The right to ignore genetic status of late onset genetic disease in the genomic era; Prenatal testing for Huntington disease as a paradigm.

During the last decade, the field of human genome research has gone through a phase of rapid discovery that has provided scientists and physicians with a wide variety of research tools that are applicable to important medical issues. We describe a true case of familial Huntington disease (HD) in which we modified personal details to protect patient's privacy, where the proband at risk preferred not to know his disease status but wanted to know the status in his unborn child. Once we found the father to be negative, the case raised an important ethical question regarding the management of this as well as future pregnancies. This article discusses the arguments for and against the right not to know of one's carrier status, as well as professional obligations in the context of withholding unwanted information that may have direct implications not only for the patient himself but also for other family members. HD has served as a model for many other adult onset genetic diseases in terms of carrier testing guidelines. Hence, we feel it is time to revisit the issue of prenatal testing for HD and consider updating the current recommendations regarding the patient's right to "genetic ignorance", or the right not to know genetic information.

Randomized Trial of Motivational Interviewing to Prevent Early Childhood Caries in American Indian Children.

INTRODUCTION: In a randomized controlled trial, the effectiveness of motivational interviewing (MI) combined with enhanced community services (MI + ECS) was compared with ECS alone for reducing dental caries in American Indian children on the Pine Ridge Reservation. The intervention was developed and delivered with extensive tribal collaboration. METHODS: A total 579 mother-newborn dyads were enrolled and randomized to the MI + ECS and ECS groups. They were followed for 36 mo. Four MI sessions were provided, the first shortly after childbirth and then 6, 12, and 18 mo later. Both groups were exposed to ECS, which included public service announcements through billboards and tribal radio, as well as broad distribution of brochures on behavioral risk factors for early childhood caries (ECC), toothbrushes, and toothpaste. MI impact was measured as decayed, missing, and filled tooth surfaces (dmfs). Secondary outcomes included decayed surfaces, caries prevalence, and maternal oral health knowledge and behaviors. Modified intention-to-treat analyses were conducted. Eighty-eight percent of mothers completed at least 3 of 4 MI sessions offered. RESULTS: After 3 y, dmfs was not significantly different for the 2 groups (MI + ECS = 10, ECS = 10.38, P = 0.68). In both groups, prevalence of caries experience was 7% to 9% after 1 y, 35% to 36% at 2 y, and 55% to 56% at 3 y. Mean knowledge scores increased by 5.0, 5.3, and 5.9 percentage points at years 1, 2, and 3 in the MI + ECS group and by 1.9, 3.3, and 5.0 percentage points in the ECS group (P = 0.03), respectively. Mean maternal oral health behavior scores were not statistically significantly different between the treatment arms. CONCLUSION: In summary, the MI intervention appeared to improve maternal knowledge but had no effect on oral health behaviors or on the progression of ECC (ClinicalTrials.gov NCT01116726). KNOWLEDGE TRANSFER STATEMENT: The findings of this study suggest that motivational interviewing focusing on parental behaviors may not be as effective as previously hoped for slowing the development of childhood caries in some high-risk groups. Furthermore, social factors may be even more salient determinants of oral health than what we previously supposed, perhaps interfering with the capacity to benefit from behavioral strategies that have been useful elsewhere. The improvement of children's oral health in high-risk populations characterized by poverty and multiple related life stresses may require more holistic approaches that address these formidable barriers.

Morphological apsects of the coronary artery in the neonates.

Knowledge of the morphometric quantities of the coronary arteries in neonates is an increasingly vital component in the management of congenital and acquired heart disease. Because of the considerable heterogeneity of coronary vasculature, what is considered atypical and aberrant or insignificant anatomy is often unclear. The purpose of our present study is to define the normal anatomy of neonates. This was done by focusing on segment analysis of the coronary arteries, which was used to obtain accurate definitions of the length and diameter of the coronary network. The lengths, widths and numbers of collateral branches of the coronary arteries of neonates were measured. The coronary vessels of 50 neonate hearts were visualised post mortem by injection of the coronary arteries with opaque X-ray dye for the imaging study. Black ink cast and silver impregnation specimens were also studied. The longest segment of the circumflex branches of the left coronary arteries was the first, the lengths measuring 7188.5 +/- 839.6 microm and the diameters 850 +/- 90.8 mum. The lengths of segments II, III and IV were 5780 +/- 1182.7 microm, 5397.5 +/- 2070.2 microm and 6932.8 +/- 2236.5 microm and the diameters were 680 +/- 90.8 microm, 510 +/- 90.8 microm and 408 +/- 77.58 microm respectively. The longest segment of the anterior interventricular branches of the left coronary arteries was the first, with lengths of 10151.4 +/- 1298.6 microm and diameters of 1141.9 +/- 82.1 microm. The lengths of segments II, III and IV were 8208.5 +/- 1222.3 microm, 3278.5 +/- 602.4 microm and 5370 +/- 1657.6 mum and the diameters were 971 +/- 82.1 microm, 801.42 +/- 82.1 microm and 631.4 +/- 82.1 microm respectively. The lateral branches were increased in number in the fourth segment. Its diameters ranged from 157.8 +/- 31.7 microm to 655.7 +/- 99.7 microm. The main branch of the right coronary artery was short at the base of the heart. In the newborn the lateral branches of the right coronary artery were short, scattered and curved. Analysis of the data suggests a new anatomical system for classifying the vasculature of the coronary arteries in neonates.

The neural system of language: structure and development.

Recent neuroimaging and neuropsychological research in adults and infants suggests that the neural system for language is widely distributed and shares organizational principles with other cognitive systems in the brain. Connectionist modelling has clarified that networks operating with associative mechanisms can display properties typically associated with genetically predetermined and dedicated symbolic functions.

Theories of early language acquisition.

What features of brain processing and neural development support linguistic development in young children? To what extent is the profile and timing of linguistic development in young children determined by a pre-ordained genetic programme? Does the environment play a crucial role in determining the patterns of change observed in children growing up? Recent experimental, neuroimaging and computational studies of developmental change in children promise to contribute to a deeper understanding of how the brain becomes wired up for language. In this review, the muttidisciplinary perspectives of cognitive neuroscience, experimental psycholinguistics and neural network modelling are brought to bear on four distinct areas in the study of language acquisition: early speech perception, word recognition, word learning and the acquisition of grammatical inflections. It is suggested that each area demonstrates how linguistic development can be driven by the interaction of general learning mechanisms, highly sensitive to particular statistical regularities in the input, with a richly structured environment which provides the necessary ingredients for the emergence of linguistic representations that support mature language processing. Similar epigenetic principles, guiding the emergence of linguistic structure, apply to all these domains, offering insights into phenomena ranging from the precocity of young infant's sensitivity to speech contrasts to the complexities of the problem facing the young child learning the arabic plural.

N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 2. Structure-activity relationship and optimization of the phenyl alkyl ether moiety.

We previously reported the identification of (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propanoic acid (2) (PPARgamma pKi = 8.94, PPARgamma pEC50 = 9.47) as a potent and selective PPARgamma agonist. We now report the expanded structure-activity relationship around the phenyl alkyl ether moiety by pursuing both a classical medicinal chemistry approach and a solid-phase chemistry approach for analogue synthesis. The solution-phase strategy focused on evaluating the effects of oxazole and phenyl ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)ethyl side chain of 2 with several replacements providing potent and selective PPARgamma agonists with improved aqueous solubility. Specifically, replacement of the phenyl ring of the phenyloxazole moiety with a 4-pyridyl group to give 2(S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-pyridin-4-yloxazol+ ++- 4-yl)ethoxy]phenyl¿propionic acid (16) (PPARgamma pKi = 8.85, PPARgamma pEC50 = 8.74) or a 4-methylpiperazine to give 2(S)-((2-benzoylphenyl)amino)-3-(4-¿2-[5-methyl-2-(4-methylpiperazin+ ++- 1-yl)thiazol-4-yl]ethoxy¿phenyl)propionic acid (24) (PPARgamma pKi = 8.66, PPARgamma pEC50 = 8.89) provided two potent and selective PPARgamma agonists with increased solubility in pH 7.4 phosphate buffer and simulated gastric fluid as compared to 2. The second strategy took advantage of the speed and ease of parallel solid-phase analogue synthesis to generate a more diverse set of phenyl alkyl ethers which led to the identification of a number of novel, high-affinity PPARgamma ligands (PPARgamma pKi's 6.98-8.03). The combined structure-activity data derived from the two strategies provide valuable insight on the requirements for PPARgamma binding, functional activity, selectivity, and aqueous solubility.

U-shaped learning and frequency effects in a multi-layered perceptron: implications for child language acquisition.

A three-layer back-propagation network is used to implement a pattern association task in which four types of mapping are learned. These mappings, which are considered analogous to those which characterize the relationship between the stem and past tense forms of English verbs, include arbitrary mappings, identity mappings, vowel changes, and additions of a suffix. The degree of correspondence between parallel distributed processing (PDP) models which learn mappings of this sort (e.g., Rumelhart & McClelland, 1986, 1987) and children's acquisition of inflectional morphology has recently been at issue in discussions of the applicability of PDP models to the study of human cognition and language (Pinker & Mehler, 1989; Bever, in press). In this paper, we explore the capacity of a network to learn these types of mappings, focusing on three major issues. First, we compare the performance of a single-layered perceptron similar to the one used by Rumelhart and McClelland with a multi-layered perceptron. The results suggest that it is unlikely that a single-layered perceptron is capable of finding an adequate solution to the problem of mapping stems and past tense forms in input configurations that are sufficiently analogous to English. Second, we explore the input conditions which determine learning in these networks. Several factors that characterize linguistic input are investigated: (a) the nature of the mapping performed by the network (arbitrary, suffixation, identity, and vowel change); (b) the competition effects that arise when the task demands simultaneous learning of distinct mapping types; (c) the role of the type and token frequency of verb stems; and (d) the influence of phonological subregularities in the irregular verbs. Each of these factors is shown to have selective consequences on both successful and erroneous performance in the network. Third, we outline several types of systems which could result in U-shaped acquisition, and discuss the ways in which learning in multi-layered networks can be seen to capture several characteristics of U-shaped learning in children. In general, these models provide information about the role of input in determining the kinds of errors that a network will produce, including the conditions under which rule-like behavior and U-shaped learning will and will not emerge. The results from all simulations are discussed in light of behavioral data on children's acquisition of the past tense and the validity of drawing conclusions about the acquisition of language from models of this sort.

From rote learning to system building: acquiring verb morphology in children and connectionist nets.

The traditional account of the acquisition of English verb morphology supposes that a dual architecture underlies the transition from early rote-learning processes (in which past tense forms of verbs are correctly produced) to the systematic treatment of verbs (in which irregular verbs are prone to error). A connectionist account supposes that this transition can occur in a single mechanism (in the form of a neural network) driven by gradual quantitative changes in the size of the training set to which the network is exposed. In this paper, a series of simulations is reported in which a multi-layered perceptron learns to map verb stems to past tense forms analogous to the mappings found in the English past tense system. By expanding the training set in a gradual, incremental fashion and evaluating network performance on both trained and novel verbs at successive points in learning, it is demonstrated that the network undergoes reorganizations that result in a shift from a mode of rote learning to a systematic treatment of verbs. Furthermore, we show that this reorganizational transition is dependent upon the number of regular and irregular verbs in the training set and is sensitive to the phonological sub-regularities characterizing the irregular verbs. The pattern of errors observed is compared to that of children acquiring the English past tense, as well as children's performance on experimental studies with nonsense verbs. It is concluded that a connectionist approach offers a viable alternative account of the acquisition of English verb morphology, given the current state of empirical evidence relating to processes of acquisition in young children.

Subjectless sentences in child Danish.

Three alternative accounts of subject omission, pragmatic, processing and grammatical, are considered from the perspective of child Danish. Longitudinal data for two Danish children are analyzed for subject omission, finite and infinitival verb usage and discourse anchorage of sentence subjects (overt and missing). The data exhibit a well-defined phase of subject omission which coincides with a well-defined phase of infinitival verbal utterances. No evidence is found for input driven accounts of subject omission. Danish adults rarely omit subjects from utterance initial position. Neither is there any evidence to support the claim that omitted subjects are anchored in previous discourse. Evidence supporting a processing constraint explanation of missing subjects is equivocal. The pattern of subject omission, infinitival usage and third person pronoun and past tense usage points to a grammatical explanation of the phenomenon. However, current grammatical accounts have difficulty accommodating several aspects of the data reported. Contrary to structure building theories, the Danish children do not exhibit a phase of development where only uninflected verb forms are used. Danish children also omit subjects from finite utterances. Furthermore, the decline of subject omissions in finite utterances coincides with decline in usage of infinitival utterances. These findings challenge tense-based accounts of children's subject omission. Finally, Danish children exhibit an asymmetry in subject omission according to verb type; subjects are omitted from main verb utterances more frequently than from copula utterances. Given the language typology associated with Danish, this asymmetry is difficult to accommodate within truncation and tense or number-based accounts of subject omission. We suggest that a proper treatment of child subject omission will involve an integration of grammatical and discourse-based approaches.

When does an ostrich become a bird? The role of typicality in early word comprehension.

Which objects and animals are children willing to accept as referents for words they know? To answer this question, the authors assessed early word comprehension using the preferential looking task. Children were shown 2 stimuli side by side (a target and a distractor) and heard the target stimulus named. The target stimulus was either a typical or an atypical exemplar of the named category. It was predicted that children first connect typical examples with the target name and broaden the extension of the name as they get older to include less typical examples. Experiment 1 shows that when targets are named, 12-month-olds display an increase in target looking for typical but not atypical targets whereas 24-month-olds display an increase for both. Experiment 2 shows that 18-month-olds display a pattern similar to that of 24-month-olds. Implications for the early development of word comprehension are discussed.

ERP correlates of unexpected word forms in a picture-word study of infants and adults.

We tested 14-month-olds and adults in an event-related potentials (ERPs) study in which pictures of familiar objects generated expectations about upcoming word forms. Expected word forms labelled the picture (word condition), while unexpected word forms mismatched by either a small deviation in word medial vowel height (mispronunciation condition) or a large deviation from the onset of the first speech segment (pseudoword condition). Both infants and adults showed sensitivity to both types of unexpected word form. Adults showed a chain of discrete effects: positivity over the N(1) wave, negativity over the P(2) wave (PMN effect) and negativity over the N(2) wave (N400 effect). Infants showed a similar pattern, including a robust effect similar to the adult P(2) effect. These observations were underpinned by a novel visualisation method which shows the dynamics of the ERP within bands of the scalp over time. The results demonstrate shared processing mechanisms across development, as even subtle deviations from expected word forms were indexed in both age groups by a reduction in the amplitude of characteristic waves in the early auditory evoked potential.

A novel 8.5 MB dup(1)(p34.1p34.3) characterized by FISH in a child presenting with congenital heart defect and dysmorphic features.

Chromosome duplications involving 1p are rarely reported but are apparently associated with short survival as well as congenital malformations and impaired development. Several of these have had congenital heart defects, although too few patients have been reported with similar breakpoints to characterize a syndrome. We present a girl with a novel interstitial duplication in the short arm of chromosome 1 [46,XX,dup(1)(p34.1p34.3)]. She presented with congenital heart defects at 1 month and by 1 year of age manifested delayed acquisition of motor milestones and subsequently of language milestones. By breakpoint-mapping using FISH analysis, we determined that her 1p duplication spans 8.5 megabases. Her 1p duplication is the smallest reported to date to contain 1p34 in patients with congenital heart defect due to abnormalities of heart looping during development. Thus, her 8.5 MB duplication provides a target region to search for a potentially dosage-sensitive gene(s) causing abnormal heart looping when duplicated. Two patients have been reported with duplication including 1p34 but without congenital heart defect, and their duplications span all but the distal approximately 2 MB segment duplicated in our patient. Thus, within our patient's 8.5 MB target region for a dosage sensitive gene leading to looping abnormalities (and thereby congenital heart defect), the distal 2 MB region might well be the region to begin the search.

Lexical segmentation and vocabulary growth in early language acquisition.

The identification of appropriate lexical segmentations of the speech signal constitutes a problem for the language learner and the child language researcher alike. Articulatory precision and fluency criteria for identifying formulaic expressions, sub-lexical forms and target lexemes in linguistic productions are defined and applied to the analysis of two Danish children's language development between the ages of 1;0 and 2;0. The results of this analysis are compared to the results of applying standard distributional and frequency criteria in the tabulation of mean length of utterance and vocabulary profiles for both standard and non-standard lexical segmentations. It is argued that although the two methods yield converging profiles of development during the latter part of the period studied, articulatory precision and fluency criteria offer a more powerful tool for identifying alternative segmentation strategies in early language acquisition. Profiles of vocabulary development for these two children suggest that the solution to the segmentation problem may be an important trigger for their vocabulary spurts.

Rapid word learning by fifteen-month-olds under tightly controlled conditions.

Infants (12 to 17 months) were taught 2 novel words for 2 images of novel objects, by pairing isolated auditory labels with to-be-associated images. Comprehension was tested using a preferential looking task in which the infant was presented with both images together with an isolated auditory label. The auditory label usually, but not always, matched one of the images. Infants looked preferentially at images that matched the auditory stimulus. The experiment controlled within-subjects for both side bias and preference for previously named items. Infants showed learning after 12 presentations of the new words. Evidence is presented that, in certain circumstances, the duration of longest look at a target may be a more robust measure of target preference than overall looking time. The experiment provides support for previous demonstrations of rapid word learning by pre-vocabulary spurt children, and offers some methodological improvements to the preferential looking task.

Infant vocabulary development assessed with a British communicative development inventory.

Communicative Development Inventories (CDIs) were collected from 669 British children aged between 1;0 and 2;1. Comprehension and production scores in each age group are calculated. This provides norming data for the British infant population. The influence of socioeconomic group on vocabulary scores is considered and shown not to have a significant effect. The data from British infants is compared to data from American infants (Fenson, Dale, Reznick, Bates, Thal & Pethick, 1994). It is found that British infants have lower scores on both comprehension and production than American infants of the same age.

Overregularization in English plural and past tense inflectional morphology: a response to Marcus (1995).

In a recent note, Marcus (1995) suggests that the rate of overregularization of English irregular plural nouns is not substantively different from that of English irregular past tense verbs. This finding is claimed to be in conflict with the predictions of connectionist models (Plunkett & Marchman, 1991, 1993) which are said to depend solely on the dominance of regular over irregular forms in determining overregulation errors. However, these conclusions may be premature given that Marcus averaged overregulation rates across irregular nominal forms that varied in token frequency and across samples representing a broad range of children's ages. A connectionist view would predict an interplay between type frequency and other item level factors, e.g. token frequency, as well as differences in the developmental trajectories of the acquisition of nouns and verbs. In this response, we briefly review longitudinal parental report data (N = 26) which indicate that children are significantly more likely to produce noun overregularizations than verb overregularizations across a prescribed age period (1:5 to 2:6). At the same time, these data also show that children are familiar with proportionately more irregular nouns than irregular verbs. These findings are consistent with the predictions of Plunkett & Marchman (1991, 1993) in that the larger regular class affects the frequency of noun errors but also that familiarity with individual irregular nouns tends to reduce the likelihood of overregularizations. In contrast to the conclusion of Marcus (1995), the connectionist approach to English inflectional morphology provides a plausible explanation of the phenomenon of overregularization in both the English plural and past tense systems.

The acquisition of past tense morphology in Icelandic and Norwegian children: an experimental study.

Icelandic and Norwegian past tense morphology contain strong patterns of inflection and two weak patterns of inflection. We report the results of an elicitation task that tests Icelandic and Norwegian children's knowledge of the past tense forms of a representative sample of verbs. This cross-sectional study of four-, six- and eight-year-old Icelandic (n = 92) and Norwegian (n = 96) children systematically manipulates verb characteristics such as type frequency, token frequency and phonological coherence--factors that are generally considered to have an important impact on the acquisition of inflectional morphology in other languages. Our findings confirm that these factors play an important role in the acquisition of Icelandic and Norwegian. In addition, the results indicate that the predominant source of errors in children shifts during the later stages of development from one weak verb class to the other. We conclude that these findings are consistent with the view that exemplar-based learning, whereby patterns of categorization and generalization are driven by similarity to known forms, appropriately characterizes the acquisition of inflectional systems by Icelandic and Norwegian children.

Connectionism and developmental psychology.

What features of brain processing and neural development support linguistic and cognitive development in young children? To what extent are the profile and timing of development in young children determined by a preordained genetic programme? Does the environment play a crucial role in determining the patterns of change observed in children growing up? These questions have been of central concern to developmental psychologists for well over a century. Yet none of them have received answers that are generally accepted by the profession. This article reviews some recent computational modelling of developmental change in children that promises to contribute to a deeper understanding of the issues behind these questions. The modelling work exploits artificial neural networks that mimic some of the basic properties of neural processing in the brain. These networks involve densely connected webs of simple processing units that propagate and transform complex patterns of activity. When exposed to a training environment, they undergo a process of self-organisation, yielding information processing systems that support new forms of behaviour. The study of the dynamics of these systems and their learning capabilities promises to provide us with important clues as to the nature of the mechanisms underlying development in infants and young children.