I wish to thank Professor Paolo Durand, Director of the International Centre of Paediatric Genetics at the Mendel Institute, for his kind words and I particularly thank him for having proposed this celebration to mark the 40th anniversary of the foundation of the Institute.

Somewhat audaciously, I borrow a metaphor when I say that the real foundation stone of the Mendel Institute is the book, “The Study of Twins” here on the bookrest [Fig. 1]. This rather large volume carries works I had collected and developed in Rome over the previous years. In the main, it relates to clinical research work which for me began in an orphanage, not too far away from here on via Nomentana, where I encountered a pair of identical twin brothers, Romolo and Remo [Fig. 2]. The boys were so alike physically that I constantly confused the two and it was this experience that drew my attention to the twinning phenomenon. The book also contains a bibliographic list of over 7,900 studies carried out on the subject of twins. One of the first, of course, is that of Darwin's cousin, Francis Galton and another example from a later period is that of Chiarugi, the Florentine anatomist.

Published in 1951, “The Study of Twins” provoked such overwhelming interest in the medical world that it led me to vigorously promote two initiatives which began to take shape the following year. In 1952 the first issue of the journal “Acta Geneticae Medicae et Gemellologiae” was published and the construction of the Gregor Mendel Institute of Medical Genetics and Gemellology got under way to be finally inaugurated on 6 September 1953. One of the earliest and certainly most important figures in establishing the Institute is here with us today, Dr. Ildo Avetta, the Roman architect who designed the building. Let me take this opportunity to thank him once again for his brilliant work which has drawn the attention and admiration of many over the years.

Here, before you, is the complete 40-volume series of Acta Geneticae Medicae et Gemellologiae from its birth to date. [Fig. 1].

Temperament differences between cotwins at least 15% discordant for birth-weight were compared for a group of 66 preterm twin pairs and a group of 70 fullterm twin pairs, assessed in the neonatal period. The assessment focused on irritability, resistance to soothing, activity, reactivity, and reinforcement value. For the most part, significant differences were not obtained between discordant preterm cotwins. Previous research [10] had demonstrated that the larger fullterm twin of discordant pairs was more irritable, more difficult to soothe, more active while awake and during sleep, less reactive to visual and auditory stimuli, and less reinforcing to the examiner than the smaller cotwin. It was concluded that, for the behavioral variables measured, the fullterm group is at higher risk than the preterm group, and that both the lighter and the heavier discordant twins displayed signs of early behavioral risk. The findings suggested that the continued gestation for cotwins discordant in weight may be a risk period for early temperament development of the twins.

A randomized controlled trial of periconceptional multivitamin supplementation (including 0.8 mg folic acid – see the Materials and Methods section for the precise composition of the multivitamin and trace-element supplementation) was carried out for at least 28 days before conception. The trial was continued until at least until the second missed menstrual period to test the effectiveness of this new primary preventive method in the reduction of neural tube defects. However, other pregnancy outcomes were also evaluated. Of a total of 5,502 pregnant women, 4,846 births were analysed in the final data base. The rate of multiple births was significantly higher in the multivitamin group (3.8%) than in the placebo-like trace-element control group (2.7%), and in both groups exceeded the multiple birth rate of 2.2% in the Hungarian population at large. 7.3% of women in the multivitamin and 7.9% of women in the trace-element groups had received ovarian stimulation treatment (mainly clomiphene) for hormonal dysfunctions, eg. anovulation. Nonetheless, our study showed that periconceptional multivitamin supplementation, with or without ovarian stimulation, increases the rate of multiple births.

Over the last decades the frequency of multiple births has been on the decline in most developed countries. This trend, however, has been restricted to dizygotic twins, while monozygotic rates have remained stable or risen slowly. In more recent years, however, the fall in multiple dizygotic birth rates has ceased and a slight increase is observed. This trend and the increased frequency of triplets or higher-order births, registered from the early 1980s onwards, are essentially related to treatments for infertility. No single risk factor, such as maternal age, parity, oral contraceptive use, or declining fertility rates can explain the overall declining trends. In this paper we review the descriptive epidemiology and the main risk factors for multiple pregnancies.

The increasing number of twin (and higher order) births is a matter of national concern for two reasons: First, the differential rates of preterm (< 37 weeks) delivery and low birthweight (< 2,500g) among twins compared to singletons; and second, the inordinate contribution of these infants to overall infant mortality, morbidity and long-term handicap. Data from all births in the U.S. during 1987 and 1988 was used to calculate distribution frequencies for gestational age at delivery, and birthweight, as well as mortality and handicap rates and the corresponding relative risks of these latter events for twins compared to singletons. A suggestion for improvement in the mortality and handicap rates and reduced costs among survivors is presented. This proposal is based upon data from the singleton and twin literature and the use of the prenatal invervention of adequate maternal nutrition during the pregnancy.

Amniotic fluid elastolytic activity was assessed in a group of 120 women who delivered preterm infants and in 35 women who delivered at term. Amniotic fluid elastolytic activity decreases as pregnancy progresses. The lecithin-to-sphingomyelin (L/S) ratio in women's amniotic fluid was determined by the method developed by Gluck and associates [6] and elastolytic activity by that developed by Mehdi and associates. A significant negative correlation was found between the amniotic fluid L/S ratio and amniotic fluid elastolytic activity (r = −0.932; p<0.001).

The border value of elastolytic activity that indicates lung maturity (L/S ratio equal to or greater than 2) is 2.01 ± 0.05 mmol/min ml. In the amniotic elastolytic activity test, it is the value that differentiates mature from immature lungs. The amniotic fluid elastolytic activity test is characterized by high sensitivity (91.43%) and specificity (91.67%), high positive prognostic value (76.19%) and low negative prognostic value (2.65%). The test parameters do not therefore differ greatly from those of the Gluck test. Moreover, the amniotic fluid elastolytic activity test is cheaper and takes less time to perform.

In the present study 90 multiple pregnancies were examined. These were subdivided on the basis of the number of embryos involved (74 twins, 10 triplets, 6 quintuplets) and on whether they were followed at our clinic for the entire pregnancy or not. In each group we analysed certain variables, calculating the respective mean values and standard deviations. We used the ANOVA test to discriminate the eventual differences in the means of the variables analysed, operating a p<0.05 significance value. In addition, significant differences were analysed by the test of Contrasts (Scheffe F-test). The concept that emerged from the data investigated is that careful management of these pregnancies, carried out in high-level structures, can reduce the incidence of complications on both the maternal and fetal side and thus prevent “minimal brain damage” in the newborn.

Cette étude nous a permis de mettre à jour les différents modes d'intéractions qu'une mère établit avec ses jumeaux, ainsi que les évolutions possibles qui en résultent. Mais, bien plus, nous avons modélisé la façon dont les jumeaux élaborent leurs structures de l'activité de connaissance en fonction des sollicitations du milieu, ainsi que l'interdépendance qui les caractérisent.

Grâce à des examens opératoires, réalisés sur une population de 14 couples âgés de 6 a 10 ans, nous avons mis à jour un décalage intra-couple au niveau de la genèse de ces mêmes structures de l'activité de connaissance. Nous nous sommes apercus que sur le plan de la genèse de l'organisation cognitive l'un des enfants a développé des structures figuratives, et l'autre des structures opératives lui permettant d'avoir une connaissance de la réalité plus étendue.

Les liens de dépendance, de fusion, unissant les jumeaux entre eux, pourraient être dus à un développement cognitif parasitaire. Ils génèrent un lien gémellaire à partir de défaillances structurales qui vont apparaître chez chacun d'eux, ce qui ne permet aucunement leur autonomisation réciproque.

Puisque des déficiences apparaissent dans les structures de l'activité de connaissance de ces enfants, les problèmes qu'ils recontrent pourraient trouver leur solution dans une remédiation cognitive opératoire.

A sophisticated regionalization plan in maternal and child care, including risk assessment, maternal transfer mechanisms, 24 hour communication availability, and regional tertiary perinatal intensive care units (high risk obstetrics integrated with level III neonatal intensive care), has allowed the Province of Ontario to significantly decrease perinatal mortality. Data collection by hospital of birth, birthweight and gestational age shows that this effect is most marked in the preterm infant between 25 and 32 weeks and in hospitals with small obstetrical volumes. Little decrease in incidence of preterm birth has occurred. Multiple births provide a significant number of the preterm births; singleton rates between 20-36 weeks are 5.48%, twins 42.97%, and triplets 95.3%. However, when compared with singletons of the same birthweight, the mortality rates for twins are less than those of singletons, and triplets are even less again. High incidence of prematurity in multiple pregnancies means that a regional perinatal unit has a large occurrence of maternally transferred high risk pregnancies. In our institute, a 10-year review between 1978 and 1988, showed an incidence of 24 triplet, four quadruplet, and one quintuplet pregnancies. Review of outcome and data relative to these pregnancies showed an early neonatal mortality rate of 31.6, a perinatal mortality rate of 51.5 and survival to discharge of 93%. The occurrence of neonatal complications was respiratory distress syndrome in 43%, bronchopulmonary dysplasia in 6%, and intraventricular hemorrhage in 4%. Long term follow-up showed only one severely handicapped child (mental retardation and cerebral palsy), 10 infants with a mild hypotonia and mild delay in gross motor development (both considered functional and transient), and 74% entirely normal. It is concluded that integrated perinatal care can result in excellent outcomes for multiple pregnancies as long as all components of antenatal, intrapartum, and neonatal care are combined effectively.

The 20 reported cases of MZ female twins discordant for X-linked diseases are reviewed. In such twins the X-inactivation pattern is opposite skewing (abnormal allele inactivated in most cells of the normal twin, and normal allele inactivated in most cells of the affected twin) or skewing in one twin and random in the cotwin. The diseases involved map in two specific regions: Xq27-28 and Xp21. The only exceptions are Fabry's disease and Aicardi's syndrome, which map in Xq22 and Xp22 respectively. No concordant MZ female carrier twins, either normal or affected, have been described. Three main hypotheses have been proposed to explain such characteristics [2, 5, 14], but none is completely satisfactory. The constant discordance for X-linked diseases in MZ female twins has important consequences for genetic counselling.

For many parents, the joy of having twins and triplets is reduced by the unexpected emotional as well as physical and financial stresses which they experience with children who may suffer from prematurity and low birthweight, and who have a higher risk of language delay and disability. Paediatric care should start from the time of ultrasound diagnosis. The Multiple Births Foundation holds regular meetings for expectant parents. Twins Clinics are held in three centres in the UK as well as three special clinics (Growth, Supertwins and Bereavement), where families may discuss problems relating to the twinship as well as sharing their experiences with parent volunteers.

The prevalence of twinning and higher order multiple births is high and is increasing in many countries, due at least in part to fertility-enhancing medical therapies. About 1 in 40-45 births is a twin; it is thus important to investigate whether the twinning status confers a higher risk for morbidity and mortality, particularly early in life. Birth defects are a major cause of morbidity and mortality in the pediatric age-group. The purpose of this review is to consider the evidence for an increased risk of some birth defects associated with twinning, using data from the literature and the Italian Multicentre Birth Defects Registry (IPIMC), to illustrate some of the challenging aspects of the study of birth defects in twins, and to suggest some guidelines for future investigations.

Twins are a heterogeneous group. They may differ in origin and genetic similarity, as for monozygotic (MZ) and dizygotic (DZ) twins; and in placentation (monochorial monoamniotic, monochorial diamniotic, dichorial with separate or fused placentae). Likewise, birth defects are known to be heterogeneous in presentation, pathogenesis, and etiology. Thus, the question raised here is not whether or not birth defects ‘in general’ are more common in twins, but rather whether or not there are any specific types of defects that are more frequent among specific types of twins. To maintain the generality of the discussion, this review will focus on those structural defects which are not unique to twins; conjoined twins and arcadia, defects which are unique to the twinning process, will not be discussed.

Immune-mediated diseases affect up to 5% of the population and are a major cause of morbidity and mortality. These diseases can be organ specific, such as insulin-dependent diabetes (IDDM) and non-organ specific, such as Rheumatoid Arthritis (RA). Identical and non-identical twins have been used to establish whether these diseases are determined by genetic or environmental factors. The results of these studies have been collated in a new section of the Mendel Institute in Rome.

Diseases included in these studies included IDDM, RA, Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS) and Myasthenia. Striking differences in concordance rates between identical and non-identical twins in all these studies suggest that genetic factors are important in causing these diseases. All the diseases are known to be associated with HLA genes on chromosome 6 which may account for some or all of the genetic susceptibility. However, in the majority of pairs the affected twin has an unaffected co-twin. These observations suggest that non-genetically determined factors, probably environmental factors and not somatic mutations, are critical. The study of unaffected co-twins, who are at high disease-risk, has allowed the identification of changes which precede and predict the clinical disease. The immune-mediated destruction in many of these diseases is probably caused by T-lymphocytes. Twin studies have shown the importance of genetic factors in determining T-cell responses. Identical twins should, therefore, provide the perfect test bed to assess the role of T-cells in immune-mediated diseases.

The medical research on twins, carried out at the Gregor Mendel Institute for Medical Genetics and Twin Study in Rome over the past four decades, has resulted in a vast collection of clinical paper records. A challenge was presented by the need for a more secure method of storage to preserve this enormously valuable historical and scientific patrimony and to render its contents more easily accessible for research purposes. We met the challenge by planning and developing the computerization of this material. New concepts, currently being explored in biomedical informatics, were applied to build a Knowledge Data Base System, using a fourth-generation language (SQL). This architecturally innovative computer system enables its users to manipulate data supplied, rather than just simply storing it. Based on heuristic relational criteria between variables and parameters, the system is employed to solve problems of sibling design analysis typically arising from twins' records, but is also equipped to meet future data base requirements. Another feature of the system is its users' ability to pull off data in the form of regular automated reports, which are distributed through a Local Area Network (LAN). Through a Bulletin Board System (BBS) and modem, any scientist (outside as well as within the Institute) is thus able to access data and exchange scientific information.

With recent advances in molecular biology and genetics, cohorts such as the National Academy of Sciences-National Research Council (NAS-NRC) Twin Registry may become of increasing importance. This paper outlines the creation and history of the NAS-NRC Twin Registry, methodologies utilized for analysis of twin data, studies that have been completed or are underway, and possible future types of studies.