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Biomedical subjects

L Perrone

Publications and source records attributed to L Perrone.

At least 19 recordsLinked to original sources
PubMed2006

Adolescents carrying a missense mutation in the CART gene exhibit increased anxiety and depression.

A Leu34Phe mutation in the cocaine- and amphetamine-regulated transcript (CART) gene has been associated with severe early-onset obesity in an affected family. It has been shown that, in a cell culture system, the mutation resulted in altered CART peptide levels, and animal studies suggest that CART is involved in anxiety as well. The availability of the affected family allowed for testing of anxiety and other traits in humans carrying a mutation in CART gene. This study shows that a small group of adolescents with the mutation exhibit higher anxiety and depression scores than control subjects.

Adolescent↗
PubMed2006

Weight loss in obese children carrying the proopiomelanocortin R236G variant.

To acquire more information relative to the course of obesity in conditions of food restriction in subjects carrying mutations in the melanocortin signaling pathway, 710 obese children (mean age: 9.5+/-2.1 yr; mean z-score body mass index: 3.63+/-1.6) were genotyped for the proopiomelanocortin (POMC) R236G substitution, a variant which has been associated to early onset obesity, by restriction fragment length polymorphism (RFLP) analysis. Three children were heterozygotes for the R236G variant (0.4%). One of them had the metabolic syndrome. This variant was not found in 400 controls. The 3 probands followed a hypocaloric balanced diet and, after about 12 months, normalized their weight as well as fat mass and insulin resistance. The patient with the metabolic syndrome reversed this condition. These results show that a) the R236G substitution of POMC gene, although not a major cause of obesity among Italian obese children and adolescents, is associated with early onset obesity, and that b) inherited alterations of the melanocortin signaling pathway, independently of the degree of obesity, do not preclude the possibility to lose weight in mutated individuals following a hypocaloric diet.

Adolescent↗
PubMed2006

Perioperative fluid management in kidney transplantation: is volume overload still mandatory for graft function?

Kidney transplantation is now recognized as the treatment of choice for patients with chronic renal failure. Despite the extension of indications to patients suffering severe hypertension, ischemic heart disease, and chronic heart failure, the worldwide results are superb. However, perioperative cardiac complications occur in 6% to 10% of transplanted patients. Aggressive intraoperative volume expansion is still recommended to maximize graft functional recovery (up to 30 mL/kg/h, central venous pressure [CVP] > 15 mm Hg), but patients with preexistent cardiac disease or poor myocardial function are exposed to the risk of fluid overload, acute respiratory failure, and prolonged ventilation. Among the last 90 cases performed at our institution, good functional recovery of the graft was present in 94% of the patients within 2 weeks, despite a much more conservative intraoperative hydration policy (crystalloids 2400 +/- 1000 mL, 15 mL/kg/h, CVP 7-9 mm Hg). Graft failure which occurred in 5 patients was significantly correlated only with donor age, while perioperative cardiovascular complications had been present in 9 cases (10%) who were coronary artery disease patients (55%). Age above 50 years was the only significant risk factor. Supranormal volume loading is probably not always warranted in kidney transplantation.

Atherosclerosis↗
PubMed2004

Positive end-expiratory pressure applied to the dependent lung during one-lung ventilation improves oxygenation and respiratory mechanics in patients with high FEV1.

BACKGROUND AND OBJECTIVE: The aim of this study was to test the efficacy of positive end-expiratory pressure (PEEP) to the dependent lung during one-lung ventilation, taking into consideration underlying lung function in order to select responders to PEEP. METHODS: Forty-six patients undergoing open-chest thoracic surgical procedures were studied in an operating room of a university hospital. Patients were randomized to receive zero end-expiratory pressure (ZEEP) or 10 cmH2O of PEEP to the dependent lung during one-lung ventilation in lateral decubitus. The patients were stratified according to preoperative forced expiratory volume in 1 s (FEV1) as an indicator of lung function (below or above 72%). Oxygenation was measured in the supine position, in the lateral decubitus with an open chest, and after 20 min of ZEEP or PEEP. The respiratory system pressure-volume curve of the dependent hemithorax was measured in supine and open-chest lateral decubitus positions with a super-syringe. RESULTS: Application of 10 cmH2O of PEEP resulted in a significant increase in PaO2 (P < 0.05). This did not occur in ZEEP group, considered as a time matched control. PEEP improved oxygenation only in patients with high FEV1 (from 11.6+/-4.8 to 15.3+/-7.1 kPa, P < 0.05). There was no significant change in the low FEV1 group. Dependent hemithorax compliance decreased in lateral decubitus, more in patients with high FEV1 (P < 0.05). PEEP improved compliance to a greater extent in patients with high FEV1 (from 33.6+/-3.6 to 48.4+/-3.9 mLcmH2O(-1), P < 0.05). CONCLUSIONS: During one-lung ventilation in lateral decubitus, PEEP applied to the dependent lung significantly improves oxygenation and respiratory mechanics in patients with rather normal lungs as assessed by high FEV1.

Analysis of Variance↗
PubMed2004

Low-protein diet and progression of retinal degeneration in gyrate atrophy of the choroid and retina: a twenty-six-year follow-up.

Gyrate atrophy of the choroid and retina is an autosomal recessive chorioretinal dystrophy which leads to a slowly progressive loss of vision. The primary defect is due to a deficiency of the enzyme ornithine delta-aminotransferase, which is responsible for markedly elevated levels of ornithine in plasma and other body fluids. Although several therapeutic regimens have been proposed, the reduction in ornithine accumulation obtained by reducing the intake of its precursor arginine (semisynthetic low-arginine diet) is the one most practised. In this clinical and molecular study we report a patient with hyperornithinaemia and gyrate atrophy of the choroid and retina who had been diagnosed when she was 3 years 9 months old. She also presented mild mental retardation, delayed language development and speech defects. The patient has recently been found to be homozygous for the new Gly91Arg amino acid substitution of the enzyme ornithine delta-aminotransferase. This mutation lies in a region of the mature protein that is considered crucial for the mitochondrial targeting activity. In this patient, a 28-year treatment with a completely natural low-protein diet (0.8 g/kg per day of natural protein) has been able to significantly reduce ornithine plasma levels, and to greatly delay the natural progression of the chorioretinal changes. This study suggests that, in the long-term treatment of gyrate atrophy, the efficacy in slowing the progression of chorioretinal changes and the palatability of a completely natural low-protein diet make this treatment a potentially viable alternative in patients refusing the semisynthetic diet.

Adult↗
PubMed2004

Molecular screening of the ghrelin gene in Italian obese children: the Leu72Met variant is associated with an earlier onset of obesity.

OBJECTIVE: To test whether ghrelin variants could play a role in modulating some aspects of the obese phenotype during childhood. DESIGN: We screened the ghrelin gene in 300 Italian obese children and adolescents (mean age 10.5+/-3.2 y; range 4-19 y) and 200 controls by using the single-strand conformation polymorphism and the restriction fragment length polymoprhism analysis. RESULTS: No mutations were detected with the exception of two previously described polymorphisms, Arg51Gln and Leu72Met. For both variations, allelic frequencies were similar between patients and controls. Interestingly, we showed that the Leu72Met polymorphism was associated with differences in the age at obesity onset. Patients with the Met72 allele became obese earlier than homozygous patients for the wild Leu72 allele. The logrank test comparing the plots of the complement of Kaplan-Meier estimates between the two groups of patients was statistically significant (P<0.0001). CONCLUSION: It is unlikely that ghrelin variations cause the obesity due to single-gene mutations. The Leu72Met polymorphism of the ghrelin gene seems to play a role in anticipating the onset of obesity among children suggesting, therefore, that ghrelin may be involved in the pathophysiology of human adiposity.

Adolescent↗
PubMed2003

Renal size and function in patients with neuropathic bladder due to myelomeningocele: the role of growth hormone.

PURPOSE: Patients with spina bifida have smaller kidneys than healthy individuals. We evaluated the correlation between small size and decreased renal function, and the possible role of growth hormone deficiency. MATERIALS AND METHODS: A total of 54 patients (mean age 11.5 years, median 11, standard deviation +/- 4.52) were healthy except for neuropathic bladder due to spina bifida. Renal function was evaluated with mercaptoacetyltriglycine renal scintigraphy and creatinine clearance. Renal anatomy was evaluated with renal ultrasound and voiding cystourethrography. Serum insulin-like growth factor-1 (IGF-1) levels were measured in all patients with immunoradiometric assay. Renal measurements in our patients were compared using the Sutherland nomogram. RESULTS: A total of 22 patients (41%) had smaller kidneys than normal subjects and 31 appeared to have creatinine clearance values lower than 120 ml per minute per 1.73 m2. The statistical comparison between kidney size and creatinine clearance was significant (p <0.05, r = 0.381). Scintigraphic data showed total effective renal plasma flow less than 568 ml per minute per 1.73 m2 body surface area (normal mean value for age). Comparison between effective renal plasma flow and creatinine clearance was significant (p <0.05, r = 0.31). Serum levels of IGF-1 were normal for age in all patients (mean 332.06 ng/ml, median 303.4, range 39.4 to 732.3). CONCLUSIONS: The kidneys are smaller in patients with spina bifida than in healthy subjects when compared using the Sutherland nomogram. There is a significant correlation between smaller renal length and decreased renal function in all patients, even in those who are healthy except for neurogenic bladder secondary to spina bifida. IGF-1 levels were normal for age, and, therefore, these patients had no growth hormone deficiency. These findings call into question the hypothesis that growth hormone deficiency contributes to smaller kidney size. Other hypotheses can be suggested, such as a defect of embryological growth secondary to malformation, or the result of a defect in homocysteine-methionine metabolism.

Adolescent↗
PubMed2002

Low frequency of melanocortin-4 receptor (MC4R) mutations in a Mediterranean population with early-onset obesity.

BACKGROUND: Melanocortin-4 receptor (MC4R) mutations have been reported as the most common single genetic cause of obesity in some populations and it has been suggested that they may be responsible for more than 4% of early-onset obesity. OBJECTIVES: To verify the presence of mutations of the MC4R coding region in children from southern Italy with early-onset obesity. SUBJECTS AND METHODS: Two-hundred and eight unrelated obese children and adolescents were included in the study. The average age at obesity onset was 4.5+/-2.6 y. MC4R coding region was screened using both single-strand conformation polymorphism (SSCP) analysis and denaturing high-performance liquid chromatography (DHPLC). Automatic sequencing of PCR products of all individuals that showed an aberrant SSCP and/or DHPLC pattern was performed. RESULTS: One novel missense mutation and one previously described polymorphism (Vall03Ile) were identified. The missense mutation C142T, resulting in the substitution of proline with serine at codon 48, within the first MC4R transmembrane domain, was detected at the heterozygous state in a 15-y-old obese girl (body mass index (BMI)=35 kg/m(2)) who has been obese since she was 8 y old. The mutation co-segregated with the obesity phenotype for over three generations and was not found in the control population. CONCLUSIONS: Our data show MC4R obesity causing mutations in less than 0.5% of the patients (ie 1 out of 208 patients) and therefore indicate a low prevalence of MC4R variants in the obese population from southern Italy. The specific genetic background of the Mediterranean population could make it difficult for MC4R mutations to produce an essentially polygenic trait such as common obesity, at least during childhood.

Adolescent↗
PubMed2002

Inadequate leptin level negatively affects body fat loss during a weight reduction programme for childhood obesity.

UNLABELLED: Obesity is a typical example of a complex multifactorial disease arising from behavioural, environmental and genetic factors that may affect individual responses to dietary intake and physical activity. Observational, longitudinal dietary interventional studies in obese patients present contrasting reports on the predictive value of baseline leptin levels. We report on the effect of a weight reduction programme in three different groups of obese children (82 patients in all) assembled on the basis of their baseline leptin levels adjusted for body mass index (BMI), gender and pubertal development. The effectiveness of this programme was decreased in patients with relative hyperleptinaemia or hypoleptinaemia compared to children with baseline leptin levels appropriate to BMI gender and pubertal development. CONCLUSION: Information gained from leptin assays could provide predictive insight into an individual's ability to lose body fat and may therefore have important implications for our approach to the treatment and prevention of childhood obesity.

Adolescent↗
PubMed2001

Molecular screening of the proopiomelanocortin (POMC ) gene in Italian obese children: report of three new mutations.

BACKGROUND: Although linkage studies strongly suggest that proopiomelanocortin (POMC) alterations could play a role in the genetic predisposition to obesity, systematic POMC mutational analysis did not completely confirm this hypothesis. OBJECTIVES: To verify the presence of mutations of the POMC coding region in Italian children with very early onset obesity. SUBJECTS AND METHODS: Eighty seven unrelated Italian obese children and adolescents were studied. Mean age at obesity onset was 4.7+/-2.5 y. The POMC gene coding region was screened using single-strand conformation polymorphism (SSCP) analysis. Bi-directional automatic sequencing of PCR products was performed for all individuals who showed an aberrant SSCP pattern. RESULTS: Three new mutations have been identified in the heterozygous state in three patients: (a) G3834C, resulting in the substitution of Ser with Thr at codon 7 within the POMC signal peptide; (b) C3840T, resulting in the substitution of Ser with Leu at codon 9 of the pre-proopiomelanocortin signal peptide; and (c) C7406G, producing the substitution of Arg with Gly at codon 236 within the beta-endorphin peptide. A polymorphism consisting of a 9 bp insertion, AGC AGC CGC, between position 6997 and 6998 has been found at the heterozygous state in nine patients. They showed leptin levels adjusted for BMI, gender and pubertal stage significantly higher than obese subjects homozyous for the POMC wild-type allele. CONCLUSIONS: Mutations in codons 7 and 9 of the signal peptide may alter the translocation of the pre-proopiomelanocortin into the endoplasmic reticulum and, therefore, can be implicated in obesity. Although further studies are required, the polymorphism between position 6997 and 6998 may represent one of the genetic variations that explain the linkage between obesity and POMC. International Journal of Obesity (2001) 25, 61-67

Adolescent↗
PubMed2001

Mutational screening of the CART gene in obese children: identifying a mutation (Leu34Phe) associated with reduced resting energy expenditure and cosegregating with obesity phenotype in a large family.

Cocaine- and amphetamine-regulated transcript (CART) inhibits feeding and induces the expression of c-Fos in hypothalamic areas implicated in appetite regulation. Furthermore, the CART peptide is found in neurons regulating sympathetic outflow, which in turn play an integral role in regulating body temperature and energy expenditure. The CART gene was screened by single-strand conformation polymorphism and automatic sequencing in 130 (72 girls) unrelated obese Italian children and adolescents. Their Z-scores (mean +/- SD) of relative to BMI percentiles was 3.9 +/- 1.8, and the average age at obesity onset was 4.7 +/- 2.6 years. Two previously described silent polymorphisms were found in the 3' untranslated region: an adenine deletion at position 1457 in 9 patients (allele frequency 0.035) and an A/G substitution at position 1475 in 11 patients (allele frequency 0.042). We found no difference between the obese patients heterozygous for one of these polymorphisms and those patients homozygous for the wild allele with respect to their age of obesity onset, BMI Z-scores, and leptin levels. A missense mutation of G729C resulting in the substitution of Leu with Phe at codon 34, within the NH2-terminal CART region, has been detected in the heterozygous state in a 10-year-old obese boy who has been obese since the age of 2 years. The patient belongs to a large family of obese subjects. The mutation cosegregated with the severe obesity phenotype over three generations and was not found in the control population. Resting metabolic rates were lower than expected in the propositus (-14%) and his mother (-16%), who carried the mutation. Leucine at codon 34, conserved in this position in the human and in the rat sequences, immediately precedes a couple of lysine residues that may well represent a dibasic processing site. The Leu34Phe mutation might alter the susceptibility to proteolysis of this potential processing site, likely altering the CART effect on thermogenesis and energy expenditure.

Adolescent↗
PubMed2000

The thyroid transcription factor 2 (TTF-2) is a promoter-specific DNA-binding independent transcriptional repressor.

The thyroid transcription factor TTF-2 is a forkhead-containing protein involved in thyroid-specific gene expression and necessary for thyroid morphogenesis. In this paper, we demonstrate that TTF-2 is able to inhibit the activity of the thyroid-specific transcription factors TTF-1 and Pax-8 only on certain promoters. We identified the minimal protein domain responsible for repressor activity, which behaves as an independent functional domain, and we show that repression by TTF-2 is DNA-binding independent. We suggest that TTF-2 is able to interfere with a specific cofactor required for TTF-1 and Pax-8 activity.

DNA↗
PubMed1999

Calreticulin enhances the transcriptional activity of thyroid transcription factor-1 by binding to its homeodomain.

Transcription factors are often regulated by associated protein cofactors that are able to modify their activity by several different mechanisms. In this study we show that calreticulin, a Ca2+-binding protein with chaperone activity, binds to thyroid transcription factor-1 (TTF-1), a homeodomain-containing protein implicated in the differentiation of lung and thyroid. The interaction between calreticulin and TTF-1 appears to have functional significance because it results in increased transcriptional stimulation of TTF-1-dependent promoters. Calreticulin binds to the TTF-1 homeodomain and promotes its folding, suggesting that the mechanism involved in stimulation of transcriptional activity is an increase of the steady-state concentration of active TTF-1 protein in the cell. We also demonstrate that calreticulin mRNA levels in thyroid cells are under strict control by the thyroid-stimulating hormone, thus implicating calreticulin in the modulation of thyroid gene expression by thyroid-stimulating hormone.

Binding Sites↗
PubMed1999

Long-term zinc and iron supplementation in children of short stature: effect of growth and on trace element content in tissues.

We evaluated the effect of one year of supplementation with iron plus zinc (12 mg/day of Fe+++ and 12.5 mg/day of Zn++), zinc alone (12.5 mg/day of Zn++) and placebo on growth and on the iron, zinc, copper and selenium tissue contents in 30 well-selected children of short stature (16 M and 14 F; 4-11 years old). Before and after supplementation, we measured the concentrations of iron, transferrin, ferritin, zinc and copper in serum, of zinc in erythrocytes and leukocytes, and of zinc, copper and selenium in hair, as well as glutathione peroxidase activity in erythrocytes. Before supplementation, ferritin and serum, erythrocyte and hair zinc contents were significantly lower than in age-matched controls, while the other measured indices were in the normal range. Iron plus zinc supplementation caused an improvement in growth rate in all subjects, i.e., the median Z-score increased from -2.22 +/- 0.45 to -0.64 +/- 0.55; (p < 0.01). In the zinc-supplemented group, only the subjects whose ferritin levels were higher than 20 ng/L before supplementation showed a similar improvement of growth rate. Iron plus zinc supplementation could be a reasonable treatment in short, prepubertal children affected by marginal zinc and iron deficiency.

Age Determination by Skeleton↗
PubMed1999

Epidemiological study of blood lead levels of children and adolescents living in Campania, Italy.

The aim of the present study is to evaluate blood levels (PbB) in a group of 500 (245 M, 255 F) children and adolescents of Campania (Italy) aged from 0.197 to 16.915 years, 269 (136 M, 133 F) of whom lived in urban zones and 231 (109 M, 122 F) in rural zones. PbB was assayed by electrothermal atomic absorption spectroscopy. The parents of the examined subjects children were interviewed about common risk factors for lead exposure using a standardized questionnaire. The PbB of children living in urban zones were significantly higher than the PbB of those living in rural zones (60.0 +/- 3.0 mg/L vs. 40.0 +/- 2.0 mg/L, p < 0.001). A PbB higher than 100 mg/L was found in 27 children (5.4%). We observed a significant correlation between age and PbB (p < 0.001, r = 0.529). Our data regarding children and adolescents demonstrate that the prevalence of PbB higher than 100 mg/L is greater in children living in urban areas (6.89%) than in subjects living in rural areas (3.89%). The findings can be explained by the higher presence of risk factors of Pb exposure in urban areas. Our data, if compared with those of previous studies concerning children of Campania, show a clear decrease of PbB. The correlation that we found between age and PbB indicates that long-term exposure at low doses more than a more intensive but short-term exposure seems to be important for the increase of blood lead levels.

Adolescent↗
PubMed1998

Structural and functional properties of the N transcriptional activation domain of thyroid transcription factor-1: similarities with the acidic activation domains.

The thyroid transcription factor 1 (TTF-1) is a tissue-specific transcription factor involved in the development of thyroid and lung. TTF-1 contains two transcriptional activation domains (N and C domain). The primary amino acid sequence of the N domain does not show any typical characteristic of known transcriptional activation domains. In aqueous solution the N domain exists in a random-coil conformation. The increase of the milieu hydrophobicity, by the addition of trifluoroethanol, induces a considerable gain of alpha-helical structure. Acidic transcriptional activation domains are largely unstructured in solution, but, under hydrophobic conditions, folding into alpha-helices or beta-strands can be induced. Therefore our data indicate that the inducibility of alpha-helix by hydrophobic conditions is a property not restricted to acidic domains. Co-transfections experiments indicate that the acidic domain of herpes simplex virus protein VP16 (VP16) and the TTF-1 N domain are interchangeable and that a chimaeric protein, which combines VP16 linked to the DNA-binding domain of TTF-1, undergoes the same regulatory constraints that operate for the wild-type TTF-1. In addition, we demonstrate that the TTF-1 N domain possesses two typical properties of acidic activation domains: TBP (TATA-binding protein) binding and ability to activate transcription in yeast. Accordingly, the TTF-1 N domain is able to squelch the activity of the p65 acidic domain. Altogether, these structural and functional data suggest that a non-acidic transcriptional activation domain (TTF-1 N domain) activates transcription by using molecular mechanisms similar to those used by acidic domains. TTF-1 N domain and acidic domains define a family of proteins whose common property is to activate transcription through the use of mechanisms largely conserved during evolutionary development.

Amino Acid Sequence↗