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Spina bifida myelomeningocele (SBM) is one of the world's most common disabling birth defects, yet, until recently, its genetic, neural, and cognitive phenotypes have been less systematically investigated than those of other neurogenetic disorders, including several of those featured in this volume. This chapter describes the findings from a large-scale multi-site study of more than 260 children with SBM between the ages of 7 and 16 years and over 160 children with SBM and their typically developing peers followed from infancy into school age that involves collaboration between the University of Texas Health Science Center at Houston, the University of Houston, and the Toronto Hospital for Sick Children.
The material is organized as follows: (1) What is SBM?; (2) The SBM genotype; (3) Relations between genotype and physical and neural phenotypes; (4) The SBM behavioral phenotype in relation to lesion level and environmental factors: intelligence, academic skills, and adaptive function; (5) Theoretical questions about typical and atypical development generated from studies of the SBM phenotype; (6) Longitudinal development in SBM from infancy through childhood and into adult life; and (7) Clinical care and intervention issues.
What is SBM?
SBM, a neural tube defect that affects the development of both spine and brain, arises in the third to fourth week of embryogenesis, and results in a failure of neural tube closure. The physical phenotype includes paraplegia of the lower limbs and neurogenic bladder and bowel function (Charney, 1992).
Domestic ruminant selectivity induces floristic changes in pasturelands, risking sustainability and limiting the subsequent availability of susceptible plant species. Development of preferences for species of lower nutritional quality may help to overcome those problems. In this study, we tested the hypothesis that early experience of sheep with a low-quality food (LQF) in a nutritional enriched context increases preference for LQF in adulthood. We predicted a higher proportional consumption of LQF in experienced lambs (EL) than in inexperienced lambs (IL) in choice situations involving LQF and alternative foods. Additionally, we determined intake of LQF by EL and IL at different levels of high-quality food (HQF) availability. From 60 to 210 days of age, EL were fed in separated feed bunks mature oat hay (LQF) simultaneously with sunflower meal (SM) and corn grain (CG), whereas IL were fed alfalfa hay (HQF) simultaneously with SM and CG. After exposure, EL and IL were offered LQF in free choice situations involving alternative foods, and also at five levels of HQF availability (100%, 75%, 50%, 25% and 0% of ad libitum intake). Proportional consumption of LQF was lower or similar in EL than IL. Intake of LQF was also lower or similar in EL than IL at all levels of HQF availability, except when the LQF was the only food available. Our results did not support the hypothesis that early experience with a LQF in a nutritional enriched context increases preference for LQF in adulthood. On the contrary, experience with LQF diminished subsequent preference for LQF in adulthood. It is proposed that, in the conditions of our study, continuous comparison between the LQF and the high-quality supplements (CG and SM) during the early exposure period lead to devaluation of LQF by EL through a simultaneous negative contrast effect.
Language and communication deficits are a hallmark of autism, constituting one of its major diagnostic features (ICD-10, World Health Organization, 1993; DSM-IV, American Psychiatric Association, 2000). Problems with pragmatic aspects of verbal and nonverbal communication are common, as might be expected given the social impairments that also characterize autism. Contemporary research has shifted away from concentrating primarily on pragmatics to considering linguistic features of autism more broadly, including phonological, lexical, and grammatical abilities. This shift in focus has served, at least in part, as an impetus for investigators to explore further the overlap between language difficulties seen in autism and those observed in other types of developmental language disorders. Investigating these potential overlaps has theoretical implications relative to dimensional vs. distinct category accounts of language disorder, as well as practical ramifications for early differential diagnosis. Current research in the area of autism has also expanded beyond classic autistic disorder to include children diagnosed with PDD-NOS/atypical autism and Asperger disorder, with these three pervasive developmental disorders referred to as autism spectrum disorders (ASD) (Charman & Baird, 2002; Lord et al., 2000; and see Chapter 2).
Several new and exciting lines of inquiry have been made possible by recent advances in early clinical diagnosis, as well as the application of new technologies in brain imaging and developments in human genetics research.
Eight multiparous lactating Holstein–Friesian cows were used to evaluate the partitioning of dietary nitrogen (N) from diets based on mixtures of red clover and maize silages in comparison with diets based on ryegrass silage. All cows received 4 kg/day of a standard dairy concentrate with one of four forage treatments in an incomplete changeover design with three 4-week periods. Three treatments were based on mixtures of red clover and maize silage. N intake was altered both by varying the ratio of these silages (40/60 and 25/75 on a dry matter (DM) basis) and by an additional treatment for which the DM intake of the 40/60 mixture was restricted to the level achieved with grass silage. Rumen passage rates were estimated from faecal excretion curves following a pulse oral dose of Dysprosium-labeled silage and urinary excretion of purine derivatives (PD) was used as an index of rumen microbial protein synthesis. Red clover silage mixtures led to significantly increased feed intake (21.5, 20.7 and 15.2 kg DM/day for 40/60 and 25/75 red clover/maize silage mixtures and grass silage, respectively), milk production (25.8, 27.8 and 20.0 kg/day for the same treatments, respectively) and milk component yields, but were without effect on milk fat and protein concentrations. The large increase in the yield of milk (24.5 kg/day) and milk components for the restricted red clover/maize silage treatment, in comparison with the grass silage treatment, was proportionately greater than the increase in DM intake (16.6 kg DM/day). There were no significant treatment effects on diet digestibility, while the higher intakes of red clover silage mixtures were associated with higher rumen passage rates (5.82%, 6.24% and 4.55%/h, respectively). There were significant effects of both N intake and forage source on the partitioning of dietary N between milk and urine. When dietary protein was diluted by the inclusion of maize silage, red clover silage led to increased milk N and reduced urinary N in comparison with grass silage. Improvements in N utilisation may be related to increased dietary starch and/or rumen passage rates leading to increased microbial protein synthesis for these treatments. Urinary excretion of PD was significantly higher for all diets based on mixtures of red clover and maize silages, in comparison with grass silage. Urinary N output was close to literature predictions based on N intake for the diet based on ryegrass silage, but 40 to 80 g/day (25% to 30%) less than predicted for the diets based on the mixtures of red clover and maize silages.
Autism is a highly heritable disorder with variable physiological, behavioral, and cognitive expression, and a widely variable set of outcomes. In some ways, not enough is known about each of these levels of expression of the disorder; in some ways, however, too much is known – many findings at the genetic, anatomical, and neurochemical levels have been reported, but are often not replicated or are directly opposite to each other (low vs. high chemical levels, increased vs. decreased volume of particular brain structures), and no successful synthesis of findings across or within levels has yet been made. Given this complex and disjointed set of studies, we have not attempted a comprehensive or synthetic review.
We will not address studies on neurochemistry or other physiological factors that have been raised as possibilities in autism, such as inflammatory processes (Vargas et al., 2005), but will focus on genetics, anatomy, and behavioral/cognitive outcome. We will first describe the basic phenomenology and epidemiology of the autistic syndromes. Second, we will review what is known about the genetic basis of autism. Third, we will describe the current state of knowledge about the neuroanatomy of autism. Finally, we will address outcome: what is known about the outcome of affected children; and most intriguingly, if autism has a genetic basis, which seems to affect basic neuroanatomy, how is it possible that some children “recover” from their autism? (Discussion of autism associated with fragile X syndrome can be found in Chapter 1.)
There has been a significant decline in the reproductive performance of dairy cattle in recent decades. Cows, take longer time to return to the oestrus after calving, have poorer conception rates, and show fewer signs of oestrus. Achieving good reproductive performance is an increasing challenge for the dairy producer. In this study we focus on understanding the overall biological phenomena associated with nutritional sub-fertility rather than the underlying multiplicity of physiological interactions (already described in a number of recent studies). These phenomena are important because they represent the natural adaptations of the animal for dealing with variations in the nutritional environment. They can also be used to monitor and modulate reproductive performance on-farm. There is an underlying trade-off between two aspects of reproduction: investment in the viability of the current calf and investment in future offspring. As the investment in, and viability of, the current calf is related to maternal milk production, we can expect that level of milk production per se has effects on subsequent reproductive performance (investment in future offspring). Lactating cows have a lower proportion of viable embryos, which are of poorer quality, than do non-lactating cows. The same applies to high- compared to medium-genetic merit cows. Another important biological property is the adaptive use of body reserves in support of reproduction. Orchestrated endocrine changes in pregnancy and lactation facilitate the deposition of body lipid during pregnancy and mobilisation in early lactation. When the cow fails to accumulate the reserves she needs to safeguard reproduction she delays committing to further reproductive investment. But how does the cow ‘know’ that she is failing in energy terms? We argue that the cow does this by ‘monitoring’ both the body fat mobilisation and body fatness. Excessive body fat mobilisation indicates that current conditions are worse than expected. Body fatness indicates the future ability of the cow to safeguard her reproductive investment is compromised. Both delay further reproductive commitment. The relationship between reproductive performance and; milk production as an index of maternal investment, body fatness as an index of ability to safeguard reproductive investment, and body fat mobilisation as an index of the current nutritional environment – are examined. Nutritional strategies that seek to modulate body mobilisation and the endocrine environment by use of glucogenic and lipogenic diets, and the use of in-line progesterone profiles to monitor reproductive status are then discussed in this biological context.
The study was carried out on 42 breeder couples (42 males and 42 females) of European brown hare (Lepus europaeus), divided into three groups fed three different experimental diets (14 couples/treatment). Two diets were supplemented with n-3 and n-6 polyunsaturated fatty acids (PUFAs; 2% of linseed oil and soybean oil, respectively) and were compared with a control diet supplemented with a monounsaturated fatty acids (2% of olive oil). During the experimental period (from 15 April to 30 September), the following parameters were recorded: days from the beginning of trial to the first parturition, parturition interval, number of parturitions, number of leverets born (alive and dead), dead during suckling, the total number of leverets weaned and feed intake per cage (of males, females and leverets until weaning). Feed intake was not influenced by treatments. In hares fed n-3 and n-6 diets, the days from the beginning of the trial to the first parturition and the parturition interval were similar and were lower compared with control group (63.1 v. 70.6 days, and 37.8 v. 40.9 days, respectively; P < 0.05). Hares from n-6 group had a higher (P < 0.05) number of parturitions per cage during the experimental period than the n-3 and control group that showed a similar value (3.00 v. 2.36, respectively). The total number of leverets born per cage and parturition in n-6 and n-3 groups increased with respect to those fed control diet (P < 0.05). The leverets’ mortality rate at birth was higher in n-6 than in n-3 and control group (3.50 v. 2.17, respectively; P < 0.05). In control group, leverets’ mortality rate during suckling was lower with respect to n-3 (P < 0.05) and n-6 (P < 0.05), showing the highest value for the latter (P < 0.05). In spite of this higher mortality, the number of leverets weaned per cage and parturition was higher (P < 0.05) in n-6 compared with n-3 group, being the latter higher than the control group (3.12, 2.79 and 2.43, respectively). Our results show that the dietary PUFAs, particularly n-6 supplementation, have a positive influence on the reproductive performances of the European brown hare.
The study of genetic disorders that affect neurodevelopment has led to a rich body of interdisciplinary research in genetics, neuroscience, and psychology. These collaborations have not only promoted a better understanding of genetic disorders themselves, but have also resulted in new discoveries about the connections between genes, brain, and cognition. When people consider genetic disorders that affect cognitive development they often think about single gene disorders such as fragile X syndrome or chromosome disorders such as Down syndrome. However, there is a growing recognition that many neurodevelopmental disorders have strong genetic components even though their genetic underpinnings may be less well understood than those diagnosed through genetic testing. And, increasingly, cross-disorder comparisons with overlapping phenotypic variability are proving to be useful models for understanding the interplay of genes, brain, and behavior across development. Given the increasing recognition of the role that genes play in developmental disorders, an exhaustive survey of disorders that affect cognitive development is beyond the scope of any one book. The purpose of this book is to represent some of the ways in which a number of disorders, both those diagnosed through genetic testing, and those identified through their physical and behavioral phenotypes, are being used to test models of neurobehavioral development and to understand relations between genes, brain, and behavior.
There have been remarkable advances in genetics over the past decade including the sequencing of the human genome which was completed in 2003, 50 years after the discovery of the double-helix structure of DNA by Watson and Crick (Valle, 2004). These advances have furthered our understanding of many forms of mental retardation, including X-linked mental retardation of which fragile X syndrome (FXS) is the most common type.
There are approximately 30, 000 genes in the human genome, and approximately 1000 genes on the X chromosome. Over 200 of these genes on the X chromosome have been associated with mental retardation. The X chromosome has more genes associated with mental retardation than any other chromosome. Approximately 20–25% of all cases of mental retardation are X-linked. Because males only have one X chromosome, they are much more vulnerable to the effects of an abnormal gene on the chromosome. There are approximately 20% more males with mental retardation than females in the general population. In this chapter we will review the most common inherited cause of mental retardation and neurodegeneration; fragile X associated tremor/ataxia syndrome (FXTAS), the most common cause of ataxia in those over 50 years of age; and the fragile X mental retardation 1 gene (FMR1), the most common gene associated with X-linked mental retardation.
In recent years, several researchers have attempted to apply the adult neuropsychological model to neurodevelopmental disorders. In the adult model, localized brain damage gives rise to a juxtaposed pattern of impaired and intact abilities. When applied to neurodevelopmental disorders, this approach fails to capture the role of development itself in the formation of the final phenotype. An alternative to this common strategy is a neuroconstructivist approach that considers the contribution of the infant start state, the entire developmental trajectory, and underlying cognitive processes to the phenotypic outcome. Results from studies of language and number in infants and toddlers with Williams syndrome and Down syndrome, along with a briefer discussion of face processing, will be presented in support of this position. The application of this approach to other developmental disorders such as autism will also be discussed.
The traditional adult neuropsychological approach to disorder is a static one, in contrast to a neuroconstructivist perspective, which emphasizes the importance of development and of studying early development and not just the endstate in older children and adults. A theoretically driven investigation of the cognitive processes underlying behavior as well as the use of converging measures to describe these processes are crucial aspects of understanding neurodevelopmental disorders from a neoconstructivist approach.
Three developmental disorders, i.e., Williams syndrome, Down syndrome, and autism, will be used to illustrate the developmental neoconstructive approach. The majority of studies to be discussed concern the first two groups.
Neurodevelopmental disorders and mathematics learning disability
Poor math achievement is well documented in both children and adults with fragile X or Turner syndrome (Bennetto et al., 2001; Brainard et al., 1991; Grigsby et al., 1990; Mazzocco, 1998, 2001; Rovet, 1993; Rovet et al., 1994; Temple & Marriott, 1998). However, there is limited understanding of the cognitive mechanisms that contribute to these poor math outcomes. Specification of these underlying causes is the necessary next step in research on the cognitive phenotypes for these disorders (Mazzocco & McCloskey, 2005). Our efforts to understand the origins of mathematical cognition in fragile X and Turner syndromes are guided by existing knowledge in the field of mathematics learning disability (MLD). This body of research provides a conceptual framework for the contribution of different cognitive systems, such as executive function, visual–spatial, and language skills, to overall competence in mathematics (see Geary, 1993, 1994) as elaborated later in this chapter. Accordingly, the assessment of math ability in persons with fragile X or Turner syndrome is most informative when examined in the context of the overall cognitive phenotype, or the set of cognitive characteristics, associated with each disorder.
Although models of MLD are informative for understanding mathematical functioning in genetic conditions such as fragile X or Turner syndrome, the study of these syndromes may also inform the broader field of MLD research.
In mature male sheep and goats, changes in feed intake seem to have little effect on gonadal endocrine function but induce profound changes on sperm production. These outcomes are due to changes in size of the seminiferous tubules and in spermatogenic efficiency. Except with severe underfeeding, there are only minor changes in the endocrine function of the testis (testosterone production) unless season-long treatments are imposed. For cattle, nutrition clearly affects testicular development and the production of spermatozoa in young bulls, as it does in other species but, after the period of rapid growth has ended, there appears to be little or no response to nutrition. We are developing a clear picture of the metabolic signals, neuroendocrine processes and hormonal control systems that are involved, particularly for the mature male sheep. The energetic components of the diet, rather than protein, seem to be responsible, so we have envisaged a model of the relationship between energy balance and reproduction that has 4 ‘dimensions’: genotype, structure (organs), communication (chemical and neural signals, nutrient sensing) and time (dynamics, metabolic memory, programming). We have linked these perspectives to ‘resource allocation theory’ and incorporated them into strategies for ‘clean, green and ethical animal production’. In contrast to the clear outcomes with respect to spermatogenesis, the effects of nutrition on sexual behaviour are more difficult to define, perhaps because the behaviour is affected by a complex mix of physiological factors and because of flawed methods for quantifying male behaviour. For example, sexual behaviour is compromised by severe feed restriction, but male sexual behaviour requires intensive motor activity so a decline in libido could be caused by general weakness rather than specific nutritional limitations. The interaction between sexual activity and feeding behaviour also complicates the issue under field conditions. At the other end of the scale, overweight males can show reduced sexual success because they have difficulty courting and mounting. For this reason, exercise can enhance the fertilising capacity of rams. This will be important in extensive mating systems where males need to assemble and guard a harem and then mate many times for several weeks. For artificial insemination centres, there seems to be very few data on the nutritional management of males, but problems with overfed animals appear to be a risk. Future research should concentrate on the intra-testicular systems mediating the effects of nutrition on the production of spermatozoa.
Mammalian hair follicles are complex multicellular structures in the skin, which produce hair fibre under the influence of locally produced and systemic signalling systems. Investigation to determine mechanisms of regulation, follicular responses and the importance of nutritional supply have utilised a number of in vivo and in vitro approaches. Included in these are studies on isolated intact anagen secondary follicles singly or in groups with incubation in culture medium. These utilise techniques developed for investigation of follicles from human skin. Results from selected studies reviewed here demonstrate differences in capacity for hair growth and protein synthesis between secondary follicles from Angora and cashmere-bearing goats. Mohair follicles were shown to exhibit faster hair shaft elongation both in vivo and in vitro, to have greater DNA content per follicle and to deposit significantly more protein per follicle and per unit of DNA. Incubation of anagen mohair and cashmere follicles in the presence of melatonin or prolactin showed positive responses in hair shaft growth and protein synthesis to both signalling molecules. This result indicated directly acting effects on the follicle in addition to any indirect effects arising at a whole animal level in response to, for example, variation in photoperiod. Similarly, epidermal growth factor was shown to alter elongation and protein synthesis in mohair follicles and to produce, at higher concentration, club hair structures similar to effects observed in other species. The vitamin biotin was shown to be important in maintaining viability of isolated sheep secondary hair follicles where supplementation increased the proportion continuing to grow. Effects on growth and apparent protein synthesis suggested comparatively lesser effects on follicles, which remained viable. Histology on follicles indicated effects of biotin deficiency in reducing proliferation of basal keratinocytes. The final study, included in this review, demonstrated that supply of the essential sulphur-containing amino acid l-methionine was necessary to maintain the viability and growth of mohair follicles. l-cysteine was not required in the presence of l-methionine, although there was evidence of an optimisation when both amino acids were present in adequate concentrations. Consideration is given to the importance of transport mechanisms and capacity to utilise absorbed nutrients when considering optimising nutritional supply to individual follicles. These may then provide targets for attainment in applied nutrition of animals in vivo.
This book is the first of its kind to provide a large collection of bioinformatics problems with accompanying solutions. Notably, the problem set includes all of the problems offered in Biological Sequence Analysis, by Durbin et al. (Cambridge, 1998), widely adopted as a required text for bioinformatics courses at leading universities worldwide. Although many of the problems included in Biological Sequence Analysis as exercises for its readers have been repeatedly used for homework and tests, no detailed solutions for the problems were available. Bioinformatics instructors had therefore frequently expressed a need for fully worked solutions and a larger set of problems for use on courses. This book provides just that: following the same structure as Biological Sequence Analysis and significantly extending the set of workable problems, it will facilitate a better understanding of the contents of the chapters in BSA and will help its readers develop problem-solving skills that are vitally important for conducting successful research in the growing field of bioinformatics. All of the material has been class-tested by the authors at Georgia Tech, where the first ever MSc degree program in Bioinformatics was held.