PubMed Health⌕ Search

Biomedical subjects

Stefano Bonassi

Publications and source records attributed to Stefano Bonassi.

At least 19 recordsLinked to original sources
PubMed2007

Normalization of low-density microarray using external spike-in controls: analysis of macrophage cell lines expression profile.

BACKGROUND: The normalization of DNA microarrays allows comparison among samples by adjusting for individual hybridization intensities. The approaches most commonly used are global normalization methods that are based on the expression of all genes on the slide and on the modulation of a small proportion of genes. Alternative approaches must be developed for microarrays where the proportion of modulated genes and their distribution are unknown and they may be biased towards up- or down-modulated trends. RESULTS: The aim of the work is to study the use of spike-in controls to normalize low-density microarrays. Our test-array was designed to analyze gene modulation in response to hypoxia (a condition of low oxygen tension) in a macrophage cell line. RNA was extracted from controls and cells exposed to hypoxia, mixed with spike RNA, labeled and hybridized to our test-array. We used eight bacterial RNAs as source of spikes. The test-array contained the oligonucleotides specific for 178 mouse genes and those specific for the eight spikes. We assessed the quality of the spike signals, the reproducibility of the results and, in general, the nature of the variability. The small values of the coefficients of variation revealed high reproducibility of our platform either in replicated spots or in technical replicates. We demonstrated that the spike-in system was suitable for normalizing our platform and determining the threshold for discriminating the hypoxia modulated genes. We assessed the application of the spike-in normalization method to microarrays in which the distribution of the expression values was symmetric or asymmetric. We found that this system is accurate, reproducible and comparable to other normalization methods when the distribution of the expression values is symmetric. In contrast, we found that the use of the spike-in normalization method is superior and necessary when the distribution of the gene expression is asymmetric and biased towards up-regulated genes. CONCLUSION: We demonstrate that spike-in controls based normalization is a reliable and reproducible method that has the major advantage to be applicable also to biased platform where the distribution of the up- and down-regulated genes is asymmetric as it may occur in diagnostic chips.

Action Potentials↗
PubMed2006

Chromosomal aberrations and cancer risk: results of a cohort study from Central Europe.

A high level of chromosomal aberrations in peripheral blood lymphocytes may be an early marker of cancer risk, but data on risk of specific cancers and types of chromosomal aberrations (chromosome type and chromatid type) are limited. A total of 6,430 healthy individuals from nine laboratories in Croatia, Hungary, Lithuania, Poland, and Slovakia, included in chromosomal aberration surveys performed during 1978-2002, were followed up for cancer incidence or mortality for an average of 8.5 years; 200 cancer cases were observed. Compared with that for the low-tertile level of chromosomal aberrations, the relative risks of cancer for the medium and high tertiles were 1.78 (95% confidence interval: 1.19, 2.67) and 1.81 (95% confidence interval: 1.20, 2.73), respectively. The relative risk for chromosome-type aberrations above versus below the median was 1.50 (95% confidence interval: 1.12, 2.01), while that for chromatid-type aberrations was 0.97 (95% confidence interval: 0.72, 1.31). The analyses of risk of specific cancers were limited by small numbers, but the association was stronger for stomach cancer. This study confirms the previously reported association between level of chromosomal aberrations and cancer risk and provides novel information on the type of aberrations more strongly predictive of cancer risk and on the types of cancer more strongly predicted by chromosomal aberrations.

Adolescent↗
PubMed2006

Prealbumin serum concentrations as a useful tool in the assessment of malnutrition in hospitalized patients.

BACKGROUND: Protein-energy malnutrition (PEM) is a common condition among patients admitted to hospitals, and it is associated with a worse prognosis and increased mortality. Although several screening systems have been developed, PEM is still poorly recognized, and there is no consensus on which test is more reliable and feasible in clinical practice. Prealbumin (PAB) is a potential useful PEM marker because its serum concentrations are closely related to early changes in nutritional status. METHODS: We studied PEM prevalence and PAB serum concentrations in 108 hospitalized patients. The Detailed Nutritional Assessment (DNA) was used as the reference method to determine PEM. PAB performance was compared with that of 2 other methods, the Subjective Global Assessment (SGA) and the Prognostic Inflammatory and Nutritional Index score (PINI). RESULTS: According to the DNA reference method, 41% of patients were classified with mild malnutrition and 19% with severe malnutrition. PAB showed the best concordance with the standard DNA method (concordance index, 76.8%) and a good sensitivity/specificity profile (83.1%/76.7%) compared with SGA and PINI. CONCLUSIONS: We conclude that PAB could represent a feasible and reliable tool in the evaluation of malnutrition, especially in settings where it is difficult to obtain a more detailed and comprehensive nutritional assessment such as the DNA.

Adult↗
PubMed2006

An increased micronucleus frequency in peripheral blood lymphocytes predicts the risk of cancer in humans.

The frequency of micronuclei (MN) in peripheral blood lymphocytes (PBL) is extensively used as a biomarker of chromosomal damage and genome stability in human populations. Much theoretical evidence has been accumulated supporting the causal role of MN induction in cancer development, although prospective cohort studies are needed to validate MN as a cancer risk biomarker. A total of 6718 subjects from of 10 countries, screened in 20 laboratories for MN frequency between 1980 and 2002 in ad hoc studies or routine cytogenetic surveillance, were selected from the database of the HUman MicroNucleus (HUMN) international collaborative project and followed up for cancer incidence or mortality. To standardize for the inter-laboratory variability subjects were classified according to the percentiles of MN distribution within each laboratory as low, medium or high frequency. A significant increase of all cancers incidence was found for subjects in the groups with medium (RR=1.84; 95% CI: 1.28-2.66) and high MN frequency (RR=1.53; 1.04-2.25). The same groups also showed a decreased cancer-free survival, i.e. P=0.001 and P=0.025, respectively. This association was present in all national cohorts and for all major cancer sites, especially urogenital (RR=2.80; 1.17-6.73) and gastro-intestinal cancers (RR=1.74; 1.01-4.71). The results from the present study provide preliminary evidence that MN frequency in PBL is a predictive biomarker of cancer risk within a population of healthy subjects. The current wide-spread use of the MN assay provides a valuable opportunity to apply this assay in the planning and validation of cancer surveillance and prevention programs.

Biomarkers↗
PubMed2006

Bronchial malondialdehyde DNA adducts, tobacco smoking, and lung cancer.

Tobacco smoking is a major risk factor for lung cancer causing, among other effects, oxidative stress and lipid peroxidation. Malondialdehyde (MDA)-DNA adducts can be induced by direct DNA oxidation and by lipid peroxidation. We measured the relationship between bronchial MDA-DNA adducts and tobacco smoking, cancer status, and selected polymorphisms in 43 subjects undergoing a bronchoscopic examination for diagnostic purposes. MDA-DNA adducts were higher in current smokers than in never smokers (frequency ratio (FR) = 1.51, 95% confidence interval (CI) 1.01-2.26). MDA-DNA adducts were also increased in lung cancer cases with respect to controls, but only in smokers (FR = 1.70, 95% CI 1.16-2.51). Subjects with GA and AA cyclin D1 (CCND1) genotypes showed higher levels of MDA-DNA adducts than those with the wild-type genotype (FR = 1.51 (1.04-2.20) and 1.45 (1.02-2.07)). Lung cancer cases with levels of MDA-DNA adducts over the median showed a worse, but not statistically significant, survival, after adjusting for age, gender, and packyears (hazard ratio = 2.48, 95% CI 0.65-9.44). Our findings reinforce the role of smoking in lung carcinogenesis through oxidative stress. Subjects who carry at least one variant allele of the CCND1 gene could accumulate DNA damage for altered cell-cycle control and reduced DNA repair proficiency.

Aged↗
PubMed2006

Searching PubMed for molecular epidemiology studies: the case of chromosome aberrations.

The available tools for searching literature in the field of Molecular Epidemiology are largely unsatisfactory. To identify major problems in retrieving information on this discipline, we comment here on the results of a literature search on cytogenetic biomarkers in children exposed to environmental pollutants. The search, done on the PubMed/MedLine database, was based on a strategy combining descriptors listed in the PubMed Medical Subject Headings (MeSH) Thesaurus and other available tools (free text or phrase search tools). 178 articles were retrieved by searching the period from January 1, 1980 to November 30, 2004. Only 2 of the 178 articles were indexed by the MeSH term "Epidemiology, molecular" (introduced in 1994) and 30 of 178 by the MeSH term "Biological markers" (introduced in 1989). The case of chromosome aberration (CA) was emblematic of the problem: 44 of 78 articles (56.4%) were not pertinent to the search. The reasons for this poor performance are reported and discussed. Authors and indexers may be able to improve the efficiency of article retrieval in the field of molecular epidemiology by using relevant terms in the title and abstract. This may suggest appropriate MeSH terms to the indexers for the indexing process. As regards the difficulty in identifying population studies using CA, the introduction of a specific MeSH term for chromosome aberrations when used as a biomarker would improve the search process.

Abstracting and Indexing↗
PubMed2006

Population screening for coeliac disease in a low prevalence area in Italy.

OBJECTIVE: A screening program was proposed for the village of Carcare (population 5700), located in a region of Italy with an apparently low prevalence of coeliac disease (CD): only 1 patient diagnosed out of 2557 inhabitants. The study group comprised 1002 individuals (568 F, 434 M, age range 13-90 years) recruited from blood donors, secondary school pupils and people referred to the local outpatient facilities for routine blood chemistry. MATERIAL AND METHODS: Total IgA, IgA anti-tissue transglutaminase (tTG) (ELISA, recombinant human antigen) and IgA antiendomysium (EMA) (IFI, umbilical cord substrate) antibodies were measured in the serum of all participants. All patients with IgA deficiency were investigated for IgG tTG antibodies, and in the case of disagreement between tTG and EMA, they were typed for HLA DQ2-DQ8 haplotypes. RESULTS: Thirteen subjects were positive and 988 negative for autoantibodies (3/988 had IgA deficiency). One serum sample was positive for tTG antibodies but negative for EMA. Ten out of 13 positive subjects consented to undergo duodenal biopsy, which invariably produced evidence of CD despite the absence of clinical signs/symptoms. A post-diagnostic clinical investigation provided evidence showing mild iron deficiency (4 subjects) and osteoporosis (2 subjects). After counselling, all subjects accepted a gluten-free diet. CONCLUSIONS: The prevalence of CD in the study group was 1:100 (1.0%; 95% CI: 0.5-1.8%): this indicates that CD is largely underdiagnosed in Carcare. Our results suggest that the low prevalence of CD observed in some regions is likely to be due to underdiagnosis.

Adolescent↗
PubMed2006

The effects of GSTM1 and GSTT1 polymorphisms on micronucleus frequencies in human lymphocytes in vivo.

The influence of genetic polymorphisms in GSTM1 and GSTT1 genes on micronucleus frequencies in human peripheral blood lymphocytes was assessed through a pooled analysis of data from seven laboratories that did biomonitoring studies using the in vivo cytokinesis-block micronucleus assay. A total of 301 nonoccupationally exposed individuals (207 males and 94 females) and 343 workers (237 males and 106 females) occupationally exposed to known or suspected genotoxic substances were analyzed by Poisson regression. The results of the pooled analysis indicate that the GSTT1 null subjects had lower micronucleus frequencies than their positive counterparts in the total population (frequency ratio, 0.55; 95% confidence interval, 0.33-0.89). The protective effect of this genotype is reversed with increasing age, with a frequency ratio of 1.33 (95% confidence interval, 1.06-1.68) in subjects aged 60 years. A significant overall increase in micronucleus frequency with age and gender (P < 0.001 and P = 0.024, respectively) was observed, females having higher micronucleus frequencies than males, when occupationally exposed (P = 0.002). Nonoccupationally exposed smokers had lower micronucleus frequencies than nonsmokers (P = 0.001), whereas no significant difference in micronucleus level was observed between smokers and nonsmokers in the occupationally exposed group (P = 0.79). This study confirms that pooled analyses, by increasing the statistical power, are adequate for assessing the involvement of genetic variants on genome stability and for resolving discrepancies among individual studies.

Adolescent↗
PubMed2005

DNA methylation in neuroblastic tumors.

Epigenetic modifications and particularly the methylation of cytosines 5' of guanine residues (CpGs) in gene promoter regions is an essential regulatory mechanism for normal cell development. DNA methylation can inactivate tumor suppressor genes by inducing C > T transitions in somatic and germline cells and by altering gene transcription. On the other hand, hypomethylation of specific sequences may reactivate the expression of potential oncogenes. Thus, aberrant hyper- and hypomethylation are considered crucial steps leading to cancer development. Until recently, differently from most adult tumors, only limited information was available on the methylation aberrations in neuroblastoma. In the last 2 years, however, this situation has drastically changed and many information has been gained on the relevance of methylation in this tumor. In this review, we summarize the latest findings on the role of methylation in neuroblastoma and in particular to its clinical significance.

Adult↗
PubMed2005

Distinct CpG methylation profiles characterize different clinical groups of neuroblastic tumors.

The hypermethylation of CpG islands within gene promoter regions is an epigenetic phenomenon that is often, but not always, associated with the transcriptional silencing of downstream genes and contributes to carcinogenesis. We have determined the pattern of methylation of several genes involved in distinct biological pathways, including cell proliferation and apoptosis, in neuroblastoma and in the nonmalignant ganglioneuroma. The purpose of this work was to search for epigenetic signatures that could be associated with defined clinical and biological parameters and that, in prospective, could identify specific risk categories among the patients. We have analysed 31 malignant neuroblastoma with or without MYCN amplification and 13 benign ganglioneuroma and we have observed dramatic differences in the methylation pattern of five genes (CASP8, 14.3.3sigma, DeltaN-p73, RASSF1A and DCR2) between these tumors indicating that this phenomenon is not tissue-specific and can be considered as cancer-dependent. Furthermore, the methylation pattern of 14.3.3sigma, RASSF1A and of an intragenic segment of CASP8 was significantly different between MYCN amplified and single copy neuroblastoma suggesting a specific role of epigenetic alterations in aggressive neuroblastoma.

14-3-3 Proteins↗
PubMed2005

Children's exposure to environmental pollutants and biomarkers of genetic damage. II. Results of a comprehensive literature search and meta-analysis.

The present review is based on findings from 178 publications retrieved through an extensive search of the MedLine/PubMed database for a 25 years time period (1980-2004) and 10 manually identified papers. Among the cytogenetic biomarkers that are frequently used in field studies, chromosome aberrations (CA) and micronuclei (MN) but not sister chromatid exchanges (SCE) were found consistently increased in children exposed to environmental pollutants. Meta-analysis of the studies reporting SCE in cord blood showed similar levels of SCE in exposed and in non-exposed newborns. Exposure to airborne pollutants, soil and drinking water contaminants, mostly increased CA and, to a lesser extent, MN levels in children. The effect of exposure to airborne urban pollutants was consistently reported by field studies measuring DNA, albumin and hemoglobin adducts. Prenatal (in utero) and postnatal exposure (environmental tobacco smoke, ETS) to tobacco smoke compounds were associated with increased frequencies of DNA and hemoglobin adducts and CA. The limited number of field studies measuring DNA fragmentation (Comet assay), hypoxanthine-guanine phosphoribosyltransferase (HPRT) and the glycophorinA (GPA) mutation frequency in environmentally exposed children precluded a meaningful evaluation of the usefulness of these assays. Meta-analyses performed in children exposed to ETS and in newborns exposed in utero to their mothers' smoke showed 1.3 and 7 times higher levels of hemoglobin adducts compared to referent subjects, respectively. These increases are consistent with the epidemiological evidence of higher lung cancer risks reported in adults who had never smoked and were exposed to ETS during childhood and with 7-15 times higher lung cancer risks reported in smokers than in non-smokers. Higher levels of PAH-DNA adducts were found in fetal than in maternal tissue, suggesting a specific susceptibility of the fetus to this class of ubiquitous environmental pollutants. According to these findings, future research and biomonitoring programs on children would greatly benefit from the inclusion of selected biomarkers that could provide biologically based evidence for the identification of intervention priorities in environmental health.

Adolescent↗
PubMed2005

Children's exposure to environmental pollutants and biomarkers of genetic damage. I. Overview and critical issues.

In the last decade, molecular epidemiological studies have provided new perspectives on studying environmental risks in pediatric populations, based on the growing understanding that children may be more susceptible to toxicants than adults. Protecting children's health is a social priority, and specific research programs have been initiated with this purpose in the United States and Europe. These programs address the development of (i) less invasive methods for biological specimens collection, (ii) specific tools for interpretation and validation of biomarkers, (iii) methods for translating biomarker results into intervention strategies and for integrating them with environmental monitoring and health data, (iv) optimal ways to obtain consent and provide information to children and/or their parents participating in the studies and (v) techniques for the effective communication with policy makers and the public. Critical issues in children's environmental research discussed in this paper include specific needs of study design, exposure assessment, sample collection and ethics. Special consideration is given to the autonomy of the child in giving consent, the details and nature of the information provided, and the need to warrant controlled access to sensitive information. The use of incentives such as gifts and payment to ensure the participation of school-aged children is specifically discussed. Examples of field studies that are focused on the effects of pesticides, air pollution and formaldehyde are used to illustrate advantages and limitations of biomarker studies in children.

Biomarkers↗
PubMed2005

Pleural malignant mesothelioma, genetic susceptibility and asbestos exposure.

Pleural malignant mesothelioma (MM) is a rare but extremely aggressive cancer. The limited impact of standard therapeutic treatments on survival rates makes the identification of factors that increase the individual risk a leading priority. The high proportion of cases explained by exposure to asbestos has guided intervention policies to an effective ban of this compound from our environment. However, MM cannot be solely attributed to this agent, and the role of predisposing factors and their interaction with asbestos exposure is increasingly studied. The role of mEH, GSTM1, GSTT1, NAT2, and CYP1A1 genotypes in modulating susceptibility to MM was examined in a case-control study of 80 subjects with a confirmed diagnosis of MM and 255 controls. Subjects with low mEH activity showed a significantly increased risk of MM (OR, 2.51; 95% CI, 1.11-5.68). The association was stronger in the group with low asbestos exposure (OR, 7.83; 95% CI, 0.98-62.60). A significant increased risk of MM was also found in NAT2 fast acetylators (OR, 1.74; 95% CI, 1.02-2.96). The presence of synergisms between genotypes, i.e., mEH and NAT2 (LRT for heterogeneity p<0.023), mEH and GSTM1 (LRT p<0.061), and NAT2 and GSTM1 (LRT p<0.049), combined with the interaction observed with exposure to asbestos, suggests the presence of gene-environment and gene-gene interactions in the development of MM, although the size of the study group does not allow to draw clearcut conclusions. Since genetic polymorphisms can also modify the extent of genetic damage occurring in subjects exposed to carcinogens, we measured the frequency of micronuclei in peripheral blood lymphocytes of a subgroup of MM cases. The limited number of cases (28) did not allow to observe significant effects. In conclusion, these results strengthen the hypothesis that individual susceptibility to MM can be modulated by the interaction between polymorphic genes involved in the metabolism and the intensity of asbestos exposure.

Asbestos↗
PubMed2005

Low intake of calcium, folate, nicotinic acid, vitamin E, retinol, beta-carotene and high intake of pantothenic acid, biotin and riboflavin are significantly associated with increased genome instability--results from a dietary intake and micronucleus index survey in South Australia.

The aim of this study was to determine the association between dietary intake, determined using a food frequency questionnaire, and genome damage in lymphocytes measured using the micronucleus (MN) assay. The study, performed on 190 healthy individuals (mean age 47.8 years, 46% males), also examined whether a supplementation with beta-carotene, vitamins C and E along with zinc (ACEZn), in a randomized trial for 6 months, improves genome stability. Multivariate analysis of baseline data showed that (1) the highest tertile of intake of vitamin E, retinol, folic acid, nicotinic acid (preformed) and calcium is associated with significant reductions in MN frequency, i.e. -28, -31, -33, -46 and -49%, respectively (P < 0.005) relative to the lowest tertile of intake and (2) the highest tertile of intake of riboflavin, pantothenic acid and biotin was associated with significant increases in MN frequency, i.e. +36% (P = 0.054), +51% (P = 0.021), and +65% (P = 0.001), respectively, relative to the lowest tertile of intake. Mid-tertile beta-carotene intake was associated with an 18% reduction in MN frequency (P = 0.038); however, the highest tertile of intake (>6400 microg/day) resulted in an 18% increment in MN frequency. Supplementation with ACEZn significantly reduced the MN index by 13% (P = 0.038). The study also showed interactive additive effects such as the protective effect of increased calcium intake (-46%) and the exacerbating effect of riboflavin (+42%) on increased genome damage caused by low folate intake. The results from this study illustrate the strong impact of a wide variety of micronutrients and their interactions on genome health, depending on the level of intake.

Adult↗
PubMed2005

Genome analysis and gene expression profiling of neuroblastoma and ganglioneuroblastoma reveal differences between neuroblastic and Schwannian stromal cells.

Neuroblastic tumours are a group of paediatric cancers with marked morphological heterogeneity. Neuroblastoma (Schwannian stroma-poor) (NB-SP) is composed of undifferentiated neuroblasts. Ganglioneuroblastoma intermixed (Schwannian stroma-rich) (GNBi-SR) is predominantly composed of Schwannian stromal (SS) and neuroblastic (Nb) cells. There are contrasting reports suggesting that SS cells are non-neoplastic. In the present study, laser capture microdissection (LCM) was employed to isolate SS and Nb cells. Chromosome 1p36 deletion and MYCN gene amplification were found to be associated in two out of seven NB-SPs, whereas no abnormalities were observed in five GNBi-SRs. In some cases, loss of heterozygosity (LOH) at 1p36 loci was detected in Nb cells but not in the bulk tumour by LCM; furthermore, LOH was also identified in both SS and tumour tissue of a GNBi-SR. DNA gain and loss studied by comparative genomic hybridization were observed at several chromosome regions in NB-SP but in few regions of GNBi-SR. Finally, gene expression profiles studied using an oligo-microarray technique displayed two distinct signatures: in the first, 32 genes were expressed in NB-SP and in the second, 14 genes were expressed in GNBi-SR. The results show that NB-SP is composed of different morphologically indistinguishable malignant cell clones harbouring cryptic mutations that are detectable only after LCM. The degree of DNA imbalance is higher in NB-SP than in GNBi-SR. However, when the analysis of chromosome 1p36 is performed at the level of microdissection, LOH is also observed in SS cells. These data provide supportive evidence that SS cells have a less aggressive phenotype and play a role in tumour maturation.

Chromosomes, Human, Pair 1↗
PubMed2005

Chromosomal aberrations in lymphocytes of healthy subjects and risk of cancer.

There is evidence that increased frequency of chromosomal aberration (CA) in peripheral blood lymphocytes is a predictor of cancer, but further data are needed to better characterize CA as marker of cancer risk. From the archives of 15 laboratories we gathered cytogenetic records of 11,834 subjects who were free of cancer at the moment of blood drawing and who underwent cytogenetic examination for preventive purposes in the Czech Republic during 1975-2000. We linked these records to the national cancer registry, revealing a total of 485 cancer cases. Subjects were classified according to the percentiles of CA distribution within each laboratory as low (0-33rd percentile), medium (34-66th percentile), and high (66-100th percentile). Subjects were further classified by occupational exposure and by subclass of CA. We found a significant association between the overall cancer incidence and the presence of chromosome-type aberrations [relative risk (RR) for high vs. low CA level = 1.24; 95% confidence interval (CI), 1.03-1.50] but not chromatid-type aberrations. Stomach cancer showed a strong association with frequency of total CA (RR = 7.79; 95% CI, 1.01-60.0). The predictivity of CA observed in subjects exposed to various classes of carcinogens did not significantly differ from the group of nonexposed subjects. This study contributes to validation of CA as a predictive marker of cancer risk, in particular, of stomach cancer; the association between CA frequency and cancer risk might be limited to chromosome-type aberrations.

Adult↗
PubMed2005

Baseline micronuclei frequency in children: estimates from meta- and pooled analyses.

The number of studies evaluating the effect of environmental exposure to genotoxic agents in children has rapidly increased in the last few years. The frequency of micronuclei (MN) in peripheral blood lymphocytes determined with the cytokinesis block assay is among the most popular biomarkers used for this purpose, although large inter- and intralaboratory variability of this end point has been observed in population studies. The availability of reference measures is therefore necessary for laboratories to validate protocols and analytical procedures, and for molecular epidemiologists, as well, to estimate the statistical power of studies and to assess the quality of data. In this article, we provide estimates of the baseline frequency of MN in children, conducting a meta-analysis of MN frequency reported by field studies in children and a pooled analysis of individual data [available from published studies and from the Human Micronucleus International Collaborative Study (HUMN) database]. Thirteen articles were selected for meta-analysis, and individual data included in the pooled analysis were retrieved from the databases of 12 laboratories. Overall means of 4.48 [95% confidence interval (CI), 3.35-5.98] and 5.70 (95% CI, 4.29-7.56) MN per 1,000 binucleated cells were estimated by the meta- and pooled analysis, respectively. A clear effect of age was detected, even within the restricted range of pediatric age considered, with significantly lower frequency values in newborns. No influence of sex was found. The study showed the advantage of using data from large collaborative studies and suggested a synergistic use of meta- and pooled analysis.

Adolescent↗