Hypercalcaemia in B cell chronic lymphocytic leukaemia.

Hypercalcaemia is common in some lymphoproliferative disorders such as myeloma or T-cell leukaemia-lymphoma, but is rarely described in B cell chronic lymphocytic leukaemia (BCLL). We report the case of a patient with BCLL, hypercalcaemia and osteolytic bone lesions. Parathyroid hormone-related protein (PTHrP) mRNA was identified by Northern blot analysis of liver, spleen and lymph node tumour samples. Serum levels of tumour necrosis factor alpha (TNF alpha) were increased.

Effects of dexamethasone, calcium and 1,25-dihydroxycholecalciferol on calcitonin and calcitonin gene-related peptide mRNA levels from the CA-77 C cell line.

We used the CA-77 cell, a murine C-cell line derived from a medullary thyroid carcinoma, to study the effects of glucocorticoids, calcium, and vitamin D metabolites on calcitonin (CT) gene expression. Total RNA was isolated, and CT and CT gene-related peptide (CGRP) mRNAs were measured by Northern hybridizations using specific probes. A control mRNA probe (cyclophilin) was used to quantitate the specificity of the changes in CT and CGRP mRNAs. The CA-77 C cell line cultured in basal conditions with a medium deprived of fetal calf serum, but was supplemented by insulin, expressed mainly the CGRP mRNA. Dexamethasone was found to increase both CT and CGRP mRNAs in a time- and dose-dependent way without changing the alternative splicing. A slight but significant increase in the steady-state CT mRNA level was found 3 days after addition of 10(-10) M dexamethasone; the same dose slightly decreased the CGRP mRNA level; concentrations of dexamethasone > or = 10(-9) M elevated both mRNAs. A twelve-fold increase for CT mRNA, and an eightfold increase in CGRP mRNA occurred 3 days after administration of 10(-6) M dexamethasone. Kinetic data revealed inductions of both mRNAs 24 hours after exposure to 10(-7) M dexamethasone, and highest CT and CGRP mRNAs levels were observed after 72 hours of treatment. Calcium from 1-4 mM in short-term (1 hour and 4 hour) or long-term stimulations (1 day and 4 days), with or without dexamethasone cotreatment was ineffective. CT and CGRP mRNAs levels were both half-reduced 48 hours after addition of 10(-7) M 1,25-dihydroxycholecalciferol; this effect was transient, as it disappeared 2 days later.

Effects of 1,25-dihydroxycholecalciferol and calcium on calcitonin mRNA levels in suckling rats.

The chronic administration of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) to 9-day-old suckling rats induced no change on day 13 in the calcitonin (CT) mRNA steady-state level of thyroid glands measured by Northern hybridization. Thyroidal CT contents were decreased in relation to increased plasma calcium levels in animals treated with 0.1 or 1 microgram 1,25-(OH)2D3/kg. Using a lower dose (0.01 microgram/kg), neither plasma calcium, nor thyroidal CT contents were changed. No correlation was found between CT mRNA levels and thyroidal CT contents as well as for plasma CT levels and thyroidal CT contents since hormone in blood remained unchanged after treatment by the active vitamin D3 metabolite. Intraperitoneal calcium administration in fasted 13-day-old rats was associated with a 5-fold increase in plasma CT 30 min after injection, but CT mRNA levels were unchanged within 240 min. By contrast, stomach gavage with calcium in fasted 13-day-old rats induced a sustained increase in plasma CT (X2), and a 4-fold increase in the steady-state level of CT mRNA. Calcium per se is a potent stimulator of CT release in suckling rats, but did not change the amount of CT mRNA. However, gastrointestinal factors may be implied directly or indirectly in the increased CT mRNA level after calcium gavage. In conclusion, 1,25-(OH)2D3 which is known to affect CT gene expression in adult rats is ineffective in 13-day-old suckling rats. This observation may be related to developmental changes in the amount of 1,25-(OH)2D3 receptors of C cells.

Dexamethasone increases preproparathyroid hormone messenger RNA in human hyperplastic parathyroid cells in vitro.

To determine if parathyroid hormone release in man is directly stimulated by glucocorticoids, dispersed human parathyroid cells from hyperplastic glands obtained from eight renal transplant recipients were studied in vitro. Dexamethasone (10(-11) to 10(-6) mol l-1) increased PTH release in a time- and dose-dependent manner. A plateau was reached at 10(-8) mol l-1 (1015 +/- 149 vs. 230 +/- 27 pg 10(-4) cells for control value, after 24 h incubation; P less than 0.0001). An interaction with a glucocorticoid receptor was suggested since 10(-6) mol l-1 RU 486 blunted the dexamethasone-induced PTH release. By Northern blot analysis, dexamethasone was found to increase the amount of preproPTH mRNA in these cells. The effect of dexamethasone was probably at the gene level since (1) 1,25 dihydroxy vitamin D3 inhibited both iPTH and preproPTH mRNA increases induced by dexamethasone and (2) alpha-amanitin (1,25 micrograms ml-1) also completely suppressed the dexamethasone-induced PTH release. Thus, for the first time, we demonstrate that dexamethasone induces an increase of PTH synthesis, probably by increasing PTH gene transcription. This effect may play an important pathogenic role in persisting hyperparathyroidism and steroid-induced bone complications in renal transplant recipients.