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Biomedical subjects

Stefano Mora

Publications and source records attributed to Stefano Mora.

At least 19 recordsLinked to original sources
PubMed2006

Reduced bone mineral density and increased bone metabolism rate in young adult patients with 21-hydroxylase deficiency.

CONTEXT: Patients with congenital adrenal hyperplasia (CAH) receive glucocorticoids as replacement therapy. Glucocorticoid therapy is the most frequent cause of drug-induced osteoporosis. OBJECTIVE: The objective of the study was to evaluate bone mineral density (BMD) and bone metabolism in CAH patients. DESIGN: This was a cross-sectional observational study. SETTING: The study was conducted at a referral center for pediatric endocrinology. PATIENTS AND OTHER PARTICIPANTS: Thirty young patients with the classical form of CAH (aged 16.4-29.7 yr) treated with glucocorticoid from diagnosis (duration of treatment 16.4-29.5 yr) and 138 healthy controls (aged 16.0-30.0 yr) were enrolled. MAIN OUTCOME MEASURES: BMD was measured in the lumbar spine and whole body by dual-energy x-ray absorptiometry. Bone formation and resorption rates were estimated by serum measurements of bone-specific alkaline phosphatase and C-terminal telopeptide of type I collagen, respectively. RESULTS: CAH patients were shorter than controls (women -6.8 and men -13.3 cm). Therefore, several methods were used to account for the effect of this difference on bone measurements. Whole-body BMD measurements were significantly lower, compared with controls (P < 0.03), after controlling for height (on average -2.5% in females and -9.3% in male patients). No differences were found in lumbar spine measurements. Bone-specific alkaline phosphatase and C-terminal telopeptide of type I collagen serum concentrations were higher in CAH patients than control subjects (P < 0.04). BMD measurements and bone metabolism markers did not correlate with the actual glucocorticoid dose or mean dose over the previous 7 yr. CONCLUSIONS: Young adult patients with the classical form of CAH have decreased bone density values, compared with healthy controls. This may put them at risk of developing osteoporosis early in life.

Absorptiometry, Photon↗
PubMed2005

A 12-month treatment with tenofovir does not impair bone mineral accrual in HIV-infected children.

BACKGROUND: Short-term use of tenofovir (TDF) has been associated with bone mineral loss in adults and children. OBJECTIVE: To assess whether the substitution of stavudine with TDF would result in decreased bone mineral content (BMC) and bone mineral density (BMD) accrual in HIV-infected children. METHODS: The lumbar spine and whole-body BMC and BMD were measured by dual-energy x-ray absorptiometry in 16 HIV-infected children (age range: 6.4-17.9 years) on stable highly active antiretroviral therapy. Bone measurements were obtained 12 months before the switch, at baseline, and 12 months after switching to TDF. Expected changes in bone measurements were calculated from cross-sectional data obtained from 166 healthy children. RESULTS: The BMC and BMD increments observed before switching therapy did not differ from expected increments. Similarly, the changes detected during treatment with TDF did not differ significantly from those calculated in healthy controls. CONCLUSIONS: Substitution to a TDF-containing antiretroviral regimen does not seem to impair bone mineral accrual in children showing a good immunologic response to antiretroviral treatment.

Absorptiometry, Photon↗
PubMed2005

Effects of recombinant growth hormone on visceral fat accumulation: pilot study in human immunodeficiency virus-infected adolescents.

CONTEXT: Recombinant human GH (rhGH) reduces excess accumulation of intraabdominal adipose tissue (IAT) in lipodystrophic HIV-infected adults, whereas data in pediatric patients are lacking. OBJECTIVE: The objective of this study was to assess the efficacy of rhGH treatment on lipodystrophy in HIV-infected adolescents. DESIGN: The study is a prospective, 24-wk open-label study of rhGH. SETTING: The study was conducted at a referral center for pediatric HIV infection. PATIENTS AND OTHER PARTICIPANTS: Eight HIV-infected adolescents (ages, 13.7-18.5 yr), with abnormal IAT accumulation (>41 cm(2) at L4-magnetic resonance imaging) and 97 healthy controls (HC) (ages, 9.5-19.9 yr) were enrolled. INTERVENTION: rhGH was given by sc injection at a daily dose of 0.028 mg/kg. MAIN OUTCOME MEASURES: The main outcome was change in IAT at L4-magnetic resonance imaging. Body composition by dual-energy x-ray absorptiometry, glucose and lipid metabolism, and IGF-I changes were also evaluated. RESULTS: All patients completed the study period; none of them showed adverse event, and no change in the daily dose of rhGH was required. The treatment was associated with a mean height increase of 2.4 cm. From baseline to wk 24, IAT area decreased significantly by a median of 34.5% (-19.2 to -70%). Fat mass decreased significantly in patients, compared with HC, with a median loss of total, trunk, and arm and leg fat mass of 10.4, 10.9, 12.7, and 5.4%, respectively. Total, arm, and leg lean masses increased significantly, compared with HC. IGF-I increased significantly, but supraphysiological values of mild degree (2-23% over the upper normal limit) were detected in only nine of 24 samples. No significant effects on glucose metabolism, triglyceride, and cholesterol levels were observed. CONCLUSIONS: Our data showed that rhGH 0.028 mg/kg daily for 24 wk in HIV-infected adolescents reduces IAT, trunk, and also limb fat and increases lean mass. Overall, short-term rhGH is well tolerated and is not associated with a worsening of glucose and lipid metabolism.

Adipose Tissue↗
PubMed2005

Validation of food frequency questionnaire for assessing dietary macronutrients and calcium intake in Italian children and adolescents.

OBJECTIVES: To validate a food frequency questionnaire to determine calcium and macronutrient intake in healthy children and adolescents. MATERIALS AND METHODS: The questionnaire consisted of 16 main food groups containing the main foods composing the diet of Italian children, a total of 136 items and 23 questions about food habits, supplements and servings. Color photographs to identify serving size were included. The questionnaire was validated by comparing it with the 7-day weighed record method in 37 healthy volunteers in two different age groups: children aged 6 - 10 years (n = 18) and adolescents aged 16 - 20 years (n = 19). RESULTS: The food frequency questionnaire seemed to overestimate the nutrient intake when compared with 7-day weighed records; however the two methods were highly correlated for all the nutrients considered. The range of Pearson's correlations between energy and nutrient intake (protein, fat, carbohydrates and calcium) determined from food frequency questionnaire and 7-day weighed record were 0.5-0.6 in children and 0.5-0.8 in young adults. Agreement between the two methods in classifying relative intakes was examined by determining the frequency of similar classification into terciles. Two thirds of the subjects were correctly classified for most nutrients, with a very low (2% to 5%) percentage of grossly misclassifications. DISCUSSION: The food frequency questionnaire has proved adequate to rank a pediatric population in terms of calcium and macronutrient intakes. The ranking of subjects is extremely useful for epidemiologic studies evaluating the relation between nutrient intake and disease.

Adolescent↗
PubMed2005

Improvement in dyslipidaemia after switching stavudine to tenofovir and replacing protease inhibitors with efavirenz in HIV-infected children.

OBJECTIVE: To assess the impact on immunological, virological and metabolic parameters of replacing protease inhibitors (PIs) with efavirenz and replacing stavudine with tenofovir in HIV-infected children. METHODS: A 48-week prospective evaluation of 28 HIV-infected children, with stable undetectable HIV-1 loads, who were taking highly active antiretroviral therapy (HAART) containing lamivudine, stavudine and a PI. Individuals were randomized to switch PI to efavirenz and stavudine to tenofovir at baseline (Group 1) or at week 24 (Group 2). Patient assessment included: clinical evaluation, viral load, CD4+ T-cell count, fasting blood levels and urine samples. RESULTS: All individuals maintained HIV RNA <50 copies/ml and unchanged CD4+ T-cell count through week 48. In Group 1 individuals, a significant decrease in cholesterol (P < 0.05), cholesterol:high-density lipoprotein (HDL) ratio (P < 0.01) and triglycerides (P < 0.05) was observed 24 and 48 weeks after the switch of HAART. The percentage of Group 1 children with increased cholesterol and triglycerides markedly decreased over the study period (from 43% to 0% and from 36% to 7%, respectively). In Group 2 individuals, unchanged lipids in the 24 weeks prior to the switch of HAART and a significant improvement on cholesterol (P < 0.05), cholesterol:HDL ratio (P < 0.01) and triglycerides (P < 0.05) were observed 24 weeks after the switch of HAART. The percentage of Group 2 children with increased cholesterol and triglycerides markedly decreased 24 weeks after the switch of HAART (from 46% to 7% and from 54% to 0%, respectively). Proteinuria and glucosuria were not detected in any individual. The mean values of serum creatinine, serum phosphorus, serum bicarbonate, estimated glomerular filtration rate, urinary microalbumin/creatinine, alpha-1-microglobulin/creatinine ratio and maximal tubular phosphate reabsorption remained unchanged in both groups. CONCLUSIONS: In HIV-infected children, switching PI to efavirenz and stavudine to tenofovir is virologically and immunologically safe, is not associated with renal impairment and provides a significant improvement in lipid profile.

Adenine↗
PubMed2004

A region in the seven-transmembrane domain of the human Ca2+ receptor critical for response to Ca2+.

Of 12 naturally occurring, activating mutations in the seven-transmembrane (7TM) domain of the human Ca2+ receptor (CaR) identified previously in subjects with autosomal dominant hypocalcemia (ADH), five appear at the junction of TM helices 6 and 7 between residue Ile819 and Glu837. After identifying a sixth activating mutation in this region, V836L, in an ADH patient, we studied the remaining residues in this region to determine whether they are potential sites for activating mutations. Alanine-scanning mutagenesis revealed five additional residues in this region that when substituted by alanine led to CaR activation. We also found that, whereas E837A did not activate the receptor, E837D and E837K mutations did. Thus, region Ile819-Glu837 of the 7TM domain represents a "hot spot" for naturally occurring, activating mutations of the receptor, and most of the residues in this region apparently maintain the 7TM domain in its inactive configuration. Unique among the residues in this region, Pro823, which is highly conserved in family 3 of the G protein-coupled receptors, when mutated to either alanine or glycine, despite good expression severely impaired CaR activation by Ca2+. Both the P823A mutation and NPS 2143, a negative allosteric modulator that acts on the 7TM through a critical interaction with Glu837, blocked activation of the CaR by various ADH mutations. These results suggest that the 7TM domain region Ile819-Glu837 plays a key role in CaR activation by Ca2+. The implications of our finding that NPS 2143 corrects the molecular defect of ADH mutations for treatment of this disease are also discussed.

Alanine↗
PubMed2004

Vitamin D receptor mRNA measured in leukocytes with the TaqMan fluorogenic detection system: effect of calcitriol administration.

BACKGROUND: The aim of the present study was to investigate the interactions between the circulating concentrations of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and the mRNA concentration of its specific nuclear receptor in human leukocytes. METHODS: We measured vitamin D receptor (VDR) mRNA extracted from leukocytes by use of TaqMan fluorescence analysis applied to the reverse transcription-PCR (RT-PCR) technique in 16 volunteers before and after calcitriol administration. VDR mRNA was also measured in leukocytes from calcium-stone-formers (37 hypercalciuric and 34 normocalciuric patients). The relationship between VDR mRNA concentrations and genetic VDR polymorphisms was analyzed in these patients. RESULTS: Imprecision (CV) of RT-PCR was 1.3% within assay (n = 10) and 1.7% between assays (n = 4). Oral 1,25(OH)2D3 increased mean (SE) serum 1,25(OH)2D3 1.6 (0.3)-fold and VDR mRNA 1.6 (0.1)-fold 8 h after administration. The maximum VDR mRNA was reached 3.6 (1.3) h after 1,25(OH)2D3 ingestion. No differences in leukocyte VDR mRNA concentrations were found between normocalciuric and hypercalciuric stone-formers in the absence of stimulation. Finally, no association was found between VDR mRNA concentrations and genetic VDR polymorphisms in stone-formers. CONCLUSIONS: The TaqMan RT-PCR assay is a rapid and accurate method to measure VDR mRNA, and leukocytes are a useful model to study VDR and 1,25(OH)2D3 interactions. In humans, VDR mRNA is increased by agonist 1,25(OH)2D3, a finding resembling previously reported results obtained in cellular and animal models.

Adult↗
PubMed2004

Autosomal dominant hypocalcemia in monozygotic twins caused by a de novo germline mutation near the amino-terminus of the human calcium receptor.

UNLABELLED: To define the molecular pathogenesis of severe postnatal hypocalcemia in monozygotic twin sisters, we sequenced their CaR gene and identified a missense mutation, K29E. Expression of the mutant receptor in vitro showed a marked increase in Ca2+ sensitivity explaining the observed phenotype. Additional mutagenesis studies lead us to speculate concerning a novel mechanism whereby the K29E mutation may lead to receptor activation. INTRODUCTION: Activating mutations of the Ca(2+)-sensing receptor (CaR) gene have been identified in subjects with autosomal dominant hypocalcemia. Study of such mutations has provided insight into the mechanism of activation of the CaR. MATERIALS AND METHODS: We performed biochemical and molecular genetic studies on monozygotic twin sisters who presented with early postnatal hypocalcemia and on their unaffected sister and parents. Functional characterization of mutant CaRs transfected in HEK-293 cells included immunoblots to monitor protein expression and Ca2+ stimulation of phosphoinositide hydrolysis to measure Ca2+ sensitivity. RESULTS: We identified a K29E missense mutation in the twin sisters but not in their parents or unaffected sister. The K29E mutant CaR showed a marked increase in Ca2+ sensitivity, including when it was co-transfected with wildtype CaR cDNA, consistent with a dominant effect. Substitution of K29 by aspartate equivalently increased CaR sensitivity, whereas conservative substitution by arginine did not. CONCLUSIONS: Severe postnatal hypocalcemia in the twin sisters was caused by a de novo germline activating mutation. In a model of the Venus flytrap-like domain of the extracellular amino-terminus of the CaR, K29 is located close to a peptide loop, "loop 2," that forms part of the dimer interface and is the site of 10 of the previously reported naturally occurring activating CaR mutations. We speculate that K29E increases Ca2+ sensitivity of the CaR by disrupting a salt bridge between K29 and an acidic residue in loop 2 and thereby changes the normal structure of loop 2 that maintains the CaR in its inactive conformation.

Amino Acid Sequence↗
PubMed2004

Analysis of 21-deoxycortisol, a marker of congenital adrenal hyperplasia, in blood by atmospheric pressure chemical ionization and electrospray ionization using multiple reaction monitoring.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder mainly caused by 21-hydroxylase deficit (21-OHD). Deletions or mutations of the CYP21 gene induce the impairment of glucocorticoid and mineralcorticoid synthesis. 17-Hydroxyprogesterone (17-OHP) is the hormonal marker in patients, but not in the heterozygous subjects. Excess 17-OHP is hydroxylated into 21-deoxycortisol (21-DF), and therefore 21-DF can be used as a specific marker for diagnosis of heterozygous individuals. We report an analytical method for analysis of 21-DF in blood samples using electrospray (ESI) and atmospheric pressure chemical ionization (APCI), showing that ESI is very sensitive for the analysis of this marker molecule. The multiple reaction monitoring (MRM) approach was used to increase the specificity and the sensitivity of the method.

Adrenal Hyperplasia, Congenital↗
PubMed2004

Longitudinal changes in bone metabolism and bone mineral content in children with celiac disease during consumption of a gluten-free diet.

BACKGROUND: A gluten-free diet (GFD) rapidly corrects the bone mineral deficit of children with untreated celiac disease. The mechanisms underlying such changes are still poorly understood. OBJECTIVE: In a longitudinal study, we monitored changes in bone metabolism during consumption of a GFD. DESIGN: We studied 22 white patients with celiac disease (11 girls) aged 10.5 +/- 1.0 y at the time of diagnosis. We compared bone metabolism and bone mass values in these patients with those in 428 healthy white children aged 11.3 +/- 0.2 y. Bone-specific alkaline phosphatase (a bone formation index) and N-terminal telopeptide of type I collagen (NTx; a bone resorption marker) were measured at the time of diagnosis and after 2, 6, and 12 mo of the GFD. Bone mineral content was measured at the lumbar spine and for the whole skeleton. RESULTS: The bone mineral content of patients was significantly lower than that of control subjects at the time of diagnosis but not after 1 y of the GFD. Serum bone-specific alkaline phosphatase concentrations of patients were significantly lower than those of control subjects at the time of diagnosis (P = 0.0064) and increased gradually and significantly during the GFD (ANOVA F = 4.71; P = 0.024). Conversely, patients with untreated disease had significantly higher urinary concentrations of NTx than did healthy control subjects (P < 0.0001). Urinary concentrations of NTx were not significantly affected by treatment (P = 0.37). CONCLUSIONS: The rate of bone metabolism is altered in children with untreated celiac disease, and these alterations may be the cause of osteopathy. Remarkable changes occur after the initiation of a GFD, and they result in a more balanced equilibrium.

Alkaline Phosphatase↗
PubMed2004

Longitudinal changes of bone mineral density and metabolism in antiretroviral-treated human immunodeficiency virus-infected children.

Highly active antiretroviral therapy (HAART) may be a contributory factor for a decreased bone mass and altered bone metabolism in HIV-infected children. However, the evolution of bone mineral density (BMD) and bone metabolism during HAART has not been studied yet. In the current longitudinal study we monitored the changes of BMD and bone metabolism over a period of 12 months. Thirty-two HIV-infected children (15 girls and 17 boys), aged from 6.3 to 17.7 yr, with a long duration of HAART exposure (40.0 months at baseline) were enrolled in the study. As a control group, 381 healthy volunteers of comparable age were assessed. BMD was measured at the lumbar spine and whole skeleton by dual-energy x-ray absorptiometry. Bone-specific alkaline phosphatase (BALP, as bone formation index) and N-terminal telopeptide of type I collagen (as bone resorption index) were measured in serum and urine, respectively. BMD values at baseline were significantly lower at all skeletal sites than those of control subjects. The annual increment of spine BMD was comparable to normal, whereas that of the whole skeleton was significantly lower (P < 0.04). BALP and N-terminal telopeptide of type I collagen concentrations were significantly higher compared with controls at baseline and at follow-up. BALP annual changes of HIV patients were significantly different from normal. Our data confirm the presence of low BMD and bone metabolism derangement in HIV-infected children treated with HAART. The role of possible therapeutic approach to restore bone mass and metabolism should be assessed in pediatrics.

Absorptiometry, Photon↗
PubMed2004

Adverse effects of antiretroviral therapy: focus on bone density.

Osteopenia and osteoporosis are the most important bone disorders affecting patients with HIV infection. The available data indicate that HIV-infected patients have a high prevalence of low bone mineral density. Reduced bone mass and alterations of bone metabolism have been found in HIV-infected children, adolescents and adults. The variety and complexity of changes in bone metabolism in patients with HIV infection and the different possible mechanisms triggering bone mineral loss, as well as the different stages of disease and cumulative exposure to antiretroviral drugs at the time of clinical evaluation, may contribute to the wide range of mineral loss observed and to the uncertainty of the role of specific antiretroviral medications.

Anti-Retroviral Agents↗
PubMed2003

Impaired growth hormone secretion correlates with visceral adiposity in highly active antiretroviral treated HIV-infected adolescents.

BACKGROUND: HIV-infected adults with lipodystrophy, characterized by excess accumulation of intra-abdominal adipose tissue (IAT), showed impaired growth hormone (GH) secretion. Data are lacking in paediatric lipodystrophy with the same features. METHODS: Twenty-five pubertal HIV-infected children were assessed for GH response (GH-AUC(0-120 min)) to arginine + GHRH testing, insulin-like growth factor-1 (IGF-1), IGF binding protein 3 (IGFBP-3), insulin, glucose, cholesterol, triglycerides, free fatty acids and nitric oxide levels. Body composition and IAT content were evaluated by dual-energy x-ray-absorptiometry and magnetic resonance imaging. An excess accumulation of IAT was defined as a value > 41 cm2. Differences between children with (V+) and without (V-) excess IAT were assessed by non-parametric tests and multivariate analysis. RESULTS Ten V+ (mean IAT, 82.5 cm2) and 15 V- (mean IAT, 26.8 cm2) were identified; they were similar for age (13.8 versus 14.8 years), body mass index (20.2 versus 19.5 kg/m2), male : female ratio (3/7 versus 8/7), months on highly active antiretroviral therapy (54.5 versus 55 months). V+ showed lower GH-AUC(0-120 min) (16.4 versus 31.6 microg x h/l; P = 0.002), lower IGF-1 concentrations (384 versus 515 ng/ml; P = 0.03) and higher insulin levels (17.8 versus 10.5 microIU/ml; P = 0.01) than V-. V+, as compared to V-, showed lower lean mass (total, P = 0.025; arms, P = 0.024; legs, P = 0.008) and higher fat mass (total, P = 0.0038; arms, P = 0.028; trunk, P < 0.0001). Lipid profile and glucose, IGFBP-3, nitric oxide and free fatty acids levels were similar in the two groups. GH-AUC(0-120 min) correlated negatively with IAT content and insulin levels. CONCLUSION: Impaired GH secretion is detectable in pubertal children with increased visceral adiposity and hyperinsulinemia. GH therapy should be considered in lipodystrophic HIV-infected children with excess IAT.

Adolescent↗
PubMed2003

Increased lipodystrophy is associated with increased exposure to highly active antiretroviral therapy in HIV-infected children.

OBJECTIVE: To assess body composition changes in HIV-infected children receiving highly active antiretroviral therapy (HAART). METHODS: Thirty-seven HIV-positive children were enrolled. Dual-energy X-ray absorptiometry (DXA) scans were performed in all HIV-infected children at baseline and after an additional 12 months of HAART and in 54 matched (for sex, age, body mass index [BMI], and pubertal stage) healthy controls. Abdominal MRI was performed in 14 of 37 HIV-positive children at baseline and in 28 of 37 HIV-positive children after additional 12 months of HAART. RESULTS: During the study period, mean HAART exposure increased from 39.3 to 50.9 months and the number of HIV-infected children with clinical lipodystrophy (LD) increased from 6 to 8, whereas mean BMI, CD4 percentage, and percentage of HIV-infected children with HIV RNA <50 copies/mL did not change. DXA scans showed an increase in lean mass, peripheral fat loss, and central fat accumulation in all HIV-infected children. As compared with controls, 70% and 84% of HIV-infected children showed DXA-detectable LD at baseline and at 12 months of follow-up, respectively. Mixed LD and central fat accumulation were the most common LD phenotype. At baseline and at 12 months of follow-up, intra-abdominal adipose tissue (IAT) was greater than in controls in 33% and 35% of HIV-infected children, and it was greater in those with LD than in those without. Peripheral fat loss and IAT content were associated with duration of HAART and were independent of immunologic stage of disease and immunologic response. CONCLUSIONS: Changes in body composition related to LD in HAART-treated children are frequent, precocious, and progressive. Duration of HAART negatively influences visceral adiposity and peripheral fat loss.

Abdomen↗