Ataxia-telangiectasia in Italy: genetic analysis.

Genetic analysis was performed on 72 Italian A-T families ascertained through 91 probands. The frequency of the A-T gene was estimated through Dahlberg's formula, which uses the frequencies of first cousin marriages among the patients' parents and in the general population were obtained from the collection of Catholic Church dispensations for the period 1910-1964. Accurate estimates of the disease frequency were made by subdividing data into 5-year periods and between provinces, in order to take into account temporal (decrease over time) and spatial (higher frequency in Southern Italy) heterogeneity. The estimate of the gene frequency for the whole sample was q = 0.012 +/- 0.0065, corresponding to a heterozygote frequency of 2.34% and to a disease frequency of 1 in 7090. When considering q before and after 1970, there was an apparent increase of heterozygote frequency from 1.69 to 3.43%, perhaps due to a better ascertainment of the disease in the latter period. A segregation ratio of 0.249 +/- 0.043 was obtained by analyzing the offspring of the 72 families under the model of incomplete multiple selection. This value is not significantly different from 0.25, as expected for an autosomal recessive disease.

Correlation between unscheduled DNA synthesis and chromosome condensation in mitoses from human lymphocytes.

The correlation between chromosome condensation and amount of repair synthesis after UV irradiation was studied in PHA-stimulated human lymphocytes. The length of selected chromosomes and the number of autoradiographic grains were determined in cells from late prophase to middle metaphase. The statistical analysis of data indicates a highly significant correlation between the two variables and a positive linear regression of the number of grains on chromosome length.

Incorporation of (3H)thymidine stimulated by ultraviolet radiation into human fibroblast cultures.

We studied DNA repair synthesis after ultraviolet irradiation in human fibroblasts cultured in vitro by measuring the ultraviolet-stimulated incorporation of [3H]thymidine into cells in which the semi-conservative DNA replication was inhibited by hydroxyurea. Experiments performed with five fibroblasts lines derived from healthy donors showed a relatively fast initial process ( that is completed within 1 h for 100 erg/mm2 and within 2 h for 500 erg/mm2) and a subsequent slower process, evident between 2 and 6 h after irradiation. The repair capacity of normal cells is expressed by the difference between the values of incorporation (in presence of hydroxyurea) of irradiated and control cells. The pattern of repair was similar in all five cell lines: repair capacity was positive and the amount of repair synthesis increased with incubation time after UV irratiation. Similar experiments were performed with fibroblasts derived from five patients with the classical xeroderma pigmentosum (XP) and from one patient with the De Sanctis-Cacchione syndrome. Normal and XP cells could be distinguished according to whether they displayed a positive or negative value of repair synthesis and/or according to the degree of the slope of the repair synthesis curve as a function of the incubation time after irradiation. We conclude that the technique used in our experiments can demonstrate in a rapid and simple way a defect in the repair capacity in fibroblast cultures; the data are in good agreement with those obtained in the same XP cell lines by other authors [9], who have measured unscheduled DNA synthesis in autoradiographs and repair replication after addition of BUdR.

Two positive identifications assessed with occasional dental findings on non-dental x-rays.

The cases reported here show typical difficulties of dental identification procedure in the face of a lack of AM data for the missing person and an almost edentulous mouth in the body. In the first case the image of an included third molar found in an AM CT of the skull represented the decisive evidence for identifying the corpse; the identification of the body in the second case was possible only for an oversight of the radiologist during the performance of AM x-rays. They offer the occasion to describe the decisive importance of some occasional dental findings on non-dental x-rays and to stress the need of a comprehensive AM data collection and of a truly multidisciplinary approach to the collection and examination of x-rays. Furthermore, the cases underline that some radiographic features require skill, not only to be interpreted but also to be recognized.

Fertility and malaria in Sardinia.

Using data from the 1961 Italian census, the study of fertility in Sardinia when malaria was endemic shows differential fertility between women living in areas with differing degrees of malaria. Cultural factors measured by women's level of education are negatively correlated with fertility, just as the 'urban' character of the area in which the women lived has a lowering effect on the fertility rate. The hypothesis of differential mortality according to social class, affecting lower-class women and in particular the more prolific among them, seems to be supported by data analysed through time. The subdivision of Sardinian towns and villages into those with a 'low' and a 'high' malaria rate was made on the basis of the classification given by Fermi in a period corresponding to the overall period of fertility of the women considered. Hypotheses about a greater acquired immunity and a higher frequency of heterozygotes for malarial genes, like thalassaemia and G-6-PD deficiency, in the area where malaria was more intense, are proposed to explain the higher fitness of women living in this area. The comparison between frequencies of heterozygotes for thalassaemia and G-6-PD deficiency, obtained by Siniscalco et al. for Sardinian villages in the two different malaria-infested areas, shows a significant difference when the areas are examined as a whole, but a great variability (principally for G-6-PD deficiency) between villages. Changes in ecological factors could have modified the geographical distribution of malaria today, compared with the distribution that may have determined the frequencies of heterozygotes many years ago.

PIP: Researchers used 1961 census data from Italy to study fertility in Sardinia when malaria was endemic. Results show differential fertility between women living in 335 towns and villages with varying degrees of malaria. The mean number of children/woman rose significantly from areas of low to medium to high incidence of malaria (p .001). Further, a 1984 survey on the association between fertility and diseases showed that in areas of intense transmission of malaria, infant mortality was high, but surviving adults were greatly immunized and pregnant women were protected to some degree from the risks of placental parasitization and consequent fetal loss or stillbirths. On the other hand, in areas of medium or low malarial endemicity, infant mortality was low and surviving adults were not immunized enough to protect them from malaria. Further, pregnant women whose immune systems are naturally suppressed often developed fever, anemia, and placenta parasitization. In the 1960s, a researcher analyzed 52 Sardinian villages for thalassemia and G-6-PD deficiency. The results showed that for both genes, the overall frequencies of heterozygotes were significantly higher in the areas of high malarial endemicity (p.001). When the researcher compared the variation between villages, however, the difference was not significant, especially for G-6-PD deficiency. Therefore, the increased fertility in high endemic areas may be due to the greater acquired immunity and a higher frequency of heterozygotes for malarial genes, such as thalassemia and G-6-PD deficiency. In addition, as the level of education increased the fertility rate decreased. Fertility was lower in urban areas (20,000 inhabitants) than in rural areas.

Education and birth control.

PIP: Focus is on the demographic transition in Italy in relation to education. An analysis of the data of the Italian 1961 census in 3 provinces reveals a strong stratification of the transition to lower birthrates according to degree of education. A 50-year lag exists in the transition in the highest and lowest educational classes. Adjustment to a lower number of children occurred, on average, by a decrease in the age at last childbirth. However, the more literate classes begin reproduction at a later age. Educational differences explain only about 1/2, approximately, of the rural-urban difference in birthrates; different geographical areas show additional, independent retarding factors. The relationship of mean to variance of number of children ever had in postreproductive women, evaluated on relatively homogenous strata (by cohort and educational class), is practically linear (or at most, with a slight concavity downward) with a negative intercept. The relationship during reproductive age is instead concave upward. The observed mean-variance relationship in postreprductive women is in agreement with the hypothesis of the diffusion of the Malthusian ideal through the population, if the decision in favor of a Malthusian behavior in reproduction is not limited to reproductive age, but can occur at any age. Naturally, the conversion to a Malthusian ideal in a family after some children are already born would cause only a small reduction in the fertility of that family, thus introducing an element of gradualness in the change from the "natural" fertility behavior to the Malthusian one. The beginning of the transition is different in different educational strata for a variety of reasons.^ieng

Genetic and cultural transmission in Sicily as revealed by names and surnames.

The study of names as cultural characters and of surnames, which behave like genetic markers, is useful for comparing cultural and genetic transmission. Genetic transmission has a unique vertical component, which also can be present in the transmission of cultural traits associated with a horizontal (or epidemic) component resulting from local customs or fashion. Our aims in this study are to infer genetic patterns in Sicily from surnames and names and to evaluate and compare the consequences of vertical versus horizontal transmission of cultural markers. Names and surnames of 88,383 consanguineous spouses collected in 16 dioceses of Sicily were analyzed by multivariate analysis to reveal and compare the geographic clusters obtained from both sets of data. As a result, both data sets indicate a major separation between the eastern and the western region of Sicily. Also, distance matrices obtained from names are highly correlated with those from surnames. But names seem to form fewer and larger geographic clusters, whereas surnames are more greatly subdivided into smaller clusters. The most common male names present a different pattern from surnames. Vertical transmission is the cause of the similarity of the main geographic patterns of names and surnames and their correspondence with findings from geography of genes, and horizontal cultural transmission explains the major differences. Furthermore, the genetic and cultural affinities can be correlated with the historical background of Sicily.

Differential fertility as a mechanism maintaining balanced polymorphisms in Sardinia.

Women's fertility, gathered from the 1961 Italian population census, and estimates of heterozygote frequencies for thalassemia and G6PD deficiency (Siniscalco et al. 1961, 1966) in 52 Sardinian villages were examined to study at the population level the mechanisms that have maintained the stability of these polymorphisms over long periods. Sardinian villages were classified according to low or high frequency of heterozygotes, and the reproductive behavior of the women living in these areas was analyzed. A high mean number of children per woman and a low percentage of women without children with a high heterozygote frequency was demonstrated. The observed differential fertility and sterility were interpreted as being the result of different numeric ratios within each area between normal homozygous and heterozygous women, who were less and more resistant, respectively, to malarial infection, according to Haldane's theory. The effect of differing degrees of malaria on fertility rates has been demonstrated previously (Zei et al. 1990). To account for the effect of the genetic and epidemiological composition of an area on reproductive behavior, we classified data on women's fertility and sterility by heterozygote frequency level and malarial morbidity level. A combined and direct effect of inherited and acquired immunities on fertility and sterility rates was shown. The level of endemicity in an area may contribute to decreasing or increasing fitness, which is already influenced by the stable balanced polymorphisms.

Surnames in Sardinia. III. The spatial distribution of surnames for testing neutrality of genes.

1. A study on heterogeneity of males' surnames over time and space in the island of Sardinia was carried out using data from consanguineous marriages (1800-1970) and telephone directories (1978). 2. Variation of frequency of surnames over time is barely significant and 10 times lower than that over space, which is very highly significant. 3. For sufficiently frequent surnames the estimate of the Wahlund variance, calculated from chi 2 for heterogeneity in space, is independent of the frequency of a surname: this supplies evidence of neutrality in line with that obtained from the frequency distribution of surnames. 4. The Wahlund variance, W (also called FST), decreases regularly as the average size of the area considered (number of individuals per area, N) increases. The estimate of the parameter beta in the relation W = KN beta could be of interest for the study of population structure. 5. A correction factor of 1/4 must be made on the surnames' variance in consideration of their haploid unisexual transmission. 6. It is suggested that surnames could provide a baseline for estimating the value of Wahlund variance under random genetic drift and hence evaluating whether a gene behaves as selectively neutral. 7. The distribution of the Wahlund variances obtained from two sets of gene frequency data as compared with that obtained in comparable conditions for surnames in the same areas seems to show that most genes behave as neutral, with the exception of a few, with high W values, which presumably have been under different selection pressures in the area examined.

Prognostic value of adenosine deaminase compared to other markers for progression to acquired immunodeficiency syndrome among intravenous drug users.

This study was designed to determine the prognostic value of erythrocyte adenosine deaminase (ADA) as a possible indicator of progression to AIDS, and compare this with other known cellular and serological markers. At the end of a 3-year study, a cohort of 114 human immunodeficiency virus-1 (HIV-1) seropositive intravenous drug users (IVDUs) from the five different Center for Disease Control (CDC) groups was examined in order to estimate the prognostic relevance with respect to the progression to acquired immunodeficiency syndrome (AIDS) of each of the following markers at baseline value: number and percentage of CD4+ T cells, number of CD8+ T cells, CD4+/CD8+ ratio, IgA and beta 2 microglobulin and ADA levels, and the presence of HIV antigens. Moreover, 57 IVDUs belonging to II and III CDC groups were analyzed in a follow-up study at 6-month intervals, in order to evaluate and compare the behavior of each marker over time. The prognostic significance of each marker was assessed by computing the survival distribution and the Cox analysis in a multivariate model providing the set of markers with greatest predictive value. The levels of ADA and the CD4+/CD8+ ratio showed a linear association with disease staging, whereas beta 2 microglobulin and CD4+/CD8+ ratio were the best predictors for AIDS progression. A highly significant increase in ADA and beta 2 microglobulin was observed during follow-up. The results obtained among HIV-positive IVDUs clearly indicate that the erythrocyte ADA may be considered a reliable marker of the development of HIV infection from the intermediate stages of the disease onwards.(ABSTRACT TRUNCATED AT 250 WORDS)

Past malaria, thalassemia and woman fertility in southern Italy.

The role of natural selection in maintaining the thalassemia polymorphism is examined in a southern Italy district, in the past affected by malaria endemia. The Haldane's hypothesis that the thalassemia heterozygotes enjoy more protection than the normal homozygotes against the risk of malaria infection, seems to be confirmed by this indirect study at population level. The higher number of children born of the women who lived in the highly endemic villages, where the highest proportion of heterozygotes occurs, supports the hypothesis that the woman fertility contributes to the thalassemia maintenance. The joint effects of the acquired and inherited immunities and of the reproductive compensation are assumed as the mechanisms through which malaria and thalassemia influence fertility.

Surnames in Sardinia. I. Fit of frequency distributions for neutral alleles and genetic population structure.

Distributions of surnames were examined using data from about 40 000 individuals from consanguineous marriages (1930-59) in the island of Sardinia. They fit the Karlin-McGregor (1967) distribution for neutral alleles. The logarithmic distribution by Fisher (1943) and the Karlin-McGregor (1967) distribution give practically indistinguishable fits to these data. The two parameters underlying the Fisher distribution, alpha and nu, are fully interdependent, given the sample size N. From the latter and from the number of surnames S, they can be easily and satisfactorily estimated. The quantity nu measures immigration to the area and can be taken as a measure of the richness of the gene pool, being closely related to the quantity theta = Nemu (Ne = effective population size, mu = mutation rate) after the necessary corrections have been taken care of. Surnames behave like genes transmitted by the male line. Differences of female and male migrations require correction for comparison with data from autosomal gene frequencies but there seem to be no important differences between female and male migration in this area, as judged by analysis of pedigrees of consanguineous marriages. It is probable that the migration estimates obtained in this material are lower than real ones, mostly because of a bias characteristic of the particular source of surnames here employed. The distribution of surnames from areas which have very recently undergone economic development is not at equilibrium and is not fitted as well as that of areas which have had less important recent changes. As might be expected, the disturbance is particularly marked in the class most sensitive to effects of recent increases in migration, that of rarest surnames (represented by only one individual). In fact in this material it is noticeable only in this class and correction can be made for it. At equilibrium of migration and drift, the number of surnames in a population sample of given size can give a complete description of the population structure for that sample, in the same sense that the number of alleles is a sufficient statistic for the study of neutral evolution. The study of surnames, given their nature of 'neutral' alleles, the large number of alleles and the ease with which large numbers of individual data can be collected, can be a valuable help in the study of genetic population structure.

Migration rates of human populations from surname distributions.

Migration is an important factor in the biological evolution of human populations, and surnames provide one of the simplest records of identification. The distribution of surnames can supply quantitative information on the structure of human populations. Surnames considered as alleles of a gene transmitted only by the male line can be assumed to be neutral markers and therefore satisfy the expectations of the neutral theory of evolution, which is entirely described by random genetic drift, mutation and migration. As data on surnames are easier to collect than those from genes, the information yield is potentially increased, but the validity of the conclusions must be tested in actual samples. The purpose of this report is to compare the estimates of migration rates in Italy, as inferred by the surname distribution found in the telephone directories and other sources, with the corresponding estimates from official demographic sources. Our findings show that in these samples the ratio of surnames to individuals makes it possible to calculate reliable estimates of migration rates.

Surnames in Sardinia. II. Computation of migration matrices from surname distributions in different periods.

A method is described for obtaining migration matrices from data on frequency distributions of transmissible traits in at least two different periods. In the present case, surname frequency distributions were used. In this way migration matrices describing rates of movement among nine areas of Sardinia were found for the period 1850-1970. Data were kinship matrices from surname distributions over two or three time periods. Population growth was included in the model under the assumption that expected family size in all areas was constant, or that outside estimates of the relative family sizes exist. Use of variable vs. constant growth rates did not drastically affect the estimated matrices. The matrices estimated for different time periods are similar. Estimates of net migration into the different areas were relatively insensitive to different methods of summarizing statistics. The elements of the matrices indicate strong effects on migration rates of distance between areas, and somewhat weaker effects of economic differences. The diagonal elements of the matrices show a high negative correlation with independent estimates of rates of immigration into the same areas.

Barriers to gene flow estimated by surname distribution in Italy.

Surname distributions were studied in order to reconstruct human migration patterns. Zones of sharp change in surname frequencies--presumably barriers to gene flow--were detected by the statistical technique of wombling (Barbujani et al. 1989), using data from consanguineous marriages (1910-64) collected from 280 Italian dioceses which we grouped into 80 provinces. The 28 observed surname boundaries were compared with physical (geographical) and cultural (linguistic) barriers, and with boundaries detected from distributions of 57 alleles in the same territorial subdivisions. Genetic and surname boundaries had similar locations, as expected given the analogy in the inheritance mechanism of genes and surnames. Physical barriers seemed to be the main cause of gene flow reduction. However, cultural factors alone (e.g. linguistic ones) also determined barriers that delimited areas of homogeneous gene (and surname) frequency probably due to increased endogamy. The observed similarity between spatial patterns of surnames, genes and languages supports the hypothesis of the co-evolution of genetic and linguistic variation.

High prevalence of Werner's syndrome in Sardinia. Description of six patients and estimate of the gene frequency.

Several patients with Werner's syndrome in a large family group in Sardinia were ascertained three years ago and reported briefly by Rabbiosi and Borroni (1979). Since then two sisters from a second family and a single case from a third family were ascertained. The three families originated from the Northern part Sardinia and no connection between them was found. We provide a detailed clinical description of six of these patients and attempt to estimate the prevalence and the gene frequency of Werner's syndrome in Sardinia. The prevalence was calculated as 1:94,914 for the two districts of Sassari and Nuoro and as 1:202,766 for the whole island. This is the highest prevalence thus far ascertained. Using Dahlberg's formula we obtained an estimate of the gene frequency q = 0.003288 and thus a frequency of Werner's syndrome of 1:92,515. A more rigorous estimate gave a gene frequency q = 0.001483 and thus a frequency of Werner's syndrome of 1:454,505, but because of the small sample size this estimate should be taken with caution.

Myelofibrosis in chronic granulocytic leukaemia: clinicopathologic correlations and prognostic significance.

We performed 221 marrow trephine biopsies in 139 patients with Ph1-positive (Ph1+) chronic granulocytic leukaemia (CGL) in order to assess the incidence, degree and prognostic significance of marrow fibrosis (MF) at various stages of the disease. We also attempted to elucidate the relationship between development of MF and the various clinical and haematological features of CGL. A significant correlation was found between the amount of fibrosis (graded from 0 to 3) and the stage of CGL, indicating that major fibrotic changes are associated with accelerated or blastic disease. Survival studies performed to assess the prognostic significance of the various degrees of MF, showed a progressively worse life-expectancy from grade 0 to grade 3 fibrosis. Multivariate regression analysis indicated Hb level, age, number of marrow megakaryocytes (MKs), time from diagnosis as the features most significantly correlated with the degree of MF. This study demonstrates that the natural history of CGL involves a progressive increase in reticulin deposition towards severe MF, although the rate of this progression varies widely. Monitoring changes of fibrosis with sequential biopsies could give a measure of the rate of progression of the disease and help in prognostic assessment of CGL patients. Our findings also confirm that among marrow features the number of MKs is the cytological variable most significantly correlated with MF.

Search for consanguinity within and among families of patients with trichothiodystrophy associated with xeroderma pigmentosum.

The association of two rare hereditary disorders, trichothiodystrophy (TTD) and xeroderma pigmentosum (XP), was found in four patients from three families, apparently unrelated but living in the same geographical area. In order to test the hypothesis of a common ancestor, consanguinity within and among the families was checked using three different approaches: reconstruction of genealogical trees, typing of blood markers, and surname analysis. The results of the three types of analyses strengthen the hypothesis that, in at least two out of the three families, the genetic defect determining the TTD/XP phenotype is identical by descent, as a consequence of remote inbreeding. This implies that if two mutations are responsible for the two diseases they are at linked loci or affect the same gene.

Adult acute lymphoblastic leukemia. Response to therapy according to presenting features in 62 patients.

Sixty-two adult patients with acute lymphoblastic leukemia (ALL) were treated with an induction regimen including vincristine, daunorubicin and prednisone (VDP) followed by CNS prophylaxis. Forty-five patients (72.5%) achieved complete remission (CR). The CR were maintained with daily 6-MP and weekly MTX. Monthly reinduction cycles with vincristine and prednisone (plus daunorubicin every three courses) were also given. Median duration of CR was 10.4 months. Overall survival was 17.4 months. The remission rate and length of CR were studied in relation to the clinical and hematological features present at diagnosis. CR rate was adversely influenced by age only over 40 and by tumoral presentation. The length of remission was negatively influenced by tumoral presentation, CNS involvement, high circulating blast count, L2 and L3 cytology, and T or B immunological phenotype. Multiple regression analysis confirmed the weight of FAB morphology in determining the length of remission. Among L2 adult patients, tumoral presentation appears to be the major unfavourable prognostic factor.