Galanin modulates human and murine neutrophil activation in vitro.

AIMS: Polymorphonuclear neutrophils are key players in innate immunity. The innate immune system needs to be tightly controlled to ensure proper activation but also no overactivation. Galanin has been shown to regulate inflammatory reactions, and therefore, we aimed to elucidate the expression of galanin and its three receptors (GAL1 -GAL3 ) in polymorphonuclear neutrophils and to evaluate whether galanin exerts direct or indirect effects on human and murine polymorphonuclear neutrophils. METHODS: Human peripheral polymorphonuclear neutrophils were isolated from fresh blood of healthy donors, and murine polymorphonuclear neutrophils were isolated from bone marrow of C57BL/6N mice. Gene expression was evaluated by qRT-PCR. As a marker for polymorphonuclear neutrophil activation, CD11b integrin surface expression was measured by FACS analysis. Furthermore, a label-free technology measuring ligand-induced dynamic mass redistribution was used to evaluate the response of polymorphonuclear neutrophils to galanin. RESULTS: GAL2 receptor expression was found in both human and murine polymorphonuclear neutrophils, galanin and GAL3 receptor were exclusively expressed in murine bone marrow polymorphonuclear neutrophils, and GAL1 receptor was not detectable in polymorphonuclear neutrophils of either species. Galanin treatment was not able to induce CD11b integrin surface expression or dynamic mass redistribution in human polymorphonuclear neutrophils and murine bone marrow polymorphonuclear neutrophils. However, galanin treatment significantly enhanced the response of polymorphonuclear neutrophils of both species to interleukin-8. CONCLUSION: Galanin can be regarded as an immunomodulatory peptide as it can sensitize polymorphonuclear neutrophils towards pro-inflammatory cytokines in humans and mice.

Short-term inhibition of parathyroid hormone secretion by a calcium-receptor agonist in patients with primary hyperparathyroidism.

BACKGROUND: Surgery is the usual therapy for patients with primary hyperparathyroidism. We investigated the ability of a calcimimetic drug that inhibits parathyroid hormone secretion in vitro to decrease serum parathyroid hormone and calcium concentrations in patients with this disorder. METHODS: We performed a randomized, placebo-controlled study of single oral doses of 4 to 160 mg of the calcium-receptor agonist drug R-568 in 20 postmenopausal women with mild primary hyperparathyroidism. At base line, the mean (+/-SE) serum calcium concentration was 10.7+/-0.2 mg per deciliter (2.67+/-0.05 mmol per liter). Serum parathyroid hormone and calcium were measured repeatedly after each dose, and safety was assessed. RESULTS: Administration of R-568 resulted in a dose-dependent inhibition of parathyroid hormone secretion. The mean serum parathyroid hormone concentration, which was 77+/-11 pg per milliliter (18.8+/-2.7 pmol per liter; normal range, 16 to 65 pg per milliliter [3.9 to 15.9 pmol per liter) at base line, fell by 26+/-8 percent after 20 mg of R-568 (P=0.03), by 42+/-7 percent after 80 mg (P = 0.01), and by 51+/-5 percent after 160 mg (P=0.005). Serum ionized calcium concentrations fell only after the 160-mg dose, with the decrease closely following the decrease in the serum parathyroid hormone concentration. CONCLUSIONS: The calcimimetic drug R-568 reduces serum parathyroid hormone and ionized calcium concentrations in postmenopausal women with primary hyperparathyroidism.

Optimal dietary calcium intake in primary hyperparathyroidism.

PURPOSE: The purpose of this study was to investigate whether dietary calcium intake in primary hyperparathyroidism is associated with differences in bone mineral density and biochemical parameters, and to determine whether these observations are related to 1,25-dihydroxyvitamin D. PATIENTS AND METHODS: Dietary calcium intake was determined from diet records in 71 unselected patients enrolled in an ongoing longitudinal study on the natural history of primary hyperparathyroidism. Subjects were placed into one of three dietary calcium groups based on their mean dietary calcium intake: very low (< 300 mg/day; mean = 199 +/- 14), low (300 to 800 mg/day; mean = 529 +/- 21), and US RDA (> 800 mg/day; mean = 1023 +/- 73). Biochemical indices were indicative of patients with modern day primary hyperparathyroidism, showing mild hypercalcemia (2.79 +/- 0.02 mmol/L), low normal serum phosphorus (0.90 +/- 0.03 mmol/L), elevated parathyroid hormone levels by midmolecule (764 +/- 69 pg/mL) and immunoradiometric (118 +/- 8 pg/mL) assays, and high normal 1,25-dihydroxyvitamin D (60 +/- 3 pg/mL) and urinary calcium excretion (6.3 +/- 0.4 mmol/day). Bone mineral density was measured by dual energy x-ray absorptiometry at the lumbar spine, right femoral neck and distal third of the nondominant radius for each subject. RESULTS: Over the entire range, there was no significant effect of dietary calcium on serum parathyroid hormone levels, calcium, phosphorus, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, urinary calcium excretion, or bone mineral density of the lumbar spine, femoral neck or distal one-third radius. Serum 1,25-dihydroxyvitamin D was elevated in 37 patients (52%). Despite similarly low dietary calcium intake among patients with normal and elevated levels of 1,25-dihydroxyvitamin D (477 +/- 50 mg/day vs. 533 +/- 40 mg/day), patients with elevated levels of 1,25-dihydroxyvitamin D had higher parathyroid hormone levels by immunoradiometric assay (136 +/- 11 pg/mL vs. 97 +/- 10 pg/mL; P < .05), and urinary calcium (7.4 +/- 0.05 mmol/day vs. 5.1 +/- 0.05 mmol/day; P < .05 or 0.82 +/- 0.04 mmol/mmol creatinine vs. 0.56 +/- 0.04 mmol/mmol creatinine; P < .01). CONCLUSIONS: The data suggest that patients with normal levels of 1,25-dihydroxyvitamin D can liberalize their calcium intake without adverse consequences. However those with elevated levels of 1,25-dihydroxyvitamin D are advised to be more restrictive in order to prevent hypercalciuria.

Hormonal regulation of calcium homeostasis.

Several hormones play a role in calcium homeostasis. PTH and 1,25(OH)2D exert their effects on the skeleton, kidney, and gastrointestinal tract, maintaining normal levels of calcium and phosphate in both blood and extracellular fluid. Regulation of bone turnover, reabsorption of calcium and phosphate from the glomerular filtrate, and absorption of calcium and phosphate from the diet are mechanisms by which homeostasis is preserved. Calcitonin may be involved in calcium homeostasis, but its role is less well defined.

Vertebral osteopenia: a new indication for surgery in primary hyperparathyroidism.

Most patients with primary hyperparathyroidism have reduced radial and preserved vertebral bone density. We have identified a subset of patients with low lumbar spine bone density at diagnosis. This study assessed the effect of parathyroidectomy (undertaken based upon accepted surgical guidelines) or nonintervention on bone mineral density (BMD) in these patients. Twenty-two of 143 (15%) patients with mild primary hyperparathyroidism had lumbar spine BMD more than 1.5 SD below the mean for an age- and sex-matched population (z-score). Fourteen underwent parathyroidectomy, whereas 8 were followed with no intervention. All had annual BMD measurements for 4 yr after enrollment or after surgery. After parathyroidectomy, there was a brisk sustained rise in lumbar spine BMD [yr 1, 15 +/- 3% (P < 0.005); yr 4, 21 +/- 4% (P < 0.01)]. In those followed without surgery, BMD did not change significantly at any site. Postmenopausal women showed the same pattern as the cohort as a whole, i.e. increased BMD after surgery [yr 1, 13 +/- 3% (P < 0.01); yr 4, 16 +/- 5% (P < 0.01)], but no worsening was found with nonintervention despite the passage of years in the menopause. We conclude that parathyroidectomy markedly improves lumbar spine BMD in patients with vertebral osteopenia. It is proposed that reduced cancellous bone density should become a new indication for surgery in primary hyperparathyroidism.