Comparison between intact and bioactive parathyroid hormone assays in patients with severe heart failure.

OBJECTIVES: Parathyroid hormone (PTH) is a major systemic calcium-regulating hormone. Recent evidence has suggested that measurement of PTH might provide complementary information for the diagnosis and risk stratification of patients with heart failure (HF). The aim of our study was to compare intact and bioactive PTH assays in patients with severe heart failure. DESIGN AND METHODS: The following measurements were carried out in blood samples from 73 patients with severe heart failure: bioactive PTH (1-84) assay, intact PTH assay, non-PTH (1-84), 25-hydroxyvitamin D, B-type natriuretic peptide (BNP), N-terminal proBNP (Nt-proBNP), Galectin-3 and high sensitive troponin T (hsTnT). RESULTS: The correlation between intact and bioactive PTH assays was very high in HF patients. However, the bioactive PTH concentrations were lower than those measured with the intact assay. Intact and bioactive PTH as well as non-PTH (1-84) was significantly and positively correlated to BNP, Nt-proBNP, and galectin-3 but not to hsTnT. The strongest relationships with these cardiac biomarkers and with cardiovascular death were observed with the bioactive PTH assay. CONCLUSIONS: The PTH concentrations obtained with intact and bioactive assays are not comparable in patients with severe HF. The specificity of PTH assays might therefore impact on the potential diagnosis and prognosis values of PTH testing in patients with heart failure.

Cyclic feeding behaviour and changes in hypothalamic galanin and neuropeptide Y gene expression induced by zinc deficiency in the rat.

Dietary zinc-deficiency induces a striking reduction and a cyclic pattern of food intake in rodents. To elucidate the mechanisms for these effects, we studied the hypothalamic content, synthesis, and distribution of galanin (GAL) and neuropeptide Y (NPY) during zinc deficiency and refeeding in the rat. In Wistar rats, three weeks of zinc-deprivation consistently induced a reduction and a cyclic pattern of night- and day-time food intake, as well as of water intake. This was accompanied in zinc-deficient (ZD) rats, and to a lesser extent in pair-fed (PF) rats, by a decrease of hypothalamic GAL mRNA concentration (CTR: 100 +/- 8, ZD: 61 +/- 4, PF: 78 +/- 2 arbitrary densitometric units, ADU, P < 0.01) and an increase of hypothalamic NPY (CTR: 100 +/- 11, ZD: 154 +/- 10, PF: 126 +/- 4 ADU, P < 0.05), without peptide modification. The two neuropeptidergic systems were not affected by the cycles of feeding, with the exception of the NPY-immunoreactivity in the suprachiasmatic nuclei (geniculo-hypothalamic tract), that was inversely correlated to the food intake in both ZD and PF animals. In a second experiment, we showed that zinc-repletion for 4 days suppressed the behaviour induced by a two-week zinc-deprivation, and reversed the increase of NPY mRNA in ZD animals. We finally demonstrated that zinc-deficiency induced a similar behaviour in Zucker rats. However, in these rats whose synthesis of NPY is constitutively up-regulated, no change of NPY synthesis was observed in ZD rats, suggesting that the increase observed in Wistar is adaptative rather than instrumental to the abnormal food intake. In conclusion, we have further characterized the cyclic feeding behaviour of the zinc-deficient Wistar rats, and shown in these animals a decreased activity of the GAL system and an increased activity of the NPY system, likely corresponding to a compensatory response of the two neuropeptidergic systems, as observed in food-deprived animals. As spontaneous food intake of ZD rats does not increase, a resistance to NPY could also be present. These behavioural and neuropeptidergic changes were partially reversed by reintroduction of zinc in the diet. In Zucker rats, the same behaviour occurred despite an insensitivity of the NPY system to the zinc-deficiency. In addition, we describe a nutritional regulation of the NPY-immunoreactivity in the geniculo-hypothalamic tract, that could constitute the substrate of circadian rhythm modulation by timed feeding.

Zinc supplementation increases growth and circulating insulin-like growth factor I (IGF-I) in growth-retarded Vietnamese children.

To determine whether zinc deficiency might be involved in the failure to thrive observed in undernourished Vietnamese children, we assessed growth, incidence of infections, and circulating insulin-like growth factor I (IGF-I) concentrations in a double-blind study of zinc supplementation. Growth-retarded children (n=146) aged 4-36 mo were paired according to age, sex, commune, Z scores for weight (WAZ) and for height (HAZ), and number of siblings, and were randomly assigned to receive either 153 micromol (10 mg) Zn/d or a placebo for 5 mo. Weight, height, and episodes of infection were recorded each month and plasma IGF-I was measured 1 and 5 mo after the start of zinc supplementation. Multiple-linear-regression analysis for paired data showed that zinc supplementation increased weight (+0.5 +/- 0.1 kg; P<0.001) and height (+1.5+/-0.2 cm; P<0.001) after 5 mo compared with placebo treatment. The relative risk of infectious episodes in the zinc-treated subjects was reduced 3-fold for diarrhea (P=0.012) and 2.5-fold for respiratory infections (p=0.057). The probability of having at least two episodes of diarrhea or respiratory infection was 2.9- and 3.2-fold lower, respectively, in zinc-treated subjects between 1 and 5 mo (P=0.018), whereas they did not change in placebo-treated subjects (P-0.584). After 1 mo, IGF-I concentration (-x+/-SD) in zinc-treated subjects was 2.8+/-0.3 nmol/L compared with 1.9+/-0.2 nmol/L in placebo-treated subjects (P=0.021). After 5 mo, the values were 3.4+/-0.5 nmol/L (zinc-treated) and 2.0+/-0.3 nmol/L (placebo-treated; P=0.044). Our study suggests that zinc deficiency may limit growth in nutritionally deprived children. Because the increase in growth velocity resulting from zinc supplementation was associated with increased plasma IGF-I concentrations, we suggest that the growth-stimulating effect of zinc might be mediated through changes in circulating IGF-I.

Expression of the endothelin-1 gene in the rat thyroid gland and changes in its peptide and mRNA levels in goiter formation and iodide-induced involution.

Endothelin-1 (ET-1) is a major vasoconstrictor peptide, first found in endothelial cells, and later in many other tissues, including the thyroid gland. We analysed the expression of the ET-1 gene in the rat thyroid gland and changes in ET-1 mRNA and peptide levels in goiter development and involution, two circumstances characterised by vascular changes. Thyroid hyperplasia was induced in adult Wistar rats by feeding a low iodine diet (LID) supplemented with 0.25% thiouracil for 10 days, and LID alone for 2 further days (H.12 group). Involution was induced by injecting 100 micrograms iodide and refeeding a normal diet during 6 h, 12 h, and 24 h (I.6h, I.12h, I.24h groups). Rats fed a normal iodine diet were used as controls. A specific 488 bp cDNA corresponding to the known sequence of pre-pro ET-1 was found by RT-PCR from RNA extracts in all thyroid experimental groups, as well as in lung and kidney which were used as positive controls. RP-HPLC analysis showed that ET-1 immunoreactivity eluted similarly as mature ET-1. During hyperplasia, ET-1 mRNA and peptide levels were increased 3.5- and 5-fold respectively. The relative volume of the vascular bed was more than doubled. During iodide-induced involution, the glandular ET-1 mRNA level remained elevated. The concentration of ET-1 peptide increased and was significantly greater at 12 h involution than in the H.12 group. At this time, the capillary reticulum reverted to individual capillaries and the vascular bed was significantly reduced. These data demonstrate that the ET-1 gene is expressed in the rat thyroid gland and that the ET-1 mRNA and peptide levels are increased during thyroid hyperplasia and remain elevated during a phase of rapid iodide-induced involution. These data suggest that changes in ET-1 production may play a role in control of thyroid gland trophic regulation and vascularity.

Nutritional regulation of the insulin-like growth factors.

Nutrition is one of the main regulators of circulating IGF-I. In humans, serum IGF-I concentrations are markedly lowered by energy and/or protein deprivation. Both energy and proteins are critical in the regulation of serum IGF-I concentrations. Indeed, after fasting, optimal intake of both energy and protein is necessary for the rapid restoration of circulating IGF-I. We believe, however, that in adult humans energy may be somewhat more important than protein in this regard. While the lowest protein intake is able to increase IGF-I in the presence of adequate energy, there is a threshold energy requirement below which optimal protein intake fails to raise IGF-I after fasting. When energy intake is severely reduced, the carbohydrate content of the diet is a major determinant of responsiveness of IGF-I to GH. The essential amino acid content of the diet is also critical for the optimal restoration of IGF-I after fasting, when protein intake is reduced. The exquisite sensitivity of circulating IGF-I to nutrients, the nycthemeral stability of its concentrations and its relative short half-life constitute the basis for its use as a marker of both nutritional status and adequacy of nutritional rehabilitation. For these indications, IGF-I measurement is more sensitive and more specific than measurement of the other nutrient-related serum proteins (albumin, prealbumin, transferrin, retinol-binding protein). Animal models have been developed to investigate the mechanisms responsible for the nutritional regulation of IGF-I. There is no doubt that many mechanisms are involved (Fig. 12). Decline of serum IGF-I in dietary restriction is independent of the diet-induced alterations in pituitary GH secretion. The role of the liver GH receptors is dependent on the severity of the nutritional insult. In severe dietary restriction (fasting), a marked decrease of the number of somatogenic receptors supports the role of a receptor defect in the decline of circulating IGF-I. In contrast, in less severe forms of dietary restriction (protein restriction), the decline of IGF-I results from a postreceptor defect in the GH action at the hepatic level. Nutritional deprivation decreases hepatic IGF-I production by diminishing IGF-I gene expression. Decline in IGF-I gene expression is mainly caused by nutrient deficiency and less importantly by the nutritionally induced hormonal changes (insulin and T3). Diet restriction also increases the clearance and degradation of serum IGF-I through changes in the levels of circulating IGFBPs.(ABSTRACT TRUNCATED AT 400 WORDS)