Inequalities in diagnosis and registration of pediatric very rare tumors: a European study on pleuropulmonary blastoma.

Very rare tumors (VRTs) account for up to 11% of childhood cancers. Dedicated national groups and registries only exist in some European countries. Pleuropulmonary blastoma (PPB) is a very rare intrathoracic pediatric tumor with a potentially severe prognosis. Due to its rarity, it sometimes goes unrecognized. We investigated PPB diagnostic capability and possible correlations between diagnostic performance and VRT-dedicated activities. The number of cases of PPB registered between 2000 and 2014 at pediatric oncology centers in Europe was compared with the number of expected cases. Data sources included VRT registries, population-based cancer registries, and hospital registries. Data were obtained for 25 countries, grouped into 4 geographical regions. The expected cases were 111, and the observed cases were 129. The observed-to-expected ratio was 1.86 for Northern Europe, 1.33 for Southern Europe, 1.22 for Central Europe, and 0.65 for Eastern Europe. More cases than expected were registered in all countries with an official VRT registry.Conclusion: The number of cases observed is consistent with expectations, but disparities exist across Europe. Difficulties in diagnosing PPB emerged in most Eastern countries. The incidence rate of PPB may be underestimated. The creation of VRT-dedicated groups and a European Registry for VRTs could help to reduce inequalities.What is Known:• Very rare pediatric tumors are often not recognized, despite representing almost 11% of childhood cancers .• Pleuropulmonary blastoma is a rare pediatric tumor with a poor prognosis.What is New:• The ability to diagnose and register pleuropulmonary blastoma varies in Europe.Registries dedicated to very rare pediatric tumors improve the diagnostic rates.• The incidence rate of pleuropulmonary blastoma may currently be underestimated.

Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance.

The frequencies of low-activity alleles of glucose-6-phosphate dehydrogenase in humans are highly correlated with the prevalence of malaria. These "deficiency" alleles are thought to provide reduced risk from infection by the Plasmodium parasite and are maintained at high frequency despite the hemopathologies that they cause. Haplotype analysis of "A-" and "Med" mutations at this locus indicates that they have evolved independently and have increased in frequency at a rate that is too rapid to be explained by random genetic drift. Statistical modeling indicates that the A- allele arose within the past 3840 to 11,760 years and the Med allele arose within the past 1600 to 6640 years. These results support the hypothesis that malaria has had a major impact on humans only since the introduction of agriculture within the past 10,000 years and provide a striking example of the signature of selection on the human genome.

Identification of glucose 6-phosphate dehydrogenase deficiency in a population with a high frequency of thalassemia.

High frequencies of both thalassemia trait (5.2%) and glucose 6-phosphate dehydrogenase (G6PD) deficiency for only males (1.3%) have been observed in the Calabrian population. The G6PD activity measurement was carried out on 1239 samples of whole blood from Calabrian subjects of both sexes (age range 10-55) by a differential pH-metry technique which was quite suitable to determine the G6PD deficiency in mass screenings. The analyzed subjects showed: only the thalassemia trait; or only the G6PD deficiency; or only the total iron serum deficiency; or G6PD deficiency associated with the thalassemia trait or with the total iron serum deficiency. The G6PD heterozygous subjects have an enzymatic activity which is masked by both the thalassemia trait and the total iron serum deficiency. In a population showing high frequencies of both thalassemia trait and G6PD deficiency, the comparison of G6PD activity of heterozygous subjects also affected with the thalassemia trait is more reliable if referred to the enzymatic activity of the carriers of the latter inherited anomaly rather than to G6PD activity of normal subjects.

Allotypic phenotypes displaying different frequencies in healthy and beta-thalassemic sample populations.

This paper presents data on the identification of an allotypic polymorphism carried on a beta-lipoprotein in human serum. The antigen, whose inheritance is investigated in 78 families, is coded by a polymorphic locus (As) existing in 4 allelic states. The products of these alleles exhibit a serological linear subtyping pattern with respect to the alloantisera recognizing the allotypes. The allelic frequencies prove different in healthy (beta beta) and thalassemic (beta beta thal) sample populations, thus suggesting linkage dysequilibrium between the recessive alleles of the As and beta loci.

Color-blindness in Calabria (Southern Italy): A north-south decreasing trend.

The frequency of color-blindness (CB) in 13,072 males from 409 towns in Calabria is 5.42%. Regional variation in CB within the three provinces of Calabria was studied: Cosenza (northern), Catanzaro (central), and Reggio Calabria (southern). There is a decreasing trend of mean frequencies of CB from Cosenza to Reggio Calabria through Catanzaro: 6.23%, 4.65%, and 3.43%, respectively. The mean frequencies do not take into account the two ethnic minorities present in Calabria: Albanians and Grecanicans. The frequency of CB mean Albanians (7.40%) and the indigenous Calabrian population (5.25%) differs significantly. Moreover, the Albanians do not show the protoanomalous phenotype. The small sample size of Grecanicans does not permit an evaluation of mean CB frequency. Thus, from the perspective of CB, the Calabria region may be considered a mixture of "genetic isolates" reflecting its historical, sociocultural, demographic, and genetic features. Am. J. Hum. Biol. 12:17-24, 2000. Copyright 2000 Wiley-Liss, Inc.

Genetic characterization of the historical Albanian ethnic minority of Calabria (southern Italy).

Three historical ethnic minorities are present in Calabria: Albanians, Greeks, and Occitans. The Albanian ethnic minority is the more populous, having settled in Calabria between the 15th and 17th centuries, and these populations are now located in the provinces of Cosenza and Catanzaro. In the present study the Albanian population structure is analyzed based on the allele frequencies of six classic genetic markers: ACP, GC, PGM1, AK, ADA, and 6PGD. The results show a significant heterogeneity between the Albanian population in Calabria and the population in Molise. Therefore the cultural and reproductive isolation of the Albanian ethnic minority of Calabria is related to a great genetic peculiarity. Moreover, the frequencies of some alleles, particularly those of the PGM*1W31 variant, and the analysis of the R matrix still show the actual peculiar genetic structure of the Albanians of Calabria, although the genetic flow is evident in the decrease of endogamy and in the increase in the degree of mixing.

Genetic, epidemiologic and social features of colour blindness.

Red-green colour blindness is an inherited defect which shows interesting epidemiologic and social features. Its mean frequency within the indigenous population of Calabria (Southern Italy) was found to be 5.25%, one of the highest in continental Italy, showing a decreasing trend from the province of Cosenza (Northern Calabria, 6.23%), to the province of Catanzaro (Central Calabria, 4.65%) and the province of Reggio Calabria (Southern Calabria, 3.43%). A similar trend has not been previously recognized, according to the recent literature, because no other region has been fully screened. The mean frequency (7.40%) of red-green colour blindness in the Albanian ethnic minority in Calabria is significantly different from that of the indigenous population, and this minority does not have the protanomalous phenotype. Screening showed that 96% of the colour-blind students attending middle school and 65% of the colour-blind university students are not aware of their anomalous vision status. Thus, screening during the school years would greatly help affected students to choose their future professional orientation.

G1m(1) and G1m(2) allotypes in Albanian towns of Calabria.

The G1m(1) and G1m(2) allotype distribution was analyzed in a population sample from 11 Albanian towns of Calabria. The unusually high frequency of the G1m(1) marker already observed in Calabria as well as the presence of the Gm(2) phenotype were shown. The Calabrian and Albanian populations were similar, but significantly different from other Italian populations.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency in the Albanian ethnic minority of Cosenza province, Italy.

The Albanian ethnic minority of the Cosenza province (Calabria, Southern Italy) is constituted by a population of 42,305 inhabitants living in 19 communes. The first presence of this population, in Southern Italy, dates back to the fifteenth century as a result of different immigrations. We have studied the G6PD in the population of this province by determining both the frequency of the G6PD-deficiency and the type of Gd(-) alleles in samples from 19 communes. The overall frequency estimate turned out to be 0.0294 and those of the 8 highland communes and of the 11 communes located in the valleys were 0.0242 and 0.033 respectively. Both the frequencies and the ratio between the frequencies of the different Gd(-) alleles are significantly different with respect to a previous study carried out on the non-Albanian population of the same areas. The high endogamy rate found among the grandparents' and among the parents of the probands living in the Albanian community, shows that this community is to a large extent reproductively isolated from the neighbouring populations, thus accounting for these differences.

Endogamy and inbreeding since the 17th century in past malarial communities in the Province of Cosenza (Calabria, Southern, Italy).

Many authors stressed the importance of considering mating patterns, migration and consanguinity when analysing micro-geographic differences in the distribution of the frequency of genetic traits (thalassaemia and glucose 6 phosphate dehydrogenase deficiency (G6PD) in populations living in areas of past malarial endemy. Therefore, the present work was aimed at estimating the reproductive isolation of Calabria, an Italian region that experienced endemic malaria until very recently. The research was carried out on 15311 records of marriage from Parish Books of four villages located in the past malarial area, and four situated in the non-malarial region. Endogamy rates were high in every village and decreased only in the present century as a consequence of the breakdown of isolation. In the earlier periods, the rates ranged between 93-84% in non-malarial villages, and between 96-66% in the past malarial area. The rate of consanguineous marriages was low in all villages: in the malarial area it was 2.15% on average, whereas in the non-malarial villages it ranged between 2-16%. Its trend increased with time almost everywhere. Concerning values, differences between past malarial and non-malarial villages in earlier periods are not consistent as they ranged from 0.1 x 10(-3) to 1 x 10(-3). In the present century, however, a was higher in the non-malarial villages. Observed changes of the coefficient a since the 19th century are due to the increased frequency of first cousin marriages. Isonymy rates were lower than 2% in all past malarial towns in all periods, whereas in nonmalarial villages they ranged between 1.2-9.5% and increased with time. Inbreeding coefficients F are always higher than alpha values, but show the same trend with time. They were between 0.0006-0.0045 in past malarial towns, and between 0.0017-0.024 in non-malarial villages. In non-malarial villages Fn displayed noticeable negative values in two situations in the earlier periods. In conclusion, given the above mating patterns and the observed distribution of frequencies of G6PD deficient hemizygous and thalassemic heterozygous in the investigated villages, there is clear evidence in this area for the absence of any specific role of reproductive isolation and consanguinity on the distribution of genetic traits related to past malaria presence.

Rapid determination of erythrocyte pyruvate kinase activity.

We report a new potentiometric method for determining pyruvate kinase (PK). Enzymatic activity is measured by monitoring the change in pH produced in the reaction buffer under International Committee for Standardization in Haematology (ICSH) standardized assay conditions, and the lactate dehydrogenase reaction is automatically subtracted in each measuring cycle. The analysis, performed at 37 degrees C, requires a 10-microL sample (isolated erythrocytes or whole blood) and is completed in 2.5 min. The intra-assay CV is < 4% (PK between 3 and 35 U/g Hb); the interassay CV is 4.0% (PK 15 U/g Hb); results are linear from 3 to 30 U/g Hb. A good correlation with the ICSH reference method (x) was found: y = 1.011x - 0.05; n = 32; r = 0.9939; Sylx = 0.75 (units: U/g Hb). The reference intervals of the PK activity in isolated erythrocytes (RBC-PK) were estimated in 89 normal subjects. We found that women possess a higher RBC-PK than do men (P < 0.0001) and that the biological variability (CVb) of RBC-PK is 13.5%. Applications of the proposed method to the hematological routine are reported.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency in southern Italy: a study on the population of the Cosenza province.

35,660 healthy children attending secondary school in the Cosenza province, in the North of Calabria (Southern Italy), were screened for G6PD deficiency. Of 16,787 schoolboys, 209 were found to be G6PD deficient (1.24%). Of these, 99 (47.37%) had red cell G6PD activity below 5%, and they were classified as having the G6PD Mediterranean phenotype. The remaining 110 (52.63%), had a mild to moderate degree of deficiency, with an enzyme activity between 5 and 60%. Of these, 82 (74.55%) were electrophoretically normal, while 17 (15.45%) were electrophoretically fast and 11 (10.0%) were electrophoretically slow. The highest incidence of G6PD deficiency is on the Ionian Coast and along the Crati and Esaro river valleys, in good agreement with the distribution of the past malarial endemicity.

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.

Immunochemistry of an allotypic low density lipoprotein in man.

This paper presents data on a human allotypic polymorphism carried on a low density lipoprotein (As-LDL). The As polymorphism was investigated by a rabbit antiserum which was firstly used to analyze the serum level and the isoelectric point of the As lipoprotein in sera of different phenotype. This antiserum was also used to purify As-LDL by immunochromatography. Afterwards the peptidic maps of the APO proteins from different As-LDL were compared. While no correlation did result between the serum level and the serological phenotype of the As lipoprotein, the peptidic distribution of the APO parts from different As-LDL showed differences correlated to the allotypic phenotype.