Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19

Recent data in humans and animals suggest that assisted reproductive technology (ART) might affect the epigenetics of early embryogenesis and might cause birth defects. We report the first evidence, to our knowledge, that ART is associated with a human overgrowth syndrome-namely, Beckwith-Wiedemann syndrome (BWS). In a prospective study, the prevalence of ART was 4.6% (3 of 65), versus the background rate of 0.8% in the United States. A total of seven children with BWS were born after ART-five of whom were conceived after intracytoplasmic sperm injection. Molecular studies of six of the children indicate that five of the six have specific epigenetic alterations associated with BWS-four at LIT1 and one at both LIT1 and H19. We discuss the implications of our finding that ART is associated with human overgrowth, similar to the large offspring syndrome reported in ruminants.     

How Precisely Do Bonobos (Pan paniscus) Grasp Small Objects?

The general objective of this study was to compare the precise grasping behavior and intermanual differences in performance between three Pan paniscus and five Homo sapiens in grasping small objects. We compared the temporal pattern of two submovements of consecutive grasping cycles, the (visuomotor) reaching and the (sensorimotor) grasping. Both species were similarly successful in this task, they showed a behavioral right-hand preference and preferred specific types of grips. Bonobos required less time for reaching an object but a much longer time to grasp it than humans did. Thus, the species pursued different strategies. We assumed that this might be due to the different grip techniques. However, grip preferences did not serve a quicker intramanual performance but they pronounced differences between hands. Intermanual differences in timing were restricted to the reaching part and more strongly in bonobos than in humans. However, the right hand need not necessarily perform quicker. As in the case of humans, we assume that attentional cues were focused more on preparing a proper grip with the right hand than on a quick performance. However, strong intermanual differences in bonobos may indicate an overall stronger neuronal asymmetry in the motor organization of the finger musculature that prepare a proper grip than is true of humans.     

Complete assignments of the (1)H and (13)C chemical shifts and J(H,H) coupling constants in NMR spectra of D-glucopyranose and all D-glucopyranosyl-D-glucopyranosides

Complete assignment of the (1)H and (13)C NMR spectra of all possible d-glucopyranosyl-d-glucopyranosides was performed and the (1)H chemical shifts and proton-proton coupling constants were refined by computational spectral analyses (using PERCH NMR software) until full agreement between the calculated and experimental spectra was achieved. To support the experimental results, the (1)H and (13)C chemical shifts and the spin-spin coupling constants between the non-hydroxyl protons of alpha- and beta-d-glucopyranose (1a and 1b) were calculated with density functional theory (DFT) methods at the B3LYP/pcJ-2//B3LYP/6-31G(d,p) level of theory. The effects of different glycosidic linkage types and positions on the glucose ring conformations and on the alpha/beta-ratio of the reducing end hydroxyl groups were investigated. Conformational analyses were also performed for anomerically pure forms of methyl d-glucopyranosides (13a and 13b) and fully protected derivatives such as 1,2,3,4,6-penta-O-acetyl-d-glucopyranoses (14a and 14b).     

Paleodontologic study of skeletal findings at Takht-i Suleiman, West Iran

Within this paleodontological study 26 Achemenid and 8 Islamic skeletons from the excavations at Tahkt-i Suleiman (Western Iran) were investigated. The diagnosis of age and sex was done repeatedly according to various methods. The adult Achemenids reached an average age of 54.4 years (n = 16; SD = +/- 9.9 y), while the Islamic adult individuals reached a lifespan of 36.9 (n = 8; SD = +/- 11.0 y). The skeletons of the Achemenid children had an average of 6.8 years (n = 9; SD = +/- 3.3 y). In the specific dental investigations the teeth of all skeletons were checked for missing teeth or dental diseases or alterations of the jaws. For the whole series intravital loss of 19.3% of the teeth was found. 21.6% of the teeth were lost postmortally. The intravital loss of single teeth was 21.9% in the Achemenid teeth, disregarding the wisdom tooth and Dentes decidui; the respective value was 12% in the Islamic skeletons. The investigation for caries yielded a morbidity of 50% in the Achemenid skeletons, and 57% in the Islamic teeth. The frequency of caries was 6.2% in Achemenids and 9% in Islamic individuals. In the Dentes decidui the frequency of caries was found to be 3.6%. Dental tartar was present in 44.8% of the teeth, 42% of Achemenid teeth and 58% of Islamic teeth being affected. 33% of all teeth showed garlands of dental tartar. Signs of parodontolysis were investigated considering the health of the individual and the preservation of the skeleton. All adult teeth showed age-dependent parodontolysis, the means of which were quantified.     

Microdeletion of LIT1 in familial Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome (BWS), which causes prenatal overgrowth, midline abdominal wall defects, macroglossia, and embryonal tumors, is a model for understanding the relationship between genomic imprinting, human development, and cancer. The causes are heterogeneous, involving multiple genes on 11p15 and including infrequent mutation of p57(KIP2) or loss of imprinting of either of two imprinted gene domains on 11p15: LIT1, which is near p57(KIP2), or H19/IGF2. Unlike Prader-Willi and Angelman syndromes, no chromosomal deletions have yet been identified. Here we report a microdeletion including the entire LIT1 gene, providing genetic confirmation of the importance of this gene region in BWS. When inherited maternally, the deletion causes BWS with silencing of p57(KIP2), indicating deletion of an element important for the regulation of p57(KIP2) expression. When inherited paternally, there is no phenotype, suggesting that the LIT1 RNA itself is not necessary for normal development in humans.     

Epigenetics and assisted reproductive technology: a call for investigation

A surprising set of recent observations suggests a link between assisted reproductive technology (ART) and epigenetic errors--that is, errors involving information other than DNA sequence that is heritable during cell division. An apparent association with ART was found in registries of children with Beckwith-Wiedemann syndrome, Angelman syndrome, and retinoblastoma. Here, we review the epidemiology and molecular biology behind these studies and those of relevant model systems, and we highlight the need for investigation of two major questions: (1) large-scale case-control studies of ART outcomes, including long-term assessment of the incidence of birth defects and cancer, and (2) investigation of the relationship between epigenetic errors in both offspring and parents, the specific methods of ART used, and the underlying infertility diagnoses. In addition, the components of proprietary commercial media used in ART procedures must be fully and publicly disclosed, so that factors such as methionine content can be assessed, given the relationship in animal studies between methionine exposure and epigenetic changes.     

Kinematics and ontogeny of locomotion in monkeys and human babies

Early ontogenetic stages are often assumed to reflect or to be similar to past phylogenetic stages within the evolution of man. Therefore, as a first step, the quadrupedal crawling locomotion of human children was analysed and compared to the quadrupedal walk of Macaca fascicularis. The movements of the human child were not only more irregular, they differed from the walk of the monkey mainly through extraordinarily short swing phases, and also through strong scoliotic movements of the spine. There is a compulsory synchronisation in the hip and knee joint movements of the human crawling baby. We conclude that human crawling may be a behavioural recapitulation of a quadrupedal evolutionary stage. However, with reference to kinematics, man is not only characterised by his unique, habitually bipedal, upright gait but also by a second, equally unique locomotion, namely crawling, which he assumes for a short phase during his first year of life.--The walking movements of the limbs in toddling infants were mainly characterised by i) rather stiff, abducted arms, which were moved mostly by spine torsions (similar to those of bipedally walking Gorilla) and not as a suspensory pendulum. However, they rather work as levers for the elastic torsion pendulum of the spine. ii) They are also characterised by frequently lacking the minor knee flexion, which occurs at about the heel strike within each stride of the adult human. Besides many other details of the results, foot movements differed from adult ones mainly in that the whole plantar surface was placed flat on the ground within a few milliseconds.     

Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects

Beckwith-Wiedemann syndrome (BWS) is a congenital cancer-predisposition syndrome associated with embryonal cancers, macroglossia, macrosomia, ear pits or ear creases, and midline abdominal-wall defects. The most common constitutional abnormalities in BWS are epigenetic, involving abnormal methylation of either H19 or LIT1, which encode untranslated RNAs on 11p15. We hypothesized that different epigenetic alterations would be associated with specific phenotypes in BWS. To test this hypothesis, we performed a case-cohort study, using the BWS Registry. The cohort consisted of 92 patients with BWS and molecular analysis of both H19 and LIT1, and these patients showed the same frequency of clinical phenotypes as those patients in the Registry from whom biological samples were not available. The frequency of altered DNA methylation of H19 in patients with cancer was significantly higher, 56% (9/16), than the frequency in patients without cancer, 17% (13/76; P=.002), and cancer was not associated with LIT1 alterations. Furthermore, the frequency of altered DNA methylation of LIT1 in patients with midline abdominal-wall defects and macrosomia was significantly higher, 65% (41/63) and 60% (46/77), respectively, than in patients without such defects, 34% (10/29) and 18% (2/11), respectively (P=.012 and P=.02, respectively). Additionally, paternal uniparental disomy (UPD) of 11p15 was associated with hemihypertrophy (P=.003), cancer (P=.03), and hypoglycemia (P=.05). These results define an epigenotype-phenotype relationship in BWS, in which aberrant methylation of H19 and LIT1 and UPD are strongly associated with cancer risk and specific birth defects.