyopathic changes. Genetic testing for mitochondrial DNA mutations in peripheral blood lymphocytes revealed an adenine (A)-to-guanine (G) substitution at nucleotide 3243 in the mitochondrial DNA encoding the transfer RNA for leucine (tRNA Leu (UUR)). The proportion of mutant mitochondrial DNA was 25%. Two of the patient's daughters, aged 13 and 21 years, who were symptom free, were found to carry the same point mutation. A short P-R interval on ECG in the younger of them was the sole manifestation of the mutation. Unfortunately, 6 months after diagnosis, the patient died suddenly at home. Accelerated cardiomyopathy can occur as a mitochondria-related complication in patients with maternally inherited diabetes and deafness associated with the 3243 mutation.
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PMID:Accelerated cardiomyopathy in maternally inherited diabetes and deafness. 1557 73

The arterial content of hyaluronan (HA) undergoes diffuse changes as part of the diabetic macroangiopathy. Because HA influences the phenotype of vascular cells in vitro such as proliferation, migration, and secretion, it is tempting to speculate that diabetes-induced hastened cardiovascular disease may be linked to the increased amount of HA. To explore the pathophysiological role of altered HA content in the arterial wall in vivo, we created transgenic (Tg) mice with HA overexpression in smooth muscle cells (SMCs) in large and small vessels, targeted by the alpha smooth-muscle-cell-actin (alphaSMA) promoter fused to the human hyaluronan synthase 2 (hHAS2) cDNA. RT-PCR demonstrated hHAS2 mRNA expression in the tunica media of large and small vessels. In situ hybridization confirmed that hHAS2 mRNA was targeted to the SMCs. The aortic HA content was elevated in the Tg mice, and by immunohistochemistry, it was seen that HA accumulated in the tunica media. The secretory profile of high- and low-molecular HA was similar in wild-type and Tg animals. Overproduction of HA in the aorta resulted in thinning of the elastic lamellae in Tg mice. Our data suggest that this may lead to increased mechanical stiffness and strength, as determined by controlled stretching until failure. Finally, overproduction of HA on the genetic background of the ApoE-deficient mouse strain promoted atherosclerosis development in the aorta. These results indicate that a single component of the diabetic macroangiopathy, diffuse accumulation of HA, accelerates the progression of atherosclerosis.
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PMID:Overexpression of hyaluronan in the tunica media promotes the development of atherosclerosis. 1570 63

Progressive diabetic neuropathy has hitherto been irreversible in humans. New approaches raise the question of whether islet cell reconstitution rendering euglycemia can reverse specific features of neuropathy. We evaluated physiological and structural features of experimental neuropathy in a long-term murine model of diabetes induced by streptozotocin. By serendipity, a subset of these diabetic mice spontaneously regained islet function and attained near-euglycemia. Our hypotheses were that this model might better reflect axon loss observed in human disease and that spontaneous recovery from diabetes might identify the features of neuropathy that are reversible. In this model, experimental neuropathy closely modeled that in humans in most critical aspects: declines in motor conduction velocities, attenuation of compound muscle (M waves) and nerve action potentials, axon atrophy, myelin thinning, loss of epidermal axons, and loss of sweat gland innervation. Overt sensory neuron loss in dorsal root ganglia was a feature of this model. In mice with recovery, there was robust electrophysiological improvement, less myelin thinning, and remarkable epidermal and sweat gland reinnervation. There was, however, no recovery of populations of lost sensory neurons. Our findings identify a robust model of human diabetic neuropathy and indicate that overt, irretrievable loss of sensory neurons is one of its features, despite collateral reinnervation of target organs. Sensory neurons deserve unique protective strategies irrespective of islet cell reconstitution.
Diabetes 2005 Mar
PMID:Experimental diabetic neuropathy with spontaneous recovery: is there irreparable damage? 1573 62

In order to investigate the diabetes-associated neuropathy and prevent effects of cyclohexenonic long-chain fatty alcohol, a neurotrophic substance, in trachea, we studied its effect on streptozotocin-diabetic hyper-reactivity in the rat trachea. Diabetes was induced in 8-week-old male Sprague-Dawley rats by administering an intraperitoneal injection of streptozotocin (50 mg/kg). The rats were divided randomly into four groups and were maintained for four weeks: age-matched control rats, diabetic rats without treatment with cyclohexenonic long-chain fatty alcohol, and diabetic rats treated with cyclohexenonic long-chain fatty alcohol (2 and 8 mg/kg, i.p. every day). The serum glucose and insulin levels were determined, and the contractile responses of the trachea induced by carbachol and KCl were investigated. Treatment with cyclohexenonic long-chain fatty alcohol did not alter the rats' diabetic status, i.e., body weight, thickness of the trachea, serum glucose levels, and serum insulin levels, but significantly improved the diabetic-induced hyper-reactivity of the rat trachea in a dose-dependent manner. There was no significant difference in either the carbachol- or KCl-induced contractile forces between groups with or without mucosa in the functional studies. In histological examinations, thinning of cricoid cartilage, thickness of basal membrane, and degeneration, fragmentation of elastic fibers in the submucosal layer, and hypertrophy of smooth muscle bundle in the membranous wall of trachea were observed in the diabetic rat trachea, which were improved by treatment with cyclohexenonic long-chain fatty alcohol. Our data indicate that this drug can prevent hyper-reactivity in the diabetic trachea.
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PMID:Effects of cyclohexenonic long-chain fatty alcohol on diabetic rat trachea. 1595 71

Little is known about the effects of antagonistic GnRH analogues vs. agonists on bone strength, specifically in context of treating precocious puberty. Peripubertal female rats were treated from postnatal day 25 - 36 with either the GnRH agonist triptorelin (TRIP) or the antagonist cetrorelix (CET). Using peripherial quantitative computerized tomography (pQCT) we investigated effects on bone parameters. Onset of puberty was retarded by both analogues as measured by prevention of vaginal opening at 36 d of age and reduced uterine weights. In the tibia, cortical content, cortical area related to body weight, and periosteal circumference related to weight were significantly reduced in CET-treated rats - indicating reduced bone modeling and reduced bone strength (cortical circumference related to body weight: CET 0.066 +/- 0.001 vs. TRIP 0.068 +/- 0.001 vs. controls 0.071 +/- 0.001 mm/g, mean +/- SEM, p < 0.05 CET vs. controls; cortical area related to body weight: CET 3.87 +/- 0.46 vs. TRIP 6.80 +/- 0.63 vs. controls 8.07 +/- 1.13, x 10 (-3) mm (2)/g, p < 0.001 CET vs. controls; cortical content: CET 0.316 +/- 0.038 vs. TRIP 0.546 +/- 0.051 vs. controls 0.624 +/- 0.089 mg/mm, p < 0.01 CET vs. controls). In conclusion, although both CET and TRIP inhibit puberty in rats, cortical thinning was only seen in CET-treated rats. This indicates that GnRH antagonist treatment might cause reduced bone strength which is partly comparable to postmenopausal bone loss. When using new GnRH antagonists for treating precocious puberty in humans, parameters for bone strength and mineralization should be monitored.
Exp Clin Endocrinol Diabetes 2005 Sep
PMID:Different effects of agonistic vs. antagonistic gnrh-analogues (triptorelin vs. cetrorelix) on bone modeling and remodeling in peripubertal female rats. 1615 79

Diabetic neuropathy, a major complication of diabetes mellitus, is associated with the development of vascular dysfunction and autonomic neuropathy. We studied the effects of cyclohexenonic long-chain fatty alcohol (FA) on streptozotocin-diabetic hyperreactivity in the rat aorta smooth muscle. The rats were divided randomly into four groups and were maintained for 4 weeks: age-matched control rats, diabetic rats without treatment with FA, and diabetic rats treated with FA (2 and 8 mg/kg, i.p. everyday). The serum glucose and insulin levels were determined, and the contractile responses of the aorta induced by a thromboxane A2 agonist, U46619 and KCl were investigated. Treatment with FA did not alter rats' diabetic status, i.e., body weight, thickness of the aorta, serum glucose levels, and serum insulin levels, but significantly improved the diabetic-induced hyperreactivity of the rat aorta in a dose-dependent manner. Removal of endothelium did not change contractile force between groups. In histological examinations, thinning of smooth muscle bundle in the wall of aorta was observed in the diabetic rat, which was not significantly improved by treatment with FA. Our data indicate that FA can prevent hyperreactivity in the diabetic aorta.
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PMID:General administration of cyclohexenonic long-chain fatty alcohol ameliorates hyperreactivity of STZ-induced diabetic rat aorta. 1631 Aug 9

The majority of pituitary tumors that cause Cushing's disease are small (<1 cm diameter), and most disease morbidity is due to the effects of elevated, non-suppressible, ACTH levels that these tumors secrete. Tumor-derived ACTH leads to adrenal-derived steroid hypersecretion and results in many disabling and sometimes life-threatening symptoms including abnormal fat deposition, skin thinning, psychological disturbances, hypertension, diabetes, osteoporosis and muscle weakness. Cushing's disease is associated with high morbidity and ultimately mortality. In experienced specialized centers, 70% of corticotroph microadenomas can be successfully resected by transsphenoidal pituitary surgery. However, surgical "cure" rates for larger ACTH-secreting pituitary tumors are achieved in only 30% of cases, and recent reports highlight a significant recurrence rate after longer term follow-up even in smaller tumors. Post-surgical persistence of ACTH hypersecretion may require pituitary-directed radiation, but this treatment may take some time to be effective, and like extensive surgical pituitary tumor resection, ultimately leads to partial- or total hypopituitarism in approximately 80% of cases. Although hypercortisolism may be completely resolved by adrenalectomy, this procedure does not suppress, and may act as a stimulus to pituitary tumor growth, and is associated with other co-morbidity. Although some currently available drug-based treatments for Cushing's disease effectively control hypercortisolism, their drawback has been that they do not impact on pituitary tumor growth. Recent studies have identified the potential utility of peroxisome-proliferator activating receptor-gamma (PPAR-gamma) novel ligands in in vitro, and in vivo Cushing's disease models, and have paved the way for early clinical studies to develop novel therapeutic approaches in Cushing's disease.
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PMID:PPAR-gamma in Cushing's disease. 1641 39


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