Inflammation is related to coronary flow reserve detected by positron emission tomography in asymptomatic male twins.

OBJECTIVES: This study sought to examine the relationship between inflammation and coronary microvascular function in asymptomatic individuals using positron emission tomography (PET) and assessment of coronary flow reserve (CFR). BACKGROUND: Coronary microvascular dysfunction is an early precursor of coronary artery disease (CAD) thought to result from endothelial cell activation and inflammation, but data are limited. METHODS: We examined 268 asymptomatic male monozygotic and dizygotic twins. Plasma biomarkers of inflammation and endothelial cell activation included C-reactive protein (CRP), interleukin (IL)-6, white blood cell count (WBC), vascular cell adhesion molecule (VCAM)-1, and intercellular adhesion molecule (ICAM)-1. Blood flow quantitation was obtained with [¹³N] ammonia PET at rest and after adenosine stress. CFR was measured as the ratio of maximum flow to baseline flow at rest; abnormal CFR was defined as a ratio < 2.5. A summed stress score for visible perfusion defects was calculated. RESULTS: In within-pair analyses, all biomarkers, except VCAM-1, were higher in twins with lower CFR than their brothers with higher CFR (p < 0.05). This was observed in the entire sample, as well as within pairs discordant for a CFR of <2.5. Associations persisted after adjusting for summed stress score and CAD risk factors. In contrast no biomarker, except IL-6, was related to the summed stress score of visible defects. CONCLUSIONS: Even in asymptomatic subjects, a decrease in coronary microvascular function is accompanied by a systemic inflammatory response, independent of CAD risk factors. Our results, using a controlled twin design, highlight the importance of coronary microvascular function in the early phases of CAD.

Leisure-time physical activity and nutrition: a twin study.

OBJECTIVE: To determine the association between long-term leisure-time physical activity/inactivity and eating behaviours in twin pairs discordant for physical activity for 30 years. DESIGN: Co-twin control design with cross-sectional data collection using questionnaire on eating habits and 5 d food diary. Differences in eating behaviours between physically active and inactive co-twins were analysed with pairwise tests. SETTING: Finland. SUBJECTS: Sixteen same-sex twin pairs (seven monozygotic and nine dizygotic, mean age 60 years) discordant for physical activity, selected from the Finnish Twin Cohort on the basis of physical activity discordance for 30 years, blinded to their possible differences in eating behaviours. RESULTS: The eating habits questionnaire revealed that physically active co-twins more frequently reported that it is easy to eat according to need, whereas overeating and/or restrictive eating was more common among the inactive co-twins (P = 0·035). Avoiding calories was more common among the active than inactive co-twins (P = 0·034). Based on food diaries the physically active co-twins had daily energy intake on average 15·5 kJ/kg higher than their inactive co-twins (P = 0·030). The active co-twins also had a higher intake of vitamin C (P = 0·004), total water (P = 0·044), legumes and nuts (P = 0·015) and sweets (P = 0·036), as well as a lower energy-adjusted intake of meat (P = 0·013). CONCLUSIONS: The physically active persons seem to eat more but not necessarily healthier food. However, habitual physical activity may help in eating according to need and in reaching and maintaining a healthy body composition. Therefore, it is necessary to incorporate both dietary and physical activity advice into health counselling.

Monozygotic twins are discordant for chronic periodontitis: clinical and bacteriological findings.

OBJECTIVES: The aim of this study was to assess, in monozygotic (MZ) and dizygotic (DZ) twin pairs in whom the proband of the twin pair was suffering from moderate to severe chronic periodontitis, the contribution of genetics, periodontal pathogens and lifestyle factors towards the clinical phenotype. MATERIAL AND METHODS: For this study, 18 adult twin pairs were selected on the basis of interproximal attachment loss (AL) >or=5 mm in >or=2 non-adjacent teeth in one twin member. The study included 10 MZ and eight DZ twin pairs, in whom the periodontal condition, presence of periodontal pathogens, educational level, smoking behaviour and body mass index (BMI) were evaluated. RESULTS: Both MZ and DZ twins were discordant regarding AL and alveolar bone loss. Discordance was greater in DZ compared with MZ twins. In MZ twins, the discordance could not be explained by education, smoking, BMI and periodontal pathogens. In DZ twins, 45.6% of the discordance could be explained by more pack-years of the probands. CONCLUSION: The results confirm a possible role of genetic factors in periodontitis. However, the magnitude of the genetic effects on disease severity may have been overestimated previously.

Neuregulin 1-induced AKT phosphorylation in monozygotic twins discordant for schizophrenia.

Patients with schizophrenia exhibit decreased neuregulin 1 (NRG1)-stimulated AKT phosphorylation in peripheral lymphoblasts. Here, we examined this peripheral marker in monozygotic twins discordant for schizophrenia and in healthy monozygotic twins without psychiatric disorders. B lymphoblasts were stimulated with NRG1a (65 amino-acid residue recombinant protein from the epidermal growth factor [EGF] domain) for 30min. The protein isolated from the cells was analysed by Western blotting. The dependent measure was the ratio of phosphorylated AKT (pAKT) and total AKT at baseline (without NRG1 stimulation) and after NRG1 stimulation (pAKT/AKT). The results revealed that in the case of the unaffected co-twins of patients with schizophrenia, NRG1-stimulated pAKT/AKT ratio was in between the values of their co-twins with schizophrenia and that of the healthy control twin pairs. When the affected twins with schizophrenia were compared with their unaffected co-twins using a Mann-Whitney U-test, we found significantly lower NRG1-induced pAKT/AKT ratios in the patients relative to their unaffected co-twins (p=0.004). However, using a more conservative analysis (Kruskal-Wallis ANOVA followed tests for multiple comparisons), this difference was not significant. The unaffected co-twins of patients with schizophrenia did not differ significantly from the healthy control twins. In the baseline condition, the pAKT/AKT ratios were similar in all groups. These results indicate that impaired AKT-related intracellular signaling is partly related to the developed illness and cannot fully be explained by the genetic background of schizophrenia.

Preliminary evidence that estradiol moderates genetic influences on disordered eating attitudes and behaviors during puberty.

BACKGROUND: Puberty moderates genetic influences on disordered eating attitudes and behaviors, with little genetic influence before puberty but large (50%) genetic effects during and after puberty. To date, however, nothing is known about the mechanisms that underlie these effects. Estradiol is a particularly promising candidate, as estrogens become elevated at puberty and regulate gene transcription within neurotransmitter systems important for eating-related phenotypes. The aim of this pilot study was to examine whether estradiol levels moderate genetic influences on disordered eating during puberty. METHOD: Participants included 198 female twins (ages 10-15 years) from the Michigan State University Twin Registry. Disordered eating attitudes and behaviors were assessed with the total score, weight preoccupation, body dissatisfaction and binge eating/compensatory behavior subscales of the Minnesota Eating Behavior Survey (MEBS). Afternoon saliva samples were assayed for estradiol levels. Moderation of genetic effects was examined by comparing twin correlations in low versus high estradiol groups. RESULTS: In the low estradiol group, monozygotic (MZ) and dizygotic (DZ) twin correlations for all MEBS scales were similar, suggesting little genetic influence. In the high estradiol group, the MZ twin correlation was more than double the DZ twin correlation, indicating the presence of genetic effects. Findings could not be accounted for by age, body mass index or the physical changes of puberty. CONCLUSIONS: Estradiol may be one important moderator of genetic effects on disordered eating during puberty. Larger twin studies are needed to replicate this pilot work and quantify the extent of genetic moderation.

Incidence of monozygotic twins in blastocyst and cleavage stage assisted reproductive technology cycles.

OBJECTIVE: To study the incidence of monozygotic twins (MZT) in blastocyst and cleavage stage ET. DESIGN: Retrospective review. PATIENT(S): Four hundred ninety-six women undergoing IVF/intracytoplasmic sperm injection cycles at a private assisted reproductive technology (ART) center. INTERVENTION(S): Patients undergoing ART were divided according to the stage of ET into blastocyst transfer (BT) and cleavage stage (CS) ET. MAIN OUTCOME MEASURE(S): Incidence of MZT as noted on vaginal ultrasound at 6 to 8 weeks. RESULT(S): There were 374 (75.4%) BT cycles, and 122 (24.6%) CS cycles. Women in the BT group were significantly younger, had more oocytes retrieved, and had less embryos transferred compared with the CS group. The clinical pregnancy rate was significantly higher in the BT group at 67.9% (254 of 374), compared with 37.7% (46 of 122) among the CS group. There was a significantly higher incidence of multiple gestation in the BT group compared with CS group (37.4% compared with 19.6%). The overall incidence of MZT was 1.3%, but differed with the stage of ET: the incidence of MZT was 1.57% (4 of 254) in the BT group, and 0 (0 of 46) in the CS group. CONCLUSION(S): Contrary to the older published literature on MZT in BT cycles, the incidence of MZT is low. Women undergoing ART therefore should not be discouraged to undergo BT for fear of MZT, especially in light of the higher pregnancy rate and lower number of transferred embryos noted in those cycles compared with cleavage stage transfers.

Quantification of feto-fetal transfusion rate through a single placental arterio-venous anastomosis in a monochorionic twin pregnancy.

Twin-to-twin transfusion syndrome (TTTS) is due to unbalanced inter-twin blood flow through placental vascular anastomoses. We present a TTTS-case treated with fetoscopic laser surgery that allowed us to calculate the net inter-twin blood flow. In the weeks following laser treatment, the ex-recipient developed severe fetal anemia and was treated with two intrauterine adult red cell transfusions (at 26 and 29 weeks' gestation, respectively). After birth, placental injection with color-latex identified a single residual arterio-venous anastomosis from the ex-recipient to the ex-donor. We measured the fetal and adult hemoglobin concentrations in the anemic fetus before and after both intrauterine transfusions, and in both twins at birth. On the basis of these measurements, we calculated the blood flow across the residual arterio-venous anastomosis and found it to be 5.8+/-1.5 mL/24h after the 1st transfusion and 11.4+/-2.9 mL/24h after the 2nd transfusion.

Dandy-Walker syndrome and monochorionic twins: insight into a possible etiological mechanism.

OBJECTIVE: Dandy-Walker syndrome (DWS) is a developmental malformation of the central nervous system characterized by complete or partial absence of the cerebellar vermis, the presence of a posterior fossa cyst, and ventriculomegaly. Although DWS can be seen with Mendelian and chromosomal disorders, the actual pathophysiologic mechanism responsible for the syndrome is unknown. The incidence of DWS is approximately 1-8/100,000 births. We have noted a higher than expected incidence of DWS in a population of twins referred as complicated monochorionic twins, to include twin-twin transfusion syndrome (TTTS). The purpose of this study was to assess the incidence of DWS in monochorionic twins. METHODS: The database of all patients referred with complicated monochorionic twins was queried for the diagnosis of DWS. TTTS was defined sonographically as the combined presence of a maximum vertical pocket (MVP) of >or=8 cm in the recipient and

Influence of intrauterine and extrauterine growth on neurodevelopmental outcome of monozygotic twins

There have been indications that intrauterine and early extrauterine growth can influence childhood mental and motor function. The objective of the present study was to evaluate the influence of intrauterine growth restriction and early extrauterine head growth on the neurodevelopmental outcome of monozygotic twins. Thirty-six monozygous twin pairs were evaluated at the corrected age of 12 to 42 months. Intrauterine growth restriction was quantified using the fetal growth ratio. The effects of birth weight ratio, head circumference at birth and current head circumference on mental and motor outcomes were estimated using mixed-effect linear regression models. Separate estimates of the between (interpair) and within (intrapair) effects of each measure on development were thus obtained. Neurodevelopment was assessed with the Bayley Scales of Infant Development, 2nd edition, by a psychologist blind to the exposure. A standardized neurological examination was performed by a neuropediatrician who was unaware of the exposures under investigation. After adjustment, birth weight ratio and head circumference at birth were not associated with motor or mental outcomes. Current head circumference was associated with mental but not with motor outcomes. Only the intrapair twin effect was significant. An increase of 1 cm in current head circumference of one twin compared with the other was associated with 3.2 points higher in Mental Developmental Index (95 percentCI = 1.06-5.32; P < 0.03). Thus, no effect of intrauterine growth was found on cognition and only postnatal head growth was associated with cognition. This effect was not shared by the co-twin.

Straight versus tortuous retinal arteries in relation to blood pressure and genetics.

BACKGROUND/AIMS: To assess the relative influence of genetic and environmental factors on retinal arterial tortuosity and the association between tortuosity and various health indices in healthy young to middle-aged persons. METHODS: This cross-sectional study included 57 monozygotic and 52 dizygotic same-sex healthy twin pairs, aged 20 to 46 years, who were characterised by determination of retinal vessel diameters, arterial blood pressure, blood glucose, body mass index, smoking habits and retinal arterial tortuosity, using a three-level grading scale (straight, wavy, tortuous). Heritability of retinal arterial tortuosity was estimated using structural equation modelling. RESULTS: Of 218 subjects, 79 (36.2%) had straight retinal arteries, 110 (50.5%) had wavy arteries, and 29 (13.3%) had tortuous arteries. Heritability of tortuosity was 82% (CI(95 )64, 92%), with unshared environmental factors accounting for the remaining 18% (CI(95 )8, 36%). Increasing values of mean arterial blood pressure and body mass index were both associated with decreasing levels of retinal arterial tortuosity. CONCLUSION: There was a large variation in tortuosity of retinal arteries in these healthy subjects and the predominant determinant was genetic influence, accounting for 82% of the observed variation in tortuosity.

Sex differences and heritability of two indices of heart rate dynamics: a twin study.

We investigated whether women show larger heart rate variability (HRV) than men after controlling for a large number of health-related covariates, using two indices of HRV, namely respiratory sinus arrhythmia (RSA) and approximate entropy (ApEn). In a twin design, the heritability of both indices was examined. The covariation between RSA and ApEn, a measure of heart rate dynamics derived from nonlinear dynamical systems theory, was decomposed into genetic and environmental components. Subjects were 196 male and 210 female middle-aged twins. Females showed larger HRV than men before (ApEn: p < .001; RSA: p = .052) and after adjustment for covariates (ApEn: p < .001; RSA: p = .015). This sex difference was confirmed by significant intrapair differences in the opposite-sex twin pairs for both ApEn (p < .001) and RSA (p = .03). In addition to sex, only heart period and age (both p < .001) were found to be independent predictors of ApEn, whereas RSA was also influenced by respiration rate and smoking (both p < .001). Age explained 16% and 6% of the variance in RSA and ApEn, respectively. Oral contraceptive use and menopausal status had no effect on HRV. Genetic model fitting yielded moderate heritability estimates for RSA (30%) and ApEn (40%) for both males and females. The correlation between RSA and ApEn (r = .60) could be attributed to genetic factors (48%), environmental factors (36%) and age (16%). The present study found support for a gender difference in HRV with women having greater HRV than men even after controlling for a large number of potential confounders. Indices of heart rate dynamics derived from nonlinear dynamical systems theory are moderately heritable and may be more sensitive than traditional indices of HRV to reveal subtle sex differences with important implications for health and disease.

Leptin and bone turnover in monochorionic twins complicated by twin-twin transfusion syndrome.

INTRODUCTION: To test the hypothesis that the bone metabolism of a growth-restricted foetus is regulated by genetic, placental and/or foetal factors through leptin, we investigated the foetal bone turnover in monochorionic pregnancies complicated with or without twin-twin transfusion syndrome (TTTS). METHODS: Maternal and cord bloods were collected from gestational-age-matched monochorionic twins with (n=15) and without (n=15) TTTS. The samples were assayed for leptin, cross-linked carboxyl terminal telo-peptide (ICTP, a marker of bone resorption) and pro-peptide (PICP, a marker of bone formation) of type I collagen by radioimmunoassay (RIA). RESULTS: In the growth-restricted donor twin, the plasma concentration of leptin (P < 0.001), PICP (P < 0.001) was lower, while that of ICTP (P < 0.001) was higher than the recipient twin of the TTTS group. In contrast, leptin, PICP and ICTP were comparable in non-TTTS twins. In the recipient twin of TTTS and non-TTTS twins, leptin was positively associated with PICP (r=0.73; n=45, P < 0.001) and negatively with ICTP (r=-0.68; n=45; P < 0.001). No such association was found between leptin and bone marker in the growth-restricted donor twin of the TTTS group. CONCLUSION: Our data suggest that, in AGA twins, leptin maintains bone metabolism by inhibiting resorption and enhancing bone formation. In contrast, growth-restricted donor twins have high bone turnover and this does not seem to be due to leptin deficiency.

Relationship of fat mass and serum estradiol with lower extremity bone in persons with chronic spinal cord injury.

In the spinal cord injury (SCI) population, a relationship between adiposity and leg bone has not been reported, nor one between serum estradiol and leg bone mass. A cross-sectional, comparative study of 10 male pairs of monozygotic twins discordant for SCI was performed. Relationships were determined among bone mineral density (BMD), bone mineral content (BMC), lean mass, fat mass, and serum sex steroids. In the twins with SCI, significant relationships were evident between leg BMD or BMC with total body percent fat (r2= 0.49, P < 0.05; r2= 0.45, P = 0.05), leg fat mass (r2 = 0.76, P < 0.0005; r2= 0.69, P = 0.005), and serum estradiol (r2= 0.40, P = 0.05; r2= 0.37, P = 0.05). By stepwise regression analysis, in the twins with SCI, leg fat mass was found to be the single most significant predictor of leg BMD or BMC (F = 12.01, r2= 0.76, P = 0.008; F = 50.87, r2= 0.86, P < 0.0001). In the able-bodied twins, leg lean mass correlated with leg BMD and BMC (r2= 0.58, P = 0.01; r2= 0.87, P = 0.0001). By use of within-pair differences, significant correlations were found for leg lean mass loss with leg BMD loss (r2= 0.56, P = 0.01) or leg BMC loss (r2= 0.64, P = 0.0005). In conclusion, in twins with SCI, significant correlations were observed between fat mass and leg BMD or BMC as well as between serum estradiol values and leg BMD. The magnitude of the leg muscle mass loss was correlated with the magnitude of bone loss.

Monozygotic twin model reveals novel embryo-induced transcriptome changes of bovine endometrium in the preattachment period.

Initiation and maintenance of pregnancy are critically dependent on an intact embryo-maternal communication in the preimplantation period. To get new insights into molecular mechanisms underlying this complex dialog, a holistic transcriptome study of endometrium samples from Day 18 pregnant vs. nonpregnant twin cows was performed. This genetically defined model system facilitated the identification of specific conceptus-induced changes of the endometrium transcriptome. Using a combination of subtracted cDNA libraries and cDNA array hybridization, 87 different genes were identified as upregulated in pregnant animals. Almost one half of these genes are known to be stimulated by type I interferons. For the ISG15ylation system, which is assumed to play an important role in interferon tau (IFNT) signaling, mRNAs of four potential components (IFITM1, IFITM3, HSXIAPAF1, and DTX3L) were found at increased levels in addition to ISG15 and UBE1L. These results were further substantiated by colocalization of these mRNAs in the endometrium of pregnant animals shown by in situ hybridization. A functional classification of the identified genes revealed several different biological processes involved in the preparation of the endometrium for the attachment and implantation of the embryo. Specifically, elevated transcript levels were found for genes involved in modulation of the maternal immune system, genes relevant for cell adhesion, and for remodeling of the endometrium. This first systematic study of maternal transcriptome changes in response to the presence of an embryo on Day 18 of pregnancy in cattle is an important step toward deciphering the embryo-maternal dialog using a systems biology approach.

Age-related changes on platelet membrane: a study on elderly and centenarian monozygotic twins.

Cellular senescence is a biological process associated with aging and longevity. Successful aging is believed to be related to the ability to cope with different environmental stresses. The objective of this study was to investigate if cellular senescence is associated with platelet membrane modifications on subjects of different age, in particular on monozygotic twins and if these changes might be affected by both genetic components and environmental factors. The work was performed on 81 monozygotic twin pairs of different age. Platelet membranes from centenarian twins showed: decreased both basal lipid peroxide levels and membrane fluidity compared with elderly subjects; Na(+)/K(+)-ATPase activity and SA content are similar to those evaluated in young group, suggesting one of their important roles in the successful aging. We concluded that platelet membranes from centenarians show deeper structural and functional modifications than in elderly subjects and that these changes might play a protective role against oxidative damage. No statistical difference in biochemical parameters was observed between two sibpairs in each twin pair highlighting that environmental factors (diet, life-style) affect age-related platelet membrane changes less than their common genetic component. Thus genetic factors might play an important role in the mechanisms at the basis of successful aging.

Gender mix in twins and fetal growth, length of gestation and adult cancer risk.

This study evaluated the effect of gender mix (the gender combinations of twin pairs) on fetal growth and length of gestation, and reviewed the literature on the long-term effects of this altered fetal milieu on cancer risk. In singletons, it is well established that females weigh less than males at all gestations, averaging 125-135 g less at full term. This gender difference is generally believed to be the result of the effect of androgens on fetal growth. The gender difference in fetal growth is greater before the third trimester and less towards term, with males growing not only more, but also earlier than females. Plurality is a known risk factor for reduced fetal growth and birthweight. Compared with singletons, the mean birthweight percentiles of twins fall substantially (by 10% or more) below the singleton 10th percentile by 28 weeks, below the singleton 50th percentile by 30 weeks, and below the singleton 90th percentile by 34 weeks. In unlike-gender twin pairs, it has been reported that the female prolongs gestation for her brother, resulting in a higher birthweight for the male twin than that of like-gender male twins. Other researchers have demonstrated that females in unlike-gender pairs had higher birthweights than females in like-gender pairs. Analyses from our consortium on 2491 twin pregnancies with known chorionicity showed longer gestations and faster rates of fetal growth in both males and females in unlike-gender pairs compared with like-gender male or female pairs, although these differences were not statistically significant. The post-natal effects for females growing in an androgenic-anabolic environment include increased sensation-seeking behaviour and aggression, lowered visual acuity, more masculine attitudes and masculinising effects of the auditory system and craniofacial growth. In contrast, there is no evidence to suggest that there might be a similar feminising effect on males from unlike-gender pairs. This hormonal exposure in utero may influence adult body size and susceptability to breast cancer.

The effect of moderate alcohol consumption on bone mineral density: a study of female twins.

BACKGROUND: Osteoporosis is associated with morbidity and mortality, particularly in postmenopausal women. The effect of moderate alcohol intake on bone mineral density (BMD) and fracture risk remains unclear. OBJECTIVE: To carry out a twin study to investigate this effect while controlling for genetic effects and other confounding variables. METHODS: BMD was determined at the hip and lumbar spine in 46 pairs of monozygotic twins discordant for alcohol consumption. Biochemical evidence of altered bone metabolism was sought. RESULTS: A positive association between alcohol consumption and BMD was shown, in contrast to the negative effect of smoking on BMD. Markers of bone turnover were not associated with alcohol or BMD. CONCLUSIONS: Moderate alcohol consumption is not harmful to bone health in women and may even be beneficial. Beneficial effects do not appear to be mediated through an action on bone metabolism.

The contribution of risk factors to blood pressure heritability estimates in young adults: the East flanders prospective twin study.

The heritability of blood pressure estimated in previous studies may be confounded by the influence of potential blood pressure risk factors. We applied the classical twin design to estimate the contribution of these covariates to blood pressure heritability. The study consisted of 173 dizygotic and 251 monozygotic twin pairs aged 18-34 years, randomly selected from the East Flanders Prospective Twin Survey. In a standardized examination, blood pressure and anthropometry was measured, a questionnaire was completed, and a fasting blood sample was taken. In univariate and bivariate modeling, diastolic and systolic heritability were estimated both unadjusted and adjusted for potential risk factors. Also, covariate interaction was modeled. Bivariate analysis gave heritability estimates of 0.63 (95%CI 0.55-0.59), 0.74 (95%CI: 0.68-0.79), and 0.78 (95%CI: 0.70-0.84) for diastolic, systolic, and cross-trait heritability, respectively. The remaining variances could be attributed to unique environmental influences. These heritability estimates did not change substantially in univariate analyses or after adjustment for risk factors. A sex-limitation model showed that the heritability estimates for women were significantly higher than for men, but the same genetic factors were operating across sexes. Sex and cigarette smoking appeared to be statistically significant interaction terms. The heritability of blood pressure is relatively high in young adults. Potential risk factors of blood pressure do not appear to confound the heritability estimates. However, gene by sex by smoking interaction is indicated.