Expression of PRAD1/cyclin D1, retinoblastoma gene products, and Ki67 in parathyroid hyperplasia caused by chronic renal failure versus primary adenoma.
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BACKGROUND: In primary hyperparathyroidism, certain genetic abnormalities responsible for parathyroid tumorigenesis are proposed, and it has been reported that the overexpression of PRAD1/cyclin D1 induced by a DNA rearrangement of the parathyroid hormone (PTH) gene is one of the genetic disorders in a number of primary parathyroid adenomas. However, in secondary hyperparathyroidism caused by uremia, the mechanism of monoclonal proliferation in nodular parathyroid hyperplasia is not well understood. To elucidate the mechanism, we examined the expression of PRAD1/cyclin D1, retinoblastoma gene products, and Ki67 in primary adenoma and secondary hyperplasia. METHODS: In adenomas (N = 15) and associated glands (N = 7) with normal histology obtained from patients with primary hyperparathyroidism and in diffuse (N = 14), multinodular (N = 58), and single nodular (N = 28) glands from patients who underwent parathyroidectomy for renal hyperparathyroidism, the expression of these cell cycle regulators was evaluated by immunohistochemical technique. A labeling index was used to define the proportion of cells with positive nuclear staining by each antibody. RESULTS: In 6 out of 15 (40%) primary adenomas, PRAD1/cyclin D1 was overexpressed (a labeling index of more than 500), possibly because of the PTH gene rearrangement, but not in secondary hyperplasia, including single nodular glands. Compared with diffuse hyperplasia, nodular hyperplasia showed a significantly higher expression of PRAD1/cyclin D1 (P < 0.05), retinoblastoma gene products (P < 0.05), and Ki67 (P < 0.05). However, no statistically significant correlation between the expression of PRAD1/cyclin D1 and that of Ki67 was observed in both primary adenoma and secondary hyperplasia. CONCLUSIONS: These results suggest that in secondary hyperplasia caused by uremia, at least remarkable overexpression of PRAD1/cyclin D1 induced by PTH gene rearrangement may be not the major genetic abnormality responsible for tumorigenesis. Heterogenous genetic changes seem to contribute to monoclonal proliferation of parathyroid cells induced by the expression of PRAD1/cyclin D1 or by some other mechanism independent of the amplification of the proto-oncogene. (+info)
Clinical features of 52 neonates with hyperinsulinism.
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BACKGROUND: Neonatal hyperinsulinemic hypoglycemia is often resistant to medical therapy and is often treated with near-total pancreatectomy. However, the pancreatic lesions may be focal and treatable by partial pancreatic resection. METHODS: We studied 52 neonates with hyperinsulinism who were treated surgically. The type and location of the pancreatic lesions were determined by preoperative pancreatic catheterization and intraoperative histologic studies. Partial pancreatectomy was performed in infants with focal lesions, and near-total pancreatectomy was performed in those with diffuse lesions. The postoperative outcome was determined by measurements of plasma glucose and glycosylated hemoglobin and by oral glucose-tolerance tests. RESULTS: Thirty neonates had diffuse beta-cell hyperfunction, and 22 had focal adenomatous islet-cell hyperplasia. Among the latter, the lesions were in the head of the pancreas in nine, the isthmus in three, the body in eight, and the tail in two. The clinical manifestations were similar in both groups. The infants with focal lesions had no symptoms of hypoglycemia and had normal preprandial and postprandial plasma glucose and glycosylated hemoglobin values and normal results on oral glucose-tolerance tests after partial pancreatectomy (performed in 19 of 22 neonates). By contrast, after near-total pancreatectomy, 13 of the patients with diffuse lesions had persistent hypoglycemia, type 1 diabetes mellitus developed in 8, and hyperglycemia developed in another 7; overall, only 2 patients with diffuse lesions had normal plasma glucose concentrations in the first year after surgery. CONCLUSIONS: Among neonates with hyperinsulinism, about half may have focal islet-cell hyperplasia that can be treated with partial pancreatectomy. These neonates can be identified through pancreatic catheterization and intraoperative histologic studies. (+info)
Nitric oxide synthase inhibitor attenuates intestinal damage induced by zinc deficiency in rats.
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A nitric oxide synthase (NOS) inhibitor, NG-nitro-L -arginine methyl ester (L-NAME), was given to zinc-deficient (ZD) rats to determine whether it prevents the intestinal damage usually observed under these conditions. Weanling male rats were given free access to a ZD diet (2 mg zinc/kg), whereas control rats including pair-fed (PF) and ad libitum consumption (AL) groups were given a zinc-supplemented (50.8 mg zinc/kg) diet for 4 wk. Half of the ZD rats received L-NAME (0.3 g/L in drinking water) for 3 wk starting at the wk 2 of the deficient period. Plasma zinc concentration in ZD rats was significantly lower (P < 0.05) than that of AL and PF rats. Administration of L-NAME did not alter this concentration. Intestinal zinc concentration did not differ among groups. However, metallothionein-1 (MT-1) mRNA level was significantly lower in the intestine of ZD rats than in AL or PF rats. Treatment of ZD rats with L-NAME did not affect this level. Intestinal microvascular permeability evaluated by Evans blue showed significantly higher extravasation in ZD rats than in AL rats, whereas L-NAME administration inhibited the extravasation. Expression of inducible NOS mRNA was observed in intestine of ZD but not of AL or PF rats, and there was no significant difference between ZD rats, regardless of L-NAME treatment. The activity ratio of inducible NOS to total NOS in ZD rats not receiving L-NAME was significantly higher than that in AL rats or ZD rats treated with L-NAME (P < 0.05). The number of apoptotic-positive and goblet cells in intestinal villi was significantly higher in ZD rats compared with AL or PF rats. L-NAME administration in ZD rats reversed this effect. These results indicate that inhibition of NOS ameliorates zinc deficiency-induced intestinal damage in rats. (+info)
Overexpression of glycine-extended gastrin in transgenic mice results in increased colonic proliferation.
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Gastrin is a peptide hormone involved in the growth of both normal and malignant gastrointestinal tissue. Recent studies suggest that the glycine-extended biosynthetic intermediates mediate many of these trophic effects, but the in vivo relevance of glycine-extended gastrin (G-Gly) has not been tested. We have generated mice (MTI/G-GLY) that overexpress progastrin truncated at glycine-72 to evaluate the trophic effects of G-Gly in an in vivo model. MTI/G-GLY mice have elevated serum and colonic mucosal levels of G-Gly compared with wild-type mice. MTI/G-GLY mice had a 43% increase in colonic mucosal thickness and a 41% increase in the percentage of goblet cells per crypt. MTI/G-GLY mice exhibited increased colonic proliferation compared with wild-type controls, with an expansion of the proliferative zone into the upper third of the colonic crypts. Continuous infusion of G-Gly into gastrin-deficient mice for two weeks also resulted in elevated G-Gly levels, a 10% increase in colonic mucosal thickness, and an 81% increase in colonic proliferation when compared with gastrin-deficient mice that received saline alone. To our knowledge, these studies demonstrate for the first time that G-Gly's contribute to colonic mucosal proliferation in vivo. (+info)
Age-dependent altered proportions in subpopulations of tonsillar lymphocytes.
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Age-related changes in functional subsets of lymphocytes may influence the potential to build up immune responses. In particular, the capacity of tonsillar lymphocytes to counter infections may be altered during ageing. In order to address this question we investigated the proportional distribution of several subsets of tonsillar T and B cells with regard to ageing. Tonsils were derived from 119 patients between 2 and 65 years of age. Lymphocyte subsets were monitored by three-colour fluorescence of relevant CD markers in flow cytometry. As a general tendency the percentage of CD3+ T cells steadily increased whereas that of CD19+ B cells decreased at the same time. No significant differences were observed between lymphocytes of patients with and without inflammatory history of the tonsils. The percentage of CD8+ T cells declined whereas that of CD4+ T cells increased during the same time span. CD45RA+ T cells increased during the first two decades of life and gradually decreased thereafter. In contrast, CD45RO+ T cells showed an opposite trend. No differences were seen in the population of CD3-/CD56+ natural killer (NK) cells. The mature B cell marker CD40 showed no significant changes during ageing. However, CD38+ B cells, representing B cells of late maturation stages, dramatically declined up to the age of 65. In a similar manner the CD5+ subpopulation of B cells decreased during ageing. Substantial changes in major tonsillar T and B cell populations as shown in this study may have an impact on the ageing process of the immune system. (+info)
Different mechanisms of synovial hyperplasia in rheumatoid arthritis and pigmented villonodular synovitis: the role of telomerase activity in synovial proliferation.
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OBJECTIVE: To elucidate the involvement of telomerase activity in the pathogenesis of rheumatoid arthritis (RA) and pigmented villonodular synovitis (PVS). METHODS: Peripheral blood lymphocytes (PBL), synovial infiltrating lymphocytes, and synoviocytes were isolated from peripheral blood samples and synovial tissue obtained from 18 patients with RA, 9 with PVS, 12 with osteoarthritis (OA), and 10 with knee joint trauma. Cellular telomerase activity was measured by the telomeric repeat amplification protocol assay. In RA patients, the telomerase activity level in synovial infiltrating lymphocytes was assessed for correlations with histologic features in rheumatoid synovium. RESULTS: A high level of telomerase activity was detected in the PBL and synovial infiltrating lymphocytes from RA patients and in the synoviocytes from PVS patients, whereas the enzyme activity was expressed at a low-to-borderline level in the PBL and synovial lymphocytes from OA, PVS, and trauma patients and was absent in the synoviocytes from RA as well as OA and trauma patients. In RA patients, the telomerase activity level in synovial infiltrating lymphocytes was significantly correlated with the intensity of synovial lining hyperplasia, microvessel proliferation, lymphocyte infiltration, and percentage of synovial cells positive for proliferating cell nuclear antigen in rheumatoid synovium. CONCLUSION: Telomerase activation in lymphocytes may provide insights into the progression of synovitis and synovial proliferation in RA. Moreover, the enzyme may be implicated in the proliferation of synoviocytes in PVS. (+info)
A mouse mammary tumor virus-Wnt-1 transgene induces mammary gland hyperplasia and tumorigenesis in mice lacking estrogen receptor-alpha.
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Estrogens have important functions in mammary gland development and carcinogenesis. To better define these roles, we have used two previously characterized lines of genetically altered mice: estrogen receptor-alpha (ER alpha) knockout (ERKO) mice, which lack the gene encoding ER alpha, and mouse mammary virus tumor (MMTV)-Wnt-1 transgenic mice (Wnt-1 TG), which develop mammary hyperplasia and neoplasia due to ectopic production of the Wnt-1 secretory glycoprotein. We have crossed these lines to ascertain the effects of ER alpha deficiency on mammary gland development and carcinogenesis in mice expressing the Wnt-1 transgene. Introduction of the Wnt-1 transgene into the ERKO background stimulates proliferation of alveolar-like epithelium, indicating that Wnt-1 protein can promote mitogenesis in the absence of an ER alpha-mediated response. The hyperplastic glandular tissue remains confined to the nipple region, implying that the requirement for ER alpha in ductal expansion is not overcome by ectopic Wnt-1. Tumors were detected in virgin ERKO females expressing the Wnt-1 transgene at an average age (48 weeks) that is twice that seen in virgin Wnt-1 TG mice (24 weeks) competent to produce ER alpha. Prepubertal ovariectomy of Wnt-1 TG mice also extended tumor latency to 42 weeks. However, pregnancy did not appear to accelerate the appearance of tumors in Wnt-1 TG mice, and tumor growth rates were not measurably affected by late ovariectomy. Small hyperplastic mammary glands were observed in Wnt-1 TG males, regardless of ER alpha gene status; the glands were similar in appearance to those found in ERKO/Wnt-1 TG females. Mammary tumors also occurred in Wnt-1 TG males; latency tended to be longer in the heterozygous ER alpha and ERKO males (86 to 100 weeks) than in wild-type ER alpha mice (ca. 75 weeks). We conclude that ectopic expression of the Wnt-1 proto-oncogene can induce mammary hyperplasia and tumorigenesis in the absence of ER alpha in female and male mice. The delayed time of tumor appearance may depend on the number of cells at risk of secondary events in the hyperplastic glands, on the carcinogenesis-promoting effects of ER alpha signaling, or on both. (+info)
Schwann cell hyperplasia and tumors in transgenic mice expressing a naturally occurring mutant NF2 protein.
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Specific mutations in some tumor suppressor genes such as p53 can act in a dominant fashion. We tested whether this mechanism may also apply for the neurofibromatosis type-2 gene (NF2) which, when mutated, leads to schwannoma development. Transgenic mice were generated that express, in Schwann cells, mutant NF2 proteins prototypic of natural mutants observed in humans. Mice expressing a NF2 protein with an interstitial deletion in the amino-terminal domain showed high prevalence of Schwann cell-derived tumors and Schwann cell hyperplasia, whereas those expressing a carboxy-terminally truncated protein were normal. Our results indicate that a subset of mutant NF2 alleles observed in patients may encode products with dominant properties when overexpressed in specific cell lineages. (+info)