Predicted birthweight for singletons and twins.

This population-based study determined the impact of co-twin gender on twin intrauterine growth in addition to their infant gender, maternal height, maternal age and parity on intrauterine growth rate of singletons and twins. All singletons and twins born in Western Australia during the period of 1980 to 1995 were considered for the study. The multiple linear regression models showed that 76% of the variance in the mean birthweight was explained by the selected variables for twins and 51% for singletons. Twins grew more slowly than singletons from 26 weeks gestation. Among twins, opposite-sex twin pairs grew consistently faster than like-sex twins. Primiparous twin pairs grew more slowly than subsequently born twins. These regression equations can be used to assess the appropriateness of intrauterine growth in twin pairs of various gender combinations.     

Small for gestational age as a predictor of behavioral and learning problems in twins.

The study examines the effects of being born small for gestational age (SGA) on rates of behavioral problems in twins and siblings, utilising data from the Australian Twin Study of disruptive behavior disorders in twins and their siblings. Participants were 3944 twins and their siblings who were assessed at two intervals three years apart. At the first assessment (1991), they ranged between 4 and 12 years of age. Items assessing Attention Deficit/Hyperactivity Disorder were based on DSM-III-R criteria (Time 1) and DSM-IV criteria (Time 2). Other measures included history of speech and reading therapy, demographic information and obstetric and neonatal history. Results indicated that both male and female twins, who were extremely growth restricted (small for gestational age up to the third percentile-WGA3) showed more inattention, and poorer speech and reading scores. The effects were greater for males. Male twins who were small for gestation age, up to the 10th percentile, were more likely to have a DSM-IV diagnosis of Inattention. Implications of these results included WGA3 male twins being at a "triple disadvantage" for subsequent behavioral and learning problems, in that being male, being a twin and being small for gestational age are all significant factors. Recommendations are made for early intervention for low birthweight male twins. The study is consistent with recent follow-up studies of very-low-birthweight singletons, indicating male disadvantage in cognitive outcome. While there is some genetic component to SGA, it does constitute a potentially major contribution to common environmental effects that must be considered in twin-based genetic analyses.     

Effect of dibutyryl cAMP on cell cycle progression of rat brain tumor cells in vitro.

Autoradiographic and flow microfluorometry analyses have been applied to a study of perturbed cell kinetics in 9L rat brain tumor cells treated with dibutyryl cyclic AMP and theophylline alone and in combination in vitro. At a concentration of 1 mM each, cell growth ceased shortly after the administration of these drugs. The results indicate that cells in S and G2 phase at the time of drug administration can undergo mitosis even though a considerable prolongation of G2 phase was apparent. However, cells in G1 at the time of drug administration was arrested in that phase, whereas those cells in S or G2 were able to complete one mitosis before becoming arrested in the G1 phase. This blocking effect was reversible, and cells resumed proliferation at a normal rate shortly after the removal of these drugs.     

Longitudinal studies of viral sequence, viral phenotype, and immunologic parameters of human immunodeficiency virus type 1 infection in perinatally infected twins with discordant disease courses.

Perinatal human immunodeficiency virus type 1 (HIV-1) infections cause a broad spectrum of clinical disease and are variable in both the age of the patient at onset of serious disease and the progression of the clinical course. Heterozygotic perinatally infected twins with a marked difference in their clinical courses were monitored during the first 2 years of life. Twin B, the second-born twin, developed AIDS by 6 months of age and died at 22 months of age, while twin A remained minimally symptomatic through the first 2 years. Sequential blood specimens were obtained from the twins in order to characterize the immunologic properties of the children and the phenotypes and genotypes of the HIV-1 isolates at various times. Twin A developed neutralizing antibodies and a high-level antibody-mediated cellular cytotoxicity (ADCC) response, while twin B had no neutralizing antibody and a much lower ADCC response. The virus isolates obtained from the two children at various time points proliferated equally well in peripheral blood mononuclear cells, were nonsyncytium inducing, and could not infect established T-cell lines. They differed in their ability to infect primary macrophages. In parallel to the biological studies, the HIV-1 tat and part of the env gene sequences of the longitudinal isolates at four time points were determined. Sequences of virus from both twins at different time points were highly conserved; the viruses evolved at a similar rate until the last analyzed time point, at which there was a dramatic increase in sequence diversity for the sicker child, especially in the tat gene. Our results show that the viruses isolated at different times do not have significant changes in growth properties. The absence or low levels of neutralizing antibodies may correlate with disease progression in the twins.     

Developmental studies of twins from birth on: heredity, environment, biomedical variables, and co-twin relations.

The reports in this section demonstrate several ways in which longitudinal research with twins is informative for the study of development. All of these twins have been followed for long time periods. These results are the latest stage of study for each. By virtue of their long-term nature, together these studies provide information on patterns and changes in several developmental areas from infancy to adulthood. They also document when specific variables no longer exert any influence on development. The first report, by Alin Akerman and Suurvee ("The Cognitive and Identity Development of Twins at 16 Years of Age: A Follow-up Study of 32 Twin Pairs") is a study of twins followed from birth to 16 years of age. The second report, by Ebeling, Porkka, Penninkilampi-Kerola, Berg, Jarvi, and Moilanen ("Inter-twin Relationships and Mental Health"), is a study of twins followed from pregnancy to 22-30 years of age. The third report, by Lange ("Coping Ability at Midlife in Relation to Genetic and Environmental Influences at Adolescence"), is a study of twins and singletons followed from 10 to 16 years of age to 35 years of age. The section attests to the perseverance of these authors as researchers, and to the strength of the personal relationships of these authors with the individuals in their projects.     

Twins and non-twin siblings: different estimates of shared environmental influence in early childhood.

Twin studies typically indicate shared environmental influence for cognitive abilities, especially in early childhood. However, across studies, DZ twin correlations tend to be greater than non-twin sibling correlations, suggesting that twin estimates of shared environment are to some extent specific to twins. We tested this hypothesis in a sample of more than 1800 MZ and 1800 same-sex DZ pairs from the Twins Early Development Study (TEDS), a study of twins born in England and Wales in 1994 and 1995. For this analysis, we obtained comparable data from more than 130 same-sex younger siblings of the twins. Twins and their younger siblings were assessed for language, cognitive abilities and behavior problems by their parents at 2 and 3 years of age. For language and cognitive measures at both 2 and 3 years, but not for behavior problems, estimates of shared environment were more than twice as large for twins as compared to non-twin siblings. We conclude that about half of twin study estimates of shared environment for cognitive abilities in early childhood are specific to twins. Although many possibilities exist for explaining the special shared environment effect for twins, we suggest that cognitive-relevant experiences that are not shared by siblings are shared by twins because they are exactly the same age.     

The cognitive and identity development of twins at 16 years of age: a follow-up study of 32 twin pairs.

This is a follow up study of twins within the Stockholm area, including 32 families and their twins attending grade nine. The twins have been followed from birth to 16 years of age. The main purpose of this study from its inception was to assess mental and cognitive development at different ages. Another aim was to see how the twins who were born prematurely are developing during the school ages. A third aim has been to gain a deeper insight into the relationship between co-twins and the development of their identities, which is the focus of this paper. Several ability tests have been used, as well as questionnaires about interests, attitudes toward school, and leisure activities. At the 16-year follow-up, a psychological method, the Wartegg drawing test, designed to examine identity, ego strength, dependency, ambition, anxiety, willpower, creativity, empathy and coping strategies has been used. The results indicate that it is difficult for twins to develop independence and a positive identity, as they have to emancipate themselves both from their parents and from their co-twins. Some differences in identity, anxiety and ambition were observed between female and male twins, MZ and DZ twins, preterm and fullterm twins. Prematurity, sex and zygosity no longer had any relation to cognitive development at 16 years of age.     

Parallel effects of DOCA on salt appetite, thirst, and blood pressure in sheep

Salt appetite was quantified in sheep by measuring the relative amounts of high-salt (266 meq/kg) and low-salt (6 meq/kg) pelleted alfalfa that they ate. Given a choice of these two foods, normal sheep ate twice as much low-salt as high-salt pellets. Following DOCA administration the sheep rapidly developed an increased salt appetite, and after 10 days they ate approximately three times as much high-salt as low-salt pellets. Their choice rapidly reverted to control values after the end of the DOCA treatment. The changes in salt appetite were accompanied by changes in thirst and mean arterial pressure. We hypothesize that these effects of DOCA reflect changes that parallel those this mineralocorticoid causes in the hypothalamic regulatory centers for salt appetite, thirst, and blood pressure.     

Assessment of the hereditary and environmental influence on the growth of hand bones in twin children]

Forty pairs of twins from 6 to 15 years of age were subjected to two rentgenographies of the right hand. The degree of similarity between the twins of one pair was studied by the value of the absolute and relative increase of sizes of the hand phalanges. Zygotes, sex and age of children were taken into account. The effect of hereditary factors on the growth of hand phalanges in boys is pronounced better than in girls. In the formers the degree of similarity between the twins of one pair is lower than in the latters. In 12-15 years of age such similarity is higher than in 8-11 years old twins.     

Mendelian hypertension with brachydactyly as a molecular genetic lesson in regulatory physiology

Mendelian forms of hypertension have delivered a treasure trove of novel genes. To date, the molecular mechanisms of five such syndromes have been largely clarified, including glucocorticoid-remediable aldosteronism, Liddle's syndrome, apparent mineralocorticoid excess, an activating mutation of the mineralocorticoid receptor, and pseudohypoaldosteronism type 2. Each of these conditions features salt sensitivity with increased sodium and volume reabsorption by the kidney and low plasma renin activity. None of the gene loci for these syndromes has been convincingly linked to hypertension in the general population. We are investigating kindreds who have autosomal-dominant hypertension and brachydactyly. Affected persons invariably have both anomalies. The hypertension is severe and results in death at about age 50 years from stroke. The condition resembles essential hypertension, because renin, aldosterone, and norepinephrine responses are normal and no salt sensitivity is present. The response to antihypertensive drugs is general. Another feature is diminished baroreflex sensitivity with markedly impaired blood pressure buffering. Furthermore, the ventrolateral medulla may be compromised in these patients, because neurovascular anomalies are a regular finding. We mapped the gene(s) for this disease to chromosome 12p and narrowed the chromosomal region by studying more affected families. Interestingly, the same locus was recently mapped in Chinese families with essential hypertension. Our 3-centimorgan region contains genes encoding a phosphodiesterase, an ATP-dependent potassium channel, and its regulator the sulfonylurea receptor 2. Screening of the coding regions revealed that none of these candidate genes harbor obvious mutations; however, other genetic mechanisms may nevertheless compromise their function. Our study underscores the importance of regulatory physiology to the understanding of a complex genetic syndrome.     

Mortality among twins after age 6: fetal origins hypothesis versus twin method.

OBJECTIVE--To test the validity of the fetal origins hypothesis and the classic twin method. DESIGN--Follow up study of pairs of same sex twins in which both twins survived to age 6. SETTING--Denmark. SUBJECTS--8495 twin individuals born 1870-1900, followed through to 31 December 1991. MAIN OUTCOME MEASURES--Mortality calculated on a cohort basis. RESULTS--Mortality among twins and the general population was not significantly different except among females aged 60-89, in whom mortality among twins was 1.14 times (SE 0.03) higher than in the general population. Mortality among female dizygotic twins was 1.77 times (0.18) higher than among monozygotic twins at age 30-59. Otherwise, mortality for monozygotic and dizygotic twins did not consistently differ after age 6. CONCLUSION--According to the fetal origins hypothesis the risk of adult morbidity and mortality is heightened by retardation in intrauterine growth. Twins, and in particular monozygotic twins, experience growth retardation in utero. The findings in the present study suggest that the fetal origins hypothesis is not true for the retardation in intrauterine growth experienced by twins. Furthermore, the data are inconsistent with the underlying assumption of a recent claim that the classic twin method is invalid for studies of adult diseases. The present study is, however, based on the one third of all pairs of twins in which both twins survived to age 6. The possible impact of this selection can be evaluated in future studies of cohorts of younger twins with lower perinatal and infant mortality.     

Netherlands Twin Register: a focus on longitudinal research.

In 1986 we began The Netherlands Twin Register (NTR) by recruiting young twins and multiples a few weeks or months after birth. Currently we register around 50% of all newborn multiples in The Netherlands. Their parents receive a questionnaire at registration and afterwards when the children are 2, 3, 5, 7, 10 and 12 years of age. Teachers are asked to rate the behavior of the children at ages 7, 10 and 12 years. Adolescent and young-adult twins were recruited through City Councils in the early 1990s. These twins, their parents and siblings participate in longitudinal survey studies that include items about health, fertility, lifestyle, addiction, personality and psychopathology, religion, socioeconomic status, and educational attainment. The total number of twins and multiples registered with the NTR is currently over 60,000. Subgroups of twins and siblings take part in studies of cognitive development, brain function and neuropsychological indices of attention processes, and molecular genetic studies of classical and behavioral cardiovascular risk factors. DNA samples are currently collected in selected twin families for two large linkage studies, which aim to find QTLs for anxious depression and for nicotine addiction. Sisters who are mothers of DZ twins contribute DNA samples for a linkage study of DZ twinning. Large cohorts of phenotyped family members from the general population are very valuable for genetic epidemiological studies and permit selection of informative families for gene finding studies.     

Gonadal development and growth in 46,XX and 46,XY individuals with P450scc deficiency (congenital lipoid adrenal hyperplasia).

We have investigated gonadal development and growth in 4 individuals (3 with 46,XY and 1 with 46,XX karyotype) with P450scc deficiency. One patient died at 2 months of age from adrenal insufficiency, while the remaining 3 individuals were healthy and developed normally (age at follow-up: 18, 10 and 8 years). In the surviving individuals, the diagnosis was established during the first 2-4 months of life by extensive endocrine studies of blood and urine. In the remaining patient, the diagnosis was made on the basis of karyotype (46,XY), anatomy of internal and external genitalia and adrenal pathology. Gonadectomy was performed in the 2 surviving 46,XY individuals at the age of 7 years, and histological examination showed normal testicular morphology but very few germ cells. Postmortem examination of the testes of the 2-month-old subject showed normal testicular histology, and quantitative analysis revealed a normal number of germ cells. Ultrasound of the 46,XX individual showed normal internal female genitalia including ovaries with follicles. The 3 surviving patients grew along the 75th (46,XY), the 90th (46,XY) and the 50th percentile (46,XX), respectively. The oldest girl experienced normal breast and pubic hair development after oral estrogen replacement and topical testosterone administration. The glucocorticoid and mineralocorticoid replacement was adjusted in accordance with repeated measurements of serum sodium and serum potassium, plasma renin concentration and blood pressure. No attempts were made to normalize serum ACTH. We conclude that prenatal testicular maturation and development of female internal genitalia may take place in the absence of normal steroid hormone production. Normal growth and development may be obtained in P450scc-deficient individuals with adequate hormone replacement.     

Maternal age and birth weight characteristics of twins born to nulliparous mothers: a population study.

In order to examine birth weight characteristics of twins delivered to nulliparous mothers in relation to maternal age, we used a population-based cohort of Israeli twins delivered between 1993-98 to select all 4793 (37.6%) nulliparas who delivered twins. Maternal age was subdivided as less than 20 years, 20-24, 25-29, 30-34, 35-39, and 40 years or more. We counted the frequencies of each total twin birth weight (twin A + twin B) in each of three categories (less than 3000, 3000-4999, and more than 5000 g) and the frequency of very low birth weight (VLBW, less than 1500 g) neonates in each of the six maternal age categories. There were significantly more nulliparas in the twin population at age groups less 30 years and significantly less at ages 30 years or more. We found a highly significant inverse correlation between the proportion of nulliparas and maternal age group, decreasing from 71.8% at less than 20 years to 18.6% at age 35-39 years (% nulliparas = 85 - 13.7 x age group, Pearson R2 = 0.98). However, this trend changed abruptly to the observed figure of 25.9% nulliparas aged 40 years or more instead of the expected 2.8%. We failed to reveal any significant difference in birth weight characteristics between the maternal age groups (all p > 0.05, all confidence intervals included 1.0). The more than tenfold deviation of the observed from the predicted frequency of nulliparas aged 40 years or more suggests that a different relationship between parity and age occurs at this age group. Maternal age of nulliparas is not associated with different birth weight characteristics of their twins.     

Development and representativeness of a large population-based cohort of native Californian twins.

We have established a large cohort of twins to facilitate studies of the role of genetics and environment in the development of disease. The cohort has been derived from all multiple births occurring in California between 1908-82 (256,616 in total). We report here on our efforts to contact these twins and their completion of a detailed 16 page risk factor questionnaire. Addresses of the individuals were obtained by linking the birth records with the California Department of Motor Vehicles (DMV) roster of licensees. To date this has been completed for twins born between 1908 and 1972 (200,589 individuals). The linkage has revealed 112,468 matches and, because of less complete DMV records in some years, was less successful in older females than in younger females and all males. Over 41,000 twins have participated by completing the questionnaire. Based on estimates of numbers of individuals receiving a questionnaire, we estimate our crude response rate to be between 42.2% and 49.6%, highest among females in their 40s (62.8%). We describe the representativeness of the twins in the original birth cohort, those identified by the linkage, and those completing the questionnaire. Compared to the 1990 resident population of California-born resident singletons, the respondents were of similar age, sex, race and residential distribution (for although we were able to locate fewer older females, they had a higher response rate), but were less likely to have been educated for more than 12 years. We provide a brief synopsis of studies nested within this cohort. We also elucidate our plans for expanding the cohort in the near future.     

Resemblance for age at menarche in female twins reared apart and together

Menarche is a significant developmental event in the lives of young females. Genetic and family environmental influences on the timing of its occurrence are explored in the first formal analysis using reared-apart and reared-together monozygotic (MZA, MZT) and dizygotic (DZA, DZT) twin pairs. Mean age at menarche was 12.50 years (SD = 1.67) for the reared-apart pairs and 12.86 years (SD = 1.49) for the reared-together pairs. Intraclass correlations for age at menarche were 0.56 for MZA twins, 0.16 for DZA twins, 0.70 for MZT twins, and 0.41 for DZT twins. The mean within-pair difference was 1.07 years (SD = 1.04) for MZA twins, 1.67 years (SD = 1.59) for DZA twins, 0.64 year (SD = 0.86) for MZT twins, and 1.43 years (SD = 1.34) for DZT twins. These results are consistent with genetic influence, although the lower correlations for reared-apart twins and their larger within-pair differences suggest that age at menarche is partly affected by common rearing environments. Feeling understood by one's father during the growing-up years was significantly associated with earlier age at menarche, and a comparable trend was found for feeling understood by one's mother. These findings are considered with reference to current theories of pubertal timing.     

Mineralocorticoid receptors and hypertension

Mineralocorticoid receptors (MR) have equal affinity for the mineralocorticoid aldosterone, and the physiological glucocorticoids cortisol and corticosterone. In epithelial tissues in vivo, MR are protected against glucocorticoid occupancy by the enzyme 11β-hydroxysteroid dehydrogenase, allowing access by the lower circulating levels of the physiological mineralocorticoid aldosterone. In non-epithelial tissues, including the heart and most areas of the central nervous system, MR are not so protected, and their physiological ligand is cortisol/corticosterone. Intracerebroventricular infusion studies have shown that aldosterone occupancy of such unprotected circumventricular MR is necessary for mineralocorticoid hypertension, and the hypertensinogenic effects of peripherally infused aldosterone can be blocked by intracerebroventricular infusion of the MR antagonist RU28318. Prolonged (8 weeks) administration of mineralocorticoids to salt-loaded rats has been shown to be followed by hypertension, cardiac hypertrophy and cardiac fibrosis. Whether the hypertrophy and fibrosis reflect primary effects of aldosterone via cardiac MR, or effects secondary to occupancy of protected, epithelial MR, remains to be determined, as does the mechanism of action of salt loading in this model of mineralocorticoid hypertension.     

Perinatal mortality in term and preterm twin and singleton births.

Although, in general, twins have higher perinatal mortality rates than singletons, preterm twins have lower perinatal mortality rates than singletons of the same birth weight or gestational age. This study investigated the hypotheses that this paradoxical twin advantage: 1) is due to gestational age distribution differences between the singleton and twin populations, and 2) is due to increased likelihood of birth having occurred in a tertiary perinatal center. A pre-existing, time-limited data set of all births in the province of Ontario in odd years between 1979 and 1985 was chosen for this study because of the large sample size (n = 618,579). Multivariable logistic regression of the relationship between perinatal mortality and twin status was controlled for mother's age, hospital level and gestational age. Findings confirm the lower mortality of preterm twins. After controlling for level of hospital of birth this difference remained, suggesting that level of hospital of birth was not a major factor responsible for the twin advantage. Analyses in which gestational age was standardized indicate that, for those whose gestational age was less than 2 SD below the mean for their particular group (twin or singleton), twins were actually at higher risk than singletons. These results support hypothesis 1 and do not strongly support hypothesis 2. The results also support earlier authors' suggestions that the definition of term birth should be different for twins and singletons     

Examining the dimensions of intimacy in twin and peer relationships.

While it is widely assumed that twinsh p involves high levels of intimacy to the detriment of other relationships, an examination of twinship using measures of intimacy has not yet been conducted. Participants were 214 individua twins (128 MZ, 62 DZ same-sex, and 24 DZ mixed-sex) between 16-73 years of age. Twins completed measures of intimacy in reference to their co-twin, their closest same-sex friend, and their closest other-sex friend. As expected, the highest level of intimacy was reported for the co-twin. Contrary to expectation, MZ twins did not report significantly higher levels of intimacy with their co-twin, or significantly lower levels of intimacy with their closest friends when compared to DZ same-sex or DZ mixed-sex twins. Furthermore, twins who reported high levels of intimacy with their co-twin did not report significantly lower levels of intimacy with their closest friends. Implications and directions for future research are discussed.