The influence of acute and chronic hypercalcemia on the parathyroid hormone response to hypocalcemia in rabbits.
(49/502)
OBJECTIVE: To investigate the influence of acute and chronic hypercalcemia on the parathyroid hormone (PTH) response to hypocalcemia. DESIGN: The PTH response to hypocalcemia has been evaluated in three groups of rabbits: Group I, normal rabbits, Group II, normal rabbits subjected to an acute hypercalcemic clamp (induced by CaCl(2) infusion) and Group III, rabbits with chronic hypercalcemia (due to surgical reduction of renal mass). RESULTS: In Group I (baseline Ca(2+)=1.69+/-0.02 mM), hypocalcemia resulted in stimulation of PTH secretion which reached a maximum (PTHmax) of 91.7+/-6.4 pg/ml. In rabbits from Group II, which also had normal baseline Ca(2+) (1.70+/-0.02 mM), plasma Ca(2+) was maintained at an elevated level for 2 h, at around 2.05 mM. The PTH response to hypocalcemia in Group II was attenuated and the PTHmax in these rabbits was 45.6+/-7.4 pg/ml. In rabbits from Group III, baseline Ca(2+) was elevated (2.06+/-0.06 mM) for 1 month. The PTH response to hypocalcemia in Group III was esentially the same as in Group I and PTHmax reached levels of 94.8+/-9.9 pg/ml. CONCLUSIONS: A difference in PTH response to hypocalcemia has been found in rabbits after exposure to either acute or chronic hypercalcemia. After acute hypercalcemia, an attenuated PTH response to hypocalcemia has been identified. Chronic hypercalcemia, however, did not influence the PTH response to hypocalcemia. (+info)
Phase I trial of a novel diphtheria toxin/granulocyte macrophage colony-stimulating factor fusion protein (DT388GMCSF) for refractory or relapsed acute myeloid leukemia.
(50/502)
PURPOSE: Patients with relapsed or refractory acute myeloid leukemia have a poor prognosis. We tested the safety and efficacy of a diphtheria fusion protein [diphtheria toxin (DT)388 granulocyte-macrophage colony-stimulating factor (GMCSF)] directed against the GMCSF receptor that is strongly expressed by leukemic blasts. EXPERIMENTAL DESIGN: DT388GMCSF fusion protein containing the catalytic and translocation domains of DT388 fused to human GMCSF was administered in an interpatient dose escalation trial by 15 min i.v. infusion daily for up to 5 days. RESULTS: The maximal tolerated dose was 4 microg/kg/day. The dose-limiting toxicity was liver injury and occurred at the 4.5-5-microg/kg/day dose level. Among nine treated patients at these doses, one patient developed liver failure, and one patient had transient hepatic encephalopathy. There was a positive correlation between peak serum DT388GMCSF levels and serum aspartate aminotransferase (P = 0.0002). DT388GMCSF did not damage hepatic cell lines in vitro; however, DT388GMCSF binds macrophages and induces cytokine release in vitro. Among the treated patients, we observed an early elevation in serum levels of interleukin (IL)-18 and a later rise in IL-8 but no significant changes in IL-1beta, IL-6, IFNgamma, macrophage inflammatory protein-1alpha, tumor necrosis factor alpha or IL-12. The IL-18 elevations occurred before elevations of liver enzymes and correlated with peak aspartate aminotransferase levels (P = 0.005). Of the 31 patients who were resistant to chemotherapy, 1 had a complete remission and 2 had partial remissions; all 3 of these patients were treated at or above the maximal tolerated dose, all 3 responding patients had baseline marrow blast percentage of <30%, whereas only 6 of the nonresponding 28 patients had less than 30% marrow blasts. Five of these six patients were treated with subtherapeutic doses. Eight (42%) of 19 patient courses at <4 microg/kg/day and 8 (40%) of 20 patient courses at 4-5 microg/kg/day showed marrow blast reductions at day 12. Patients with higher pretreatment anti-DT388GMCSF levels had significantly lower peak DT388GMCSF levels (P = 0.0001). CONCLUSIONS: DT388GMCSF can produce complete and partial remissions in patients with chemotherapy-resistant acute myeloid leukemia, but methods to prevent liver injury are needed before more widespread application of this novel agent. (+info)
1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system.
(51/502)
Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor-null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis are still intact in the mutant mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] synthesis also led to an increase in renin expression, whereas 1,25(OH)(2)D(3) injection led to renin suppression. We found that vitamin D regulation of renin expression was independent of calcium metabolism and that 1,25(OH)(2)D(3) markedly suppressed renin transcription by a VDR-mediated mechanism in cell cultures. Hence, 1,25(OH)(2)D(3) is a novel negative endocrine regulator of the renin-angiotensin system. Its apparent critical role in electrolytes, volume, and blood pressure homeostasis suggests that vitamin D analogues could help prevent or ameliorate hypertension. (+info)
Lymphocyte-increasing action and hypocalcemic action of parotid gland extract.
(52/502)
It has previously been shown in our laboratory that the hypocalcemic substances purified from the thymus have a potent lymphocyte-increasing action in mice. Then, lymphocyte-increasing activity was examined with bovine parotid gland extracts, which showed a hypocalcemic activity as potent as that of the thymus extracts. The lymphocyte-increasing activity was assayed in the littermates of neonatal mice of Swiss-Webster strain; the materials used for this experiment were purified preparations and several fractions obtained from the parotid gland extracts in the course of purification. It was found that the potency of lymphocyte-increasing activity rose approximately in parallel with the rise in hypocalcemic activity with progress in purification. The final product, which was purified from the gland by isoelectric precipitation at pH 5.4, fractional precipitation with ammonium sulfate, chromatography on DEAE-cellulose, gel filtration on Sepharose 6B and preparative disc electrophoresis, gave a single band in polyacrylamide gel electrophoresis. Its intravenous injection in rabbits, in a dose of 10 mug/kg, produced a significant lowering in serum calcium (percent decrease 10.24 +/- 1.06%) compared with control animals given an injection of physiological saline. Intraperitoneal injection of this purified product, in a dose of 0.5 mug/mouse, in the littermates of neonatal mice, also produced a significant increase (ratio of lymphocytes to polymorphs 2.47 +/- 0.07) in lymphocytes compared with control animals injected with physiological saline (L/P ratio 1.57 +/- 0.05). These facts suggest that this purified protein fraction inherently contains both activities, but the possibility cannot be ruled out of slight contamination by a substance having a high activity. On the other hand, a fraction having no activity for lowering serum calcium but which had activity for increasing the lymphocytes was obtained. This is the first paper to report the presence of lymphocyte-increasing substances in the bovine parotid gland and the purification of one of the substances from the gland. (+info)
Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome.
(53/502)
The extracellular Ca(2+)-sensing receptor (CaSR) plays an essential role in extracellular Ca(2+) homeostasis by regulating the rate of parathyroid hormone (PTH) secretion and the rate of calcium reabsorption by the kidney. Activation of the renal CaSR is thought to inhibit paracellular divalent cation reabsorption in the cortical ascending limb (cTAL) both directly and indirectly via a decrease in NaCl transport. However, in patients with autosomal dominant hypocalcemia (ADH), caused by CaSR gain-of-function mutations, a defect in tubular NaCl reabsorption with renal loss of NaCl has not been described so far. This article describes a patient with ADH due to a gain-of-function mutation in the CaSR, L125P, associated with a Bartter-like syndrome that is characterized by a decrease in distal tubular fractional chloride reabsorption rate and negative NaCl balance with secondary hyperaldosteronism and hypokalemia. The kinetics of activation of the L125P mutant receptor expressed in HEK-293 cells, assessed by measuring CaSR-stimulated changes in intracellular Ca(2+) and ERK activity, showed a dramatic reduction in the EC(50) for extracellular Ca(2+) compared with the wild-type and a loss-of-function mutant CaSR (I40F). This study describes the first case of ADH associated with a Bartter-like syndrome. It is herein proposed that the L125P mutation of the CaSR, which represents the most potent gain-of-function mutation reported so far, may reduce NaCl reabsorption in the cTAL sufficiently to result in renal loss of NaCl with secondary hyperaldosteronism and hypokalemia. (+info)
Unilateral versus bilateral neck exploration for primary hyperparathyroidism: a prospective randomized controlled trial.
(54/502)
OBJECTIVE: To compare unilateral and bilateral neck exploration for primary hyperparathyroidism in a prospective randomized controlled trial. SUMMARY BACKGROUND DATA: Based on the assumption that unilateral neck exploration for a solitary parathyroid adenoma should reduce operating time and morbidity, a variety of minimally invasive procedures have challenged the idea that bilateral neck exploration is the gold standard for the surgical treatment of primary hyperparathyroidism. However, to date, no open prospective randomized trial has been published comparing unilateral and bilateral neck exploration. METHODS: Ninety-one patients with the preoperative diagnosis of primary hyperparathyroidism were randomized to unilateral or bilateral neck exploration. Preoperative scintigraphy and intraoperative parathyroid hormone measurement guided the unilateral exploration. Gross morphology and frozen section determined the extent of parathyroid tissue resection in the bilateral group. The primary end-point was the use of postoperative medication for hypocalcemic symptoms. RESULTS: Eighty-eight patients (97%) were cured. Histology and cure rate did not differ between the two groups. Patients in the bilateral group consumed more oral calcium, had lower serum calcium values on postoperative days 1 to 4, and had a higher incidence of early severe symptomatic hypocalcemia compared with patients in the unilateral group. In addition, for patients undergoing surgery for a solitary parathyroid adenoma, unilateral exploration was associated with a shorter operative time. The cost for the two procedures did not differ. CONCLUSIONS: Patients undergoing a unilateral procedure had a lower incidence of biochemical and severe symptomatic hypocalcemia in the early postoperative period compared with patients undergoing bilateral exploration. Unilateral neck exploration with intraoperative parathyroid hormone assessment is a valid surgical strategy in patients with primary hyperparathyroidism with distinct advantages, especially for patients with solitary parathyroid adenoma. (+info)
Applicability of intraoperative parathyroid hormone assay during thyroidectomy.
(55/502)
OBJECTIVE: To evaluate the applicability of intraoperative parathyroid hormone (quick PTH) assay to monitor parathyroid function and to identify clinically significant hypocalcemia compared with postoperative serum calcium monitoring. SUMMARY BACKGROUND DATA: Close monitoring of serum calcium levels is a standard of care to identify post-thyroidectomy hypocalcemia due to parathyroid insufficiency. METHODS: Quick PTH assay was performed before and after thyroidectomy for 100 patients at risk of postoperative hypocalcemia and 20 control patients who underwent unilateral lobectomy. Postoperative serum calcium levels were closely monitored. RESULTS: Control patients had a normal but 38.9 +/- 5.9% (mean +/- SEM) decline in quick PTH after thyroidectomy. Eleven of 100 at-risk patients (11%) developed postoperative hypocalcemia. Hypocalcemic patients had significantly lower quick PTH values after thyroidectomy compared with that of normocalcemic patients. Serum calcium was significantly lower in hypocalcemic patients the morning after operation but not early after the operation (within 6 hours). A normal or less than 75% decline in quick PTH after thyroidectomy can accurately identify normocalcemic patients during surgery as compared to more than 24 hours by serum calcium monitoring. CONCLUSIONS: The quick PTH assay can monitor parathyroid function during thyroidectomy and identify patients at risk of clinically significant hypocalcemia much earlier than serum calcium monitoring. It may facilitate early discharge and the use of parathyroid autotransplantation during thyroidectomy. (+info)
Regulation of parathyroid vitamin D receptor expression by extracellular calcium.
(56/502)
Low extracellular calcium (Ca) stimulates parathyroid hormone (PTH) secretion and also increases the renal synthesis of calcitriol (CTR), which is known to decrease PTH production. This study began with the hypothesis that the parathyroid cell response to CTR may be modulated by extracellular Ca concentration through an effect on parathyroid cell vitamin D receptor (VDR). In the present study, rat parathyroid glands were incubated in low (0.6 mM) and high (1.5 mM) Ca concentration. The parathyroid VDRmRNA was higher in 1.5 than 0.6 mM Ca. Furthermore, this effect was not observed in incubated slices of kidney cortex and medulla, tissues which also possess both Ca and vitamin D receptors. Experiments were also performed to evaluate the effect of Ca on VDR expression in vivo. Male Wistar rats received intraperitoneal injections of CaCl(2) or a single intramuscular injection of EDTA to obtain 6 h of hypercalcemic (ionized Ca, 1.4 to 1.6 mM) or hypocalcemic (ionized Ca, 0.85 to 0.95 mM) clamp; a third group of rats was used as control. A small dose of CTR was administered to hypercalcemic rats to match the serum CTR levels of hypocalcemic rats. Parathyroid gland VDRmRNA and VDR protein were increased in hypercalcemic rats as compared with hypocalcemic rats. Increasing doses of CTR upregulated VDRmRNA and VDR only in hypercalcemic rats. Additional experiments showed that the decrease in VDR in hypocalcemic rats prevented the inhibitory effect of CTR on PTHmRNA. In conclusion, our study shows that extracellular Ca regulates VDR expression by parathyroid cells independently of CTR and that by this mechanism hypocalcemia may prevent the feedback of CTR on the parathyroids. (+info)