Hereditary colorectal cancer in the general population: from cancer registration to molecular diagnosis.
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BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited disorders predisposing to cancer. The genes responsible for the disease have recently been cloned and characterised; their mutations induce a generalised genomic instability which is particularly evident at microsatellite loci (replication error (RER)+ phenotype). AIMS: To investigate how to select individuals and families in the general population who should be screened for constitutional mutations predisposing to colorectal cancer. PATIENTS/METHODS: Between 1984 and 1995, 1899 colorectal malignancies in 1831 patients were registered, and in 1721 of these (94%), family trees could be obtained. Patients and families were classified into five categories according to a more or less likely genetic basis: HNPCC; "suspected" HNPCC; juvenile cases; aspecific cancer aggregation; sporadic cases. In 18 families with HNPCC as well as in 18 with suspected HNPCC, microsatellite instability in tumour tissues and constitutional mutations of two DNA mismatch repair genes (MSH2 and MLH1) could be evaluated. RER status was studied with five markers (BAT40, D2S123, D18S57, D17S787, and BAT26) in paraffin embedded tissues. Germline mutations of MSH2 or MLH1 genes were assessed on DNA and RNA extracted from lymphomonocytic cells, using reverse transcription polymerase chain reaction, single strand conformation polymorphism analysis, and direct DNA sequencing. RESULTS: HNPCC represented 2.6% and suspected HNPCC 4.6% of all registered colorectal neoplasms. Eleven out of 18 HNPCC families (61%) showed microsatellite instability as opposed to four (of 18) suspected HNPCC (22%; p<0.02). Three germline mutations (two in MSH2 and one in MLH1 gene) were found in three different large HNPCC families, whereas no mutations were detected in suspected HNPCC. CONCLUSIONS: In this study of cancer genetic epidemiology, data from a tumour registry were analysed and this ultimately led to the identification and selection of families that should be tested for mutator gene mutations. With the use of a population based approach, the incidence of mutations was appreciably lower than previously reported and limited to families with full blown HNPCC. It is possible that in most families with a clinical spectrum of HNPCC (or suspected HNPCC) other DNA mismatch repair genes are involved in the pathogenesis of the disease. (+info)
Mother-to-child transmission of human immunodeficiency virus in Italy: temporal trends and determinants of infection. The Italian Collaborative Study on HIV infection in pregnancy.
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In order to analyse temporal trends in vertical transmission rates of human immunodeficiency virus (HIV) and determinant of congenital HIV infection in Italy, we have considered data from a network of hospitals co-operating in the Italian Collaborative Study on HIV infection in pregnancy, conducted between 1988 and 1995. A total of 1040 women entered the study. The HIV-1 status of the babies was known in 848 cases (81.5%). Transmission rates were highest in the period 1988-1991, then tended to decrease and in 1995 the rate was 9.7 per 100 children (this finding, however, was based on only six infected children and the trend was not statistically significant). Considering the overall series, the risk of vertical HIV transmission was higher in women with low CD4 count in pregnancy [odds ratio (OR) < 400 versus > or = 400 1.8, 95% confidence interval (CI) 1.1-2.9]. In comparison with vaginal delivery the risk of transmission was 0.3 (95% CI 0.1-0.5) and 0.6 (95% CI 0.3-1.2) respectively for elective and emergency delivery. In comparison with women who delivered at term (> or = 37 gestation weeks) the OR of HIV infection of the babies for the whole series was 2.2 (95% CI 1.3-3.6) in women who delivered preterm. Similar findings emerged when the analysis was conducted considering, separately, subjects observed in the period 1988-1991 and 1992-1995. The frequency of Caesarean section increased from 26.5% of deliveries in 1988-1991 to 36.2% in 1992-1995. Consequently, most temporal differences disappeared after standardization for mode of delivery, but the rate in 1995 was still lower than in 1988-1994. (+info)
Health-related quality of life in dialysis patients. A report from an Italian study using the SF-36 Health Survey. DIA-QOL Group.
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BACKGROUND: Interest in measuring health-related quality of life (HRQoL) has increased together with an awareness that such humanistic outcomes require valid and reliable measures. In the last decade short, simple and multidimensional generic and disease-specific questionnaires have been developed. Among the several generic questionnaires available, the Short Form 36 Items Health Survey (SF-36) was translated and validated in several languages, and applied to different settings and diseases. METHODS: Within the framework of a larger, prospective, multicentre study (DIA-QOL project) the SF-36 was administered to 304 patients to test its characteristics in terms of patient acceptability, and psychometric and clinical validity. Standard psychometric techniques were used to evaluate its validity in terms of convergence, divergence and internal consistency reliability (Cronbach's alpha). Correlations between clinical variables and HRQoL scores were performed to test the questionnaire's capability to capture differences across patients groups. RESULTS: Overall, the findings show that, in this sample, the SF-36's performance was very good. Acceptability was satisfactory, with a response rate higher than 80%. All the questionnaire scales met the psychometric standards suggested in terms of grouping and scaling assumptions. The internal reliability coefficients actually replicate the satisfactory findings reported previously for the original SF-36. In terms of the ability of the questionnaire scales to discriminate between groups expected to differ in a given health concept in relation to clinical variables, the results were also good. On average, females reported lower scores, the impact of ageing was more evident for physical scales. Diabetic patients score significantly worse on the physical function scale and patients with mental health problems score significantly lower on the mental health scale. No significant association was found with the index KtV, haemoglobin levels, body mass index, parathyroid hormone and type of dialysis. A strong association was indeed found between SF-36 scales measuring physical health concepts and the serum albumin level. This association held after adjusting for the confounding effect of age. Comparison of the health profile of the present sample with others from the US and UK and from a representative sample of the Italian general population highlights the potential of such questionnaire in dialysis setting. CONCLUSIONS: The SF-36 questionnaire is easy to use in Italian dialysis patients and SF-36 scores are related to important clinical aspects. This approach can help in caring for dialysis patients and can be useful in outcome assessment programmes. (+info)
Seasonal effect on airborne pyrene, urinary 1-hydroxypyrene, and benzo(a)pyrene diol epoxide-hemoglobin adducts in the general population.
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Exposure to airborne polycyclic aromatic hydrocarbons (PAHs) in 65 employees (40 sampled both in summer and winter, 15 sampled in summer only, and 10 sampled in winter only) with no occupational exposure to PAHs was assessed by measuring: personal exposure to pyrene, urinary excretion of 1-hydroxypyrene (1-OHP), and benzo(a)pyrene diol epoxide adducts to hemoglobin (BPDE-Hb). Overall, office employees were exposed to significantly higher levels of pyrene in winter (4.54 +/- 2.35 ng/m3, mean +/- SD) than in summer (1.67 +/- 1.92 ng/m3, mean +/- SD; P < 0.001), but no such seasonal variability was observed in 1-OHP excretion. Tobacco smoking was the major determinant of 1-OHP excretion. BPDE-Hb adducts were measured by gas chromatography-mass spectrometry as benzo(a)pyrene tetrols (BPT) released from adducted hemoglobin. In the 65 employees analyzed, mean BPT levels +/- SD were higher in winter (0.14 +/- 0.38 fmol/mg Hb) than summer (0.031 +/- 0.022 fmol/mg Hb). This difference was not statistically significant, probably because of the small proportion of subjects with detectable adducts (11% in summer and 16% in winter). BPDE-Hb adducts were not significantly associated with sex, age, diet, smoking habits, or with pyrene levels and 1-OHP excretion. This is the first report providing reference BPDE-Hb adduct values for the general population not occupationally exposed to environmental PAHs and shows a tendency to seasonal variability, with higher BPT levels in winter when environmental PAHs are also high. (+info)
Detection of five rare cystic fibrosis mutations peculiar to Southern Italy: implications in screening for the disease and phenotype characterization for patients with homozygote mutations.
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BACKGROUND: The search for the eight most frequent mutations (i.e., DeltaF508, G542X, W1282X, N1303K, 1717-1G-->A, R553X, 2183AA-->G, and I148T) by allele-specific oligonucleotide dot-blot analysis revealed 78% of 396 cystic fibrosis alleles in Southern Italy. The observation of frequent haplotypes on the unidentified cystic fibrosis alleles suggested that a few mutations could account for a large number of unidentified alleles. METHODS: We screened most of the coding sequence of the cystic fibrosis transmembrane regulator gene by denaturing gradient gel electrophoresis to determine the spectrum of these mutations in 68 unrelated cystic fibrosis patients bearing one or both unidentified mutations. RESULTS: The screening revealed five mutations, R1158X, 711+1G-->T, 4016insT, L1065P, and G1244E, each of which had a frequency of 1.3-1.8% (7% collectively). The 7% increase in the detection rate (85% vs 78%) reduces by >50% the residual risk of being cystic fibrosis carriers for couples who had tested negative by molecular analysis. We therefore designed a second allele-specific oligonucleotide set to analyze the five mutations. Among the patients analyzed, one patient homozygous for the L1065P mutation expressed a mild pulmonary and intestinal form of the disease with pancreatic insufficiency. Two other patients, homozygous for mutations R1158X and 4016insT, both expressed a severe cystic fibrosis phenotype. CONCLUSIONS: Five cystic fibrosis mutations are peculiar to patients from Southern Italy. The method described for their analysis is efficient, inexpensive, and can be semi-automated by use of a robotic workstation. The results obtained in patients from Southern Italy may have an impact on laboratories in other countries, given the large migrations of populations from Southern Italy to other countries in the last two centuries. (+info)
CREST staining of micronuclei from free-living rodents to detect environmental contamination in situ.
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In this work immunofluorescent antikinetochore (CREST) staining was used to analyse bone marrow micronuclei (MN) from free-living animals belonging to four different rodent species. Yellow-necked mice (Apodemus flavicollis) and bank voles (Clethrionomys glareolus) were trapped in the Czech Republic, Algerian mice (Mus spretus) in Spain and house mice (Mus musculus domesticus) in Italy. Animals were collected in areas displaying low or high environmental pollution in order to investigate the sensitivity of CREST analysis on bone marrow MN as a biomarker of environmental stress in situ. Differences in total MN frequencies between animals collected in control or contaminated areas were statistically significant for two species, whereas the differences in CREST+ MN were statistically significant for three species. Interestingly, the percentages of CREST+ MN in animals collected in the control areas were very low (3. 2-8.7%), suggesting that activities inducing alterations in the distribution of chromosomes are very rare in natural conditions. The increased frequencies of CREST+ MN observed in areas with high environmental impact indicate that activities producing loss of chromosomes at mitosis may be characteristic of anthropogenic environments such as industrial settlements around petrochemical factories. Our data suggest that the analysis of CREST+ MN may represent a sensitive end-point for the detection of environmental contamination by genotoxic xenobiotics, offering the advantage of providing information on the mechanism of action of environmental contaminants. (+info)
Why do Italian stroke patients receive CT scans earlier than UK patients? International Stroke Trial Collaborators in Italy and the UK.
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Computed tomography (CT) scanning is important prior to acute stroke treatment. We wished to identify factors associated with being able to obtain a CT scan quickly, from a recent large stroke treatment trial. A questionnaire survey on the organisation of CT scanning services for stroke was sent to 179 UK and Italian hospitals who had randomised patients into the International Stroke Trial and performed at least one pre-randomisation CT scan. Data from the questionnaire were analysed in conjunction with other patient data. Italian doctors expected the CT scans to be done more quickly than UK doctors, their hospitals were more likely to have a CT scanner operating all the time, and a porter was used less frequently to take the patient to the CT scanner. A few simple changes in the way CT scanning is organised for stroke patients in the UK could speed access to CT considerably. (+info)
Clinical characteristics and outcome of young chronic lymphocytic leukemia patients: a single institution study of 204 cases.
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A retrospective analysis on chronic lymphocytic leukemia (CLL) patients 55 years of age) were observed. At diagnosis, younger and older patients displayed a similar distribution of clinical features, except for a significantly higher male/female ratio in younger patients (2.85 v 1. 29; P <.0001). Both groups showed an elevated rate of second primary cancers (8.3% v 10.7%), whereas the occurrence of Richter's syndrome was significantly higher in younger patients (5.9% v 1.2%; P <. 00001). Younger and older patients showed a similar overall median survival probability (10 years) but were characterized by a different distribution of causes of deaths: CLL unrelated deaths and second primary malignancies predominated in the older age group, whereas the direct effects of leukemia were prevalent in the younger age group. Although younger and older patients displayed a similar survival, the evaluation of the relative survival rates showed that the disease had a greater adverse effect on the expected survival probability of the younger population. Multivariate analysis showed that for young CLL patients only dynamic parameters, such as lymphocyte doubling time and other signs of active disease, were the independent factors that significantly influenced survival probability (P =.00001). A prolonged clinico-hematologic follow-up allowed us to identify two subsets of young CLL patients with a different prognostic outcome: a group of patients (40%) with long-lasting stable disease without treatment and an actuarial survival probability of 94% at 12 years from diagnosis and another group (60%) with progressive disease and a median survival probability of 5 years after therapy. For the latter patients, the therapeutic effect of innovative therapies with curative intents needs to be investigated in prospective, comparative clinical trials. (+info)