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Biomedical subjects

M Garabédian

Publications and source records attributed to M Garabédian.

At least 19 recordsLinked to original sources
PubMed2000

[Prevention of vitamin D deficiency in adolescents and pre-adolescents. An interventional multicenter study on the biological effect of repeated doses of 100,000 IU of vitamin D3].

UNLABELLED: Recent studies have shown a high prevalence of calcium and vitamin D deficiencies in adolescents. The aim of this present study was to follow the changes in calcium status and 25 hydroxyvitamin D (25[OH]D) and parathyroid hormone (iPTH) levels during winter in preadolescents and adolescents from four university hospitals in northern France. SUBJECTS AND METHODS: Two groups of teenagers and adolescents (range: 10-15 years) were followed from October 1996 to June 1997. They were given either 100,000 IU of vitamin D (treated group n = 33) or a placebo (control group n = 35) in October, January and April. Serum calcium, phosphate, 25(OH)D and iPTH levels were measured at inclusion and every three months thereafter. RESULTS: At inclusion, plasma or serum 25(OH)D levels were < or = 10 ng/mL in 16 subjects and < 6 ng/mL in six. In control children, no significant change in 25(OH)D occurred during the study, while plasma or serum iPTH levels increased to 34 +/- 11 pg/mL. In the treated groups, 25(OH)D levels remained > 20 ng/mL in every subject; no hypercalcemia was observed; and the mean plasma or serum iPTH level was 25 +/- 14 pg/mL at the end of the study. CONCLUSION: Teenagers presented with a high prevalence of biological vitamin D deficiency at the end of summer. The increase of iPTH during winter in the unsupplemented group suggests that this has secondary consequences on their calcium homeostasis unless they are supplemented with vitamin D. We advocate a sufficient calcium supply and a 100,000 IU vitamin D supplement given two or three times during winter to preadolescents and adolescents living in northern France.

Adolescent↗
PubMed2000

A large homozygous or heterozygous in-frame deletion within the calcium-sensing receptor's carboxylterminal cytoplasmic tail that causes autosomal dominant hypocalcemia.

Autosomal dominant hypocalcemia (ADH) can result from heterozygous missense activating mutations of the calcium-sensing receptor (CaSR) gene, a G-protein-coupled receptor playing key roles in mineral ion metabolism. We now describe an ADH kindred of three generations caused by a novel CaSR mutation, a large in-frame deletion of 181 amino acids within its carboxylterminal-tail from S895 to V1075. Interestingly, the affected grandfather is homozygous for the deletion but no more severely affected than heterozygous affected individuals. Functional properties of mutant and wild-type (WT) CaSRs were studied in transiently transfected, fura-2-loaded human embryonic kidney (HEK293) cells. The mutant receptor exhibited a gain-of-function, but there was no difference between cells transfected with mutant complementary DNA alone or cotransfected with mutant and WT complementary DNAs, consistent with the similar phenotypes of heterozygous and homozygous family members. Therefore, this activating deletion may exert a dominant positive effect on the WT CaSR. The mutant receptor's cell surface expression was greater than that of the WT CaSR, potentially contributing to its gain-of-function. This novel mutation in the CaSR gene provides the first known examples of a large naturally occurring deletion within a G-protein-coupled receptor's carboxylterminal-tail and of a homozygous, affected individual with ADH.

Adult↗
PubMed1999

[Prevention of vitamin D deficiency in the child and adolescent. I. Proposal and arguments for use of a decision tree].

A decision-making table, using three questionnaires, is proposed to determine the vitamin D status in children and adolescents. The first questionnaire assesses the vitamin D endogenous synthesis, taking into account the sunlight exposure and the time interval out of the sun. The second questionnaire quantifies the vitamin D dietary intake within three levels: optimal, medium or low. In case of a medium dietary score, a third questionnaire evaluates the daily calcium intake, taking into account the fact that vitamin D metabolism is increased by a low calcium intake (under 400 mg/day). This decision-making table should enable the detection of children and adolescents at risk of vitamin D deficiency and requiring an adapted prophylaxis. Its accuracy will be assessed in prospective surveys.

Adolescent↗
PubMed1999

Effects of IGF-I on 1,25-dihydroxyvitamin D(3) synthesis by human placenta in culture.

The aim of the present study was to assess the effects of insulin-like growth factor I (IGF-I) upon the synthesis of 1, 25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] by human placenta trophoblasts in culture. Cytotrophoblastic cells obtained from normal term human placentae were cultured in Dulbecco's modified Eagle's medium with HEPES and glucose (DMEM-HG) during 72 h and further incubated in serum-free DMEM-F12 in the presence of IGF-I prior to the addition of [(3)H]-25-(OH)D(3) used as a precursor. The results showed that 2 h preincubation time with IGF-I was required for maximal production of [(3)H]-1,25-(OH)(2)D(3). Cultures in the presence of increasing concentrations of IGF-I (0-6.5 nmol/l), added 2 h before incubation with the labelled substrate, resulted in a dose-dependent response increment of [(3)H]-1,25-(OH)(2)D(3) production with a maximal conversion rate at the dose of 2.6 nmol/l. Higher doses of IGF-I did not result in further stimulatory effects. Co-incubations in the presence of cycloheximide significantly (P < 0. 0001) inhibited the IGF-I-mediated effects upon [(3)H]-1, 25-(OH)(2)D(3) production. Identity of putative [(3)H]-1, 25-(OH)(2)D(3) produced by human placenta was confirmed by spectral and receptor binding analysis. These results demonstrate the ability of cultured human syncytiotrophoblast cells to convert 25-(OH)D(3) to 1,25-(OH)(2)D(3) and suggest a local protein-dependent regulatory effect of IGF-I upon this biotransformation.

Calcifediol↗
PubMed1999

Resistance to the lipolytic action of epinephrine: a new feature of protein Gs deficiency.

Deficiency of protein Gs (Gs; OMIM no.103580), the stimulatory regulator of adenylyl cyclase, is associated with resistance to PTH and other hormones, sc calcifications, short stature, and skeletal defects (Albright's hereditary osteodystrophy). It is caused by heterozygous loss of function mutations in GNAS 1, the gene encoding the alpha-subunit of Gs. Obesity is a classical feature of patients with Gs deficiency, but the mechanism leading to fat accumulation has not been elucidated. We measured glycerol flux, using a nonradioactive tracer dilution approach, to analyze the lipolytic response to epinephrine in 6 patients with Gs deficiency and PTH resistance and compared it to six age-matched normal controls and nine massively obese children. Basal glycerol production was reduced by 50%, and lipolytic response to epinephrine was reduced by 67%, in Gs-deficient children, as compared with controls. The degree of impairment of lipolysis was similar in Gs-deficient children who were only moderately overweight and in morbidly obese children. These findings extend the spectrum of hormonal resistance in Gs deficiency. Besides beta-adrenergic receptors, Gs protein itself should be examined as a possible step involved in the decreased lipolysis observed in common obesity.

Blood Glucose↗
PubMed1999

Hypocalcemia and chromosome 22q11 microdeletion.

This review of the diagnosis, causes, prevention and treatment of hypocalcemia emphasizes the high incidence of this biological alteration in patients with 22q11 microdeletion. It also points out its large spectrum of presentation, from cases where the most prominent feature of the syndrome is hypocalcemia with hypoparathyroidism, to cases with asymptomatic, latent or late-onset hypocalcemia. Hence, the advice to perform genetic analysis of the 22q11 region in patients with late-onset or recurrent hypoparathyroidism and to systematically include serum calcium in the survey of patients with known 22q11 microdeletion, especially during infancy, adolescence and pregnancy and especially during cardiac surgery or sepsis.

Adolescent↗
PubMed1998

[Hypocalcemia].

Hypocalcemia may be presently defined as a serum calcium value below the reference range, usually below 8,4 mg/dL, in neonates as well as adults. This alteration may remain asymptomatic or be associated with severe clinical disorders. Its causes include classical pathologies such as vitamin D deficiency, hereditary or acquired resistances to vitamin D, hypomagnesemia, hypoparathyroidisms and resistances to parathyroid hormone, renal insufficiency and massive cellular lysis. They also include iatrogenic causes as well as recently isolated diseases, like the hypocalcemic syndrome due to mutations in the calcium-sensing receptor gene. The management of hypocalcemia depends on its causes, clinical consequences, severity, and on the age of the patient.

Adult↗
PubMed1998

Interactive effect of estradiol and vitamin D receptor gene polymorphisms as a possible determinant of growth in male and female infants.

An association between vitamin D receptor (VDR) gene polymorphism and body size has been observed in infants. We hypothesized that the estradiol receptor (ER) gene is another determinant of infant growth and that the effects of the VDR and ER genotypes may interact with each other. The ER genotype (PvuII and XbaI sites), VDR genotype (BsmI site), and body size during the first 2 yr of life were analyzed in 161 healthy Caucasian full-term babies homozygous for the BsmI polymorphism of the VDR gene (BB or bb). There was no significant association between ER polymorphism and 1) body weight in boys and girls, 2) body length in girls, or 3) body length in boys with a bb genotype. In contrast, ER polymorphism and body length were significantly associated in BB boys. Boys with the BBpp genotype were shorter at birth (P < 0.005) and at 10 months of age (P < 0.001) than boys with other genotypes. They were even shorter than girls with the same genotype. These results indicate some degree of interaction between the effects of the VDR and ER genes, leading to significant variations in body growth during infancy, especially in boys.

Anthropometry↗
PubMed1997

[Fortified milk and supplements of oral vitamin D. Comparison of the effect of two doses of vitamin D (500 and 1,000 UI/d) during the first trimester of life].

BACKGROUND: Administration of oral vitamin D supplements has been the usual strategy used in France for the prevention of rickets. But this strategy needs reevaluation since the fortification of infant formulas with vitamin D is authorized in this country. We report the effects of oral daily supplements of vitamin D on the calcium metabolism and vitamin D status of infants receiving or not fortified milk during the first trimester of life. POPULATION AND METHODS: Circulating levels of 25-hydroxyvitamin D (25-(OH)D) were measured: 1) in 64 infants aged 1 to 4 months, seen as outpatients between February and October, given oral vitamin D2 (theoretically 1,000 IU/d) and fed infant formulas, fortified or not with vitamin D; 2) in healthy neonates born to unsupplemented (n = 48) or supplemented vitamin D mothers (n = 22), between April and July, followed from birth (n = 70) to 3 months of age (n = 52), fed fortified milk, and given either 500 or 1,000 IU/D of vitamin D2. Serum calcium, phosphate, intact parathyroid hormone levels and alkaline phosphatase activities were simultaneously measured in this second study. RESULTS: In the first study, the infants who had been seen during the summer and fed fortified milk had 25-(OH)D levels higher than those seen during the winter and fed the unfortified formulas (37.0 +/- 11.2 ng/mL vs 29.1 +/- 9.7 ng/mL, P = 0.013). But when daily supplements of vitamin D2 were strictly controlled (second study), all infants fed the fortified milk had 25-(OH)D levels within the adult range (10 to 37 ng/mL) at 1 and 3 months of age, whatever their vitamin D status at birth and although these infants were seen during the summer. No difference was found between infants given 500 or 1,000 IU/d as regards their mean serum calcium, phosphate and alkaline phosphatase activities. In addition, the percentage of infants with calcemia above 2.60 mM/L was even lower with the 1,000 IU/d vitamin D dosage than with the 500 IU/d dosage. CONCLUSIONS: Daily supplements of vitamin D2 (500 to 1,000 IU/d) during the first trimester of life do not appear to induce a significant vitamin D overload when fortified milk is given to the infants. These supplementations may thus be maintained, especially when neonates are at risk of vitamin D deficiency.

25-Hydroxyvitamin D 2↗
PubMed1997

[Primary hypothyroidism revealing pseudohypoparathyroidism without hypocalcemia and hyperphosphoremia].

BACKGROUND: Type la pseudohypoparathyroidism is due to a molecular defect causing Gs protein deficiency. It is responsible for multi-hormonal resistance and skeletal abnormalities. Parathyroid hormone resistance can be subtle so that the diagnosis can be difficult in patients with atypical manifestations. CASE REPORT: A 10-year-old boy was first referred for growth retardation (height standard deviation score: -2.8). He had short metacarpals, and scaphocephaly. Laboratory findings revealed an elevation of plasma TSH (8,8 microU/mL) with normal thyroid hormone levels. The investigations ruled out common causes of compensated hypothyroidism. Despite normal blood calcium and phosphate levels, parathyroid hormone was elevated to 358 pg/mL (normal values: 10-60) without renal failure, suggestive of hormonal resistance. The diagnosis of pseudohypoparathyroidism type la was confirmed by a 50% reduction of Gs activity. Melanodermia, associated with an elevation of ACTH was suggestive of ACTH resistance without MSH resistance. Moreover, skeletal radiography showed a narrow lumbar canal. CONCLUSION: Type la pseudoypoparathyroidism could be part of the etiological diagnosis of primary hypothyroidism, even in the absence of hypocalcemia and hyperphosphatemia. Similarly, skeletal abnormalities extend beyond the classical features of Albright's osteodystrophy.

Calcium↗
PubMed1997

Subclinical vitamin D deficiency in neonates: definition and response to vitamin D supplements.

To determine the biological criteria for neonatal vitamin D deficiency, serum 25-hydroxyvitamin D (calcidiol), parathyroid hormone (PTH), calcium, phosphates, and alkaline phosphatase (ALP) activity were measured during the winter-spring period in 80 healthy neonates and their mothers 3-6 d after delivery. A longitudinal 3-mo survey of the serum biology of 52 of these neonates consuming formula was also performed to test the influence of their neonatal vitamin D status on the effects of two oral ergocalciferol supplements (500 and 1000 IU or 12.5 and 25 micrograms/d). At birth, 63.7% of the infants had calcidiol concentrations < or = 30 nmol/L. Most of them had no other biological sign evocative of vitamin D deficiency, but 14 neonates had low calcidiol concentrations and serum PTH concentrations > 60 ng/L, the upper limit of the adult normal range. They also had a significantly lower mean serum calcium concentration than did neonates with calcidiol concentrations > 30 nmol/L. On the basis of the association of low calcidiol concentrations (< or = 30 nmol/L) and high PTH concentrations (> 60 ng/L) as criteria for vitamin D deficiency, 24% of the neonates born to unsupplemented mothers were found to be vitamin D-deficient. Neonatal vitamin D status influenced the response of the infants to vitamin D supplements. Neonates with no sign of vitamin D deficiency showed similar changes in their serum calcidiol, calcium, phosphate, and PTH concentrations and ALP activity and no toxic effect (hypercalcemia or highly elevated calcidiol concentration) was observed whatever their vitamin D intake. In contrast, neonates with subclinical vitamin D deficiency had normalized serum PTH within 1 mo only when they were given 1000 IU ergocalciferol (25 micrograms)/d in addition to their formula.

Adult↗
PubMed1997

Association between vitamin D receptor gene polymorphism and sex-dependent growth during the first two years of life.

An association between vitamin D receptor (VDR) gene polymorphisms and bone mass variance has been observed in adult populations. To analyze possible association between VDR genotype and growth, we studied 589 healthy infants who were homogeneous for age, diet, and vitamin D status. The Bsm I, TaqI, and ApaI alleles' frequencies and genotypes were similar to those reported for Caucasian populations. Variations in Bsm I polymorphism were not associated with calcium intakes nor with serum levels of calcium, 25-hydroxyvitamin D, 1, 25-dihydroxyvitamin D, or alkaline phosphatase activity. But, they were associated with differences in body size. At 2 yr, homozygote BB (BsmI site absent) girls had higher length, weight and body surface area, and inversely, BB boys had lower weight, body mass index and body surface area, than their respective bb counterparts. As a result, gender-related differences were observed in Bb and bb, but not in BB populations. This VDR genotypic effect was observed also at birth and at 10 months in the longitudinal analysis of 145 selected full-term babies homozygous for the Bsm I polymorphism. These findings provide support for the hypothesis that VDR genotype influences intrauterine and early postnatal growth, directly or via interactions with gender-related growth regulators.

Alleles↗
PubMed1995

Insulin-like growth factor I, a unique calcium-dependent stimulator of 1,25-dihydroxyvitamin D3 production. Studies in cultured mouse kidney cells.

Previous in vivo and in vitro studies suggest that insulin-like growth factor (IGF-I) could be a regulator of the renal production of 1,25-(OH)2D3. In the present work, the local effect of low nanomolar concentrations of IGF-I on the 25-OH-D3-1 alpha-hydroxylase activity and the mechanism of its action have been investigated. To do so, an in vitro model of mouse proximal tubular cells in primary culture has been developed. These cells bear specific high affinity IGF-I binding sites (apparent Kd = 1.95 +/- 0.46 nM) and express the ability to convert [3H]25-(OH)D3 into [3H]1,25-(OH)2D3 (Km = 139 +/- 15.7 nM). Human recombinant IGF-I (10-100 ng/ml) stimulated both sodium-dependent phosphate uptake and 1,25-(OH)2D3 synthesis by these cells, in a time- and dose-dependent manner. IGF-I did not alter the apparent Michaelis constant but increased the maximum velocity of the 25-OH-D3-1 alpha-hydroxylase activity. This effect required protein synthesis. It was not affected by calphostin or GF109203X, two protein kinase C inhibitors, and was not mimicked by phorbol 12-myristate 13-acetate. In contrast, it was blocked by verapamil, a calcium channel blocker. Calcium depletion of the medium blunted the IGF-I effect but not that of human 1-34 parathyroid hormone 5 x 10(-8) M. IGF-I thus appears to be the first example of a physiological calcium-dependent regulator of the renal metabolism of vitamin D.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1995

[Vitamin D and pubertal maturation. Value and tolerance of vitamin D supplementation during the winter season].

BACKGROUND: In France, several cases of vitamin D-deficiency rickets among adolescents have been reported, but no prophylaxis measure has been systematically recommended at this age. The aim of this study was to measure 25-hydroxyvitamin D (25-(OH)D) levels and to search for biological signs of vitamin D deficiency during adolescence. Moreover, the effects of a unique oral dose of 100,000 IU of vitamin D3, given during the winter, were analysed. POPULATION AND METHODS: Circulating levels of 25-(OH)D, 1,25-dihydroxyvitamin D, intact parathyroid hormone (iPTH), alkaline phosphatase activities, calcium and phosphate were measured in 53 adolescents aged 10-17 years (81% of metropolitan origin), seen during the winter. The effect of a single oral dose of 100,000 IU of vitamin D3 or of placebo was studied in 15 of these subjects. RESULTS: 24.5% of the adolescents had low 25-(OH)D concentrations (< 6 ng/ml), this frequency being even more elevated (38%) at the end of pubertal maturation (stages 4 and 5). An increase in iPTH concentrations was found in subjects with lowest 25-(OH)D levels (< 3 ng/ml). An oral dose of 100,000 IU of vitamin D3 resulted in a significant increase in the 25-(OH)D levels; yet, these levels remained within the normal range during the 1-2 month follow-up of the nine treated subjects. This dosage made it possible to correct the low calcium concentrations (2.20-2.24 mmol/l) found before treatment in three adolescents. CONCLUSIONS: The high frequency of low vitamin D status observed during puberty and its normalization after a 100,000 IU vitamin D3 supplementation show the interest and safety of this intermittent 100,000 IU vitamin D3 supplementation to adolescents during the winter season.

Adolescent↗
PubMed1995

Genetic aspects of osteoporosis.

Genetically determined factors strongly contribute to bone mass in healthy individuals, although their molecular nature has long remained mysterious. Structural abnormalities in type I collagen may explain some cases of severe osteoporosis. The results of recent studies also indicate that bone mass in healthy populations may be influenced by genetically controlled variations in the regulation of type I collagen synthesis and degradation, via genetic factors that appear to be different from those presumably regulating bone formation. But the major breakthrough of this past year has been the demonstration that variations in the gene encoding the vitamin D receptor may account for a substantial part of bone mass variance in healthy pre- and postmenopausal populations. Although this assertion is at present the subject of an animated controversy, it has widely opened the way to possible intervention and to the search for other regulators of bone turnover putatively underlying the genetic effect on bone mass.

Bone Density↗
PubMed1994

Synthesis of 1,25-dihydroxyvitamin D3 by rat brain macrophages in vitro.

Cultured microglial cells were examined for their ability to metabolize 25-hydroxyvitamin D3 (25-(OH) D3). Upon exposure to lipopolysaccharide, microglial cells produced a vitamin D metabolite which comigrated with synthetic 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) in two different systems of high performance liquid chromatography. This metabolite had the same affinity as synthetic 1,25-(OH)2D3 for the chick intestinal 1,25-(OH)2D3 receptor. Lipopolysaccharide-stimulated microglial cells incubated with 3 nM of 25-(OH) D3 synthesized up to 5.76 fmol 1,25-(OH)2D3/8 x 10(5) cells/2 hr. Microglial cells stimulated for 48 hr with interferon-gamma also produced a significant amount of 1,25-(OH)2D3 (4.17 fmol/8 x 10(5) cells/2 hr). In contrast, levels of 1,25-(OH)2D3 produced by resting microglial cells were barely detectable. It is concluded that activated brain macrophages may be committed to synthesize 1,25-(OH)2D3 in vitro. This raises the possibility that activation of microglial cells in vivo may be followed by an increase in the level of 1,25-(OH)2D3 in the central nervous system (CNS). These results support the emerging concept that the brain constitutes a target tissue for vitamin D metabolites.

Animals↗