Showing papers by "Medical Research Council published in 1998"

Mutation in the tau gene in familial multiple system tauopathy with presenile dementia

Abstract: Familial multiple system tauopathy with presenile dementia (MSTD) is a neurodegenerative disease with an abundant filamentous tau protein pathology. It belongs to the group of familial frontotemporal dementias with Parkinsonism linked to chromosome 17 (FTDP-17), a major class of inherited dementing disorders whose genetic basis is unknown. We now report a G to A transition in the intron following exon 10 of the gene for microtubule-associated protein tau in familial MSTD. The mutation is located at the 3′ neighboring nucleotide of the GT splice-donor site and disrupts a predicted stem-loop structure. We also report an abnormal preponderance of soluble tau protein isoforms with four microtubule-binding repeats over isoforms with three repeats in familial MSTD. This most likely accounts for our previous finding that sarkosyl-insoluble tau protein extracted from the filamentous deposits in familial MSTD consists only of tau isoforms with four repeats. These findings reveal that a departure from the normal ratio of four-repeat to three-repeat tau isoforms leads to the formation of abnormal tau filaments. The results show that dysregulation of tau protein production can cause neurodegeneration and imply that the FTDP-17 gene is the tau gene. This work has major implications for Alzheimer’s disease and other tauopathies.

The ecological validity of tests of executive function.

Abstract: Ninety-two mixed etiology neurological patients and 216 control participants were assessed on a range of neuropsychological tests, including 10 neuropsychological measures of executive function derived from 6 different tests. People who knew the patients well (relatives or carers) completed a questionnaire about the patient's dysexecutive problems in everyday life, and this paper reports the extent to which the tests predicted the patients' everyday life problems. All of the tests were significantly predictive of at least some of the behavioral and cognitive deficits reported by patients' carers. However, factor analysis of the patients' dysexecutive symptoms suggested a fractionation of the dysexecutive syndrome, with neuropsychological tests loading differentially on 3 underlying cognitive factors (Inhibition, Intentionality, and Executive Memory), supporting the conclusions that different tests measure different cognitive processes, and that there may be limits to the fractionation of the executive system.

Language-impaired preschoolers: a follow-up into adolescence.

Abstract: This paper reports a longitudinal follow-up of 71 adolescents with a preschool history of speech-language impairment, originally studied by Bishop and Edmundson (1987). These children had been subd...

The primacy model : A new model of immediate serial recall

Abstract: A new model of immediate serial recall is presented: the primacy model. The primacy model stores order information by means of the assumption that the strength of activation of successive list items decreases across list position to form a primacy gradient. Ordered recall is supported by a repeated cycle of operations involving a noisy choice of the most active item followed by suppression of the chosen item. Word-length and list-length effects are attributed to a decay process that occurs both during input, when effective rehearsal is prevented, and during output. The phonological similarity effect is attributed to a second stage of processing at which phonological confusions occur. The primacy model produces accurate simulations of the effects of word length, list length, and phonological similarity.

Responses of Neurons in Inferior Temporal Cortex During Memory-Guided Visual Search

Abstract: Chelazzi, Leonardo, John Duncan, Earl K. Miller, and Robert Desimone. Responses of neurons in inferior temporal cortex during memory-guided visual search. J. Neurophysiol. 80: 2918–2940, 1998. A ty...

Randomised trial of early diet in preterm babies and later intelligence quotient

Abstract: Objectives: To determine whether perinatal nutrition influences cognitive function at 7 1/2 - 8 years in children born preterm. Design: Randomised, blinded nutritional intervention trial. Blinded follow up at 7 1/2 - 8 years. Setting: Intervention phase in two neonatal units; follow up in a clinic or school setting. Subjects: 424 preterm infants who weighed under 1850 g at birth; 360 of those who survived were tested at 7 1/2 - 8 years. Interventions: Standard infant formula versus nutrient enriched preterm formula randomly assigned as sole diet (trial A) or supplements to maternal milk (trial B) fed for a mean of 1 month. Main outcome measures: Intelligence quotient (IQ) at 7 1/2 - 8 years with abbreviated Weschler intelligence scale for children (revised). Results: There was a major sex difference in the impact of diet. At 7 1/2 - 8 years boys previously fed standard versus preterm formula as sole diet had a 12.2 point disadvantage (95% confidence interval 3.7 to 20.6; P Conclusions: Preterm infants are vulnerable to suboptimal early nutrition in terms of their cognitive performance—notably, language based skills—at 7 1/2 - 8 years, when cognitive scores are highly predictive of adult ones. Our data on cerebral palsy generate a new hypothesis that suboptimal nutritional management during a critical or plastic early period of rapid brain growth could impair functional compensation in those sustaining an earlier brain insult. Cognitive function, notably in males, may be permanently impaired by suboptimal neonatal nutrition.

Target-cell-specific facilitation and depression in neocortical circuits.

Abstract: In neocortical circuits, repetitively active neurons evoke unitary postsynaptic potentials (PSPs) whose peak amplitudes either increase (facilitate) or decrease (depress) progressively. To examine the basis for these different synaptic responses, we made simultaneous recordings from three classes of neurons in cortical layer 2/3. We induced repetitive action potentials in pyramidal cells and recorded the evoked unitary excitatory (E)PSPs in two classes of GABAergic neurons. We observed facilitation of EPSPs in bitufted GABAergic interneurons, many of which expressed somatostatin immunoreactivity. EPSPs recorded from multipolar interneurons, however, showed depression. Some of these neurons were immunopositive for parvalbumin. Unitary inhibitory (I)PSPs evoked by repetitive stimulation of a bitufted neuron also showed a less pronounced but significant difference between the two target neurons. Facilitation and depression involve presynaptic mechanisms, and because a single neuron can express both behaviors simultaneously, we infer that local differences in the molecular structure of presynaptic nerve terminals are induced by retrograde signals from different classes of target neurons. Because bitufted and multipolar neurons both formed reciprocal inhibitory connections with pyramidal cells, the results imply that the balance of activation between two recurrent inhibitory pathways in the neocortex depends on the frequency of action potentials in pyramidal cells.

A full genome screen for autism with evidence for linkage to a region on chromosome 7q International Molecular Genetic Study of Autism Consortium

Abstract: Autism is characterized by impairments in reciprocal social interaction and communication, and restricted and stereotyped patterns of interests and activities. Developmental difficulties are apparent before 3 years of age and there is evidence for strong genetic influences most likely involving more than one susceptibility gene. A two-stage genome search for susceptibility loci in autism was performed on 87 affected sib pairs plus 12 non-sib affected relativepairs, from a total of 99 families identified by an international consortium. Regions on six chromosomes (4, 7, 10, 16, 19 and 22) were identified which generated a multipoint maximum lod score (MLS) > 1. A region on chromosome 7q was the most significant with an MLS of 3.55 near markers D7S530 and D7S684 in the subset of 56 UK affected sib-pair families, and an MLS of 2.53 in all 87 affected sib-pair families. An area on chromosome 16p near the telomere was the next most significant, with an MLS of 1.97 in the UK families, and 1.51 in all families. These results are an important step towards identifying genes predisposing to autism; establishing their general applicability requires further study.

Validation of a Three-Stage Compound Continuous Culture System for Investigating the Effect of Retention Time on the Ecology and Metabolism of Bacteria in the Human Colon

Abstract: A three-stage compound continuous culture system was used to study the effect of retention time (27.1 and 66.7 h) on the catabolism of organic carbon and nitrogen sources in mixed populations of human colonic bacteria. The fermentation system was designed to reproduce spatial, temporal, nutritional, and physicochemical characteristics of the microbiota in the proximal (vessel 1) and distal (vessels 2 and 3) colons, and was validated on the basis of chemical and microbiological measurements on intestinal contents obtained from human sudden death victims. Results showed that the majority of carbohydrate breakdown and short-chain fatty acid production occurred in V1. Conversely, dissimilatory amino acid metabolism, as evidenced by formation of branched-chain fatty acids and phenolic compounds, occurred primarily in V2 and V3. Fermentation of aromatic amino acids was strongly affected by system retention time (R), with concentrations of phenolic metabolites being three times higher in V3, at 66.7 h, compared to 27.1 h. Bacteriological measurements of intestinal contents, in which nine groups of marker organisms were studied, showed that, with the exception of bifidobacteria, no major differences in relative bacterial cell numbers were evident in the proximal and distal colons. These organisms were also studied in the continuous culture system, where marked reductions in Escherichia coli were observed in V2 and V3, especially at R= 27.1 h. Increasing R to 66.7 h reduced numbers of Clostridium perfringens, anaerobic Gram-positive cocci, and total anaerobe counts. Correlations between in vivo chemical and bacteriological measurements and data obtained in vitro demonstrate that the three-stage fermentation system provided a useful model for studying the physiology and ecology of large intestinal microorganisms under different nutritional and environmental conditions.

Intracortical inhibition and facilitation in different representations of the human motor cortex.

Abstract: Chen, Robert, Alda Tam, Cathrin Butefisch, Brian Corwell, Ulf Ziemann, John C. Rothwell, and Leonardo G. Cohen. Intracortical inhibition and facilitation in different representations of the human m...

Understanding mind and emotion : Longitudinal associations with mental-state talk between young friends

Abstract: Developmental changes in children's understanding of mind and emotion and their mental-state talk in conversations with friends were examined in a longitudinal study of 50 children (M age at each time point = 3 years 11 months, 4 years 6 months, 5 years 0 months). Significant and related improvements over time were found for both theory-of-mind task performance and affective perspective taking. Associated with these cognitive developments were quantitative and qualitative changes in children's references to mental states in their conversations with friends. Individual differences in theory of mind, emotion understanding, and mental-state talk were strikingly stable over the 13-month period. Although there were no gender differences in children's task performances, girls showed more frequent and more developed mental-state talk than boys.

Autism: The Phenotype in Relatives

Abstract: There is broad agreement that genetic influences are central in the development of idiopathic autism. Whether relatives manifest genetically related milder phenotypes, and if so how these relate to autism proper, has proved a more contentious issue. A review of the relevant studies indicates that relatives are sometimes affected by difficulties that appear conceptually related to autistic behaviors. These range in severity from pervasive developmental disorders to abnormalities in only one area of functioning, and possibly extend to related personality traits. Issues involved in clarifying the components of milder phenotypes and their relationship to autism are outlined.

X-Chromosome inactivation: a repeat hypothesis

Abstract: . Recent work has shown that X-chromosome inactivation is brought about by Xist mRNA, which coats the inactive X-chromosome. This paper presents a hypothesis on

S-phase-specific activation of Cds1 kinase defines a subpathway of the checkpoint response in Schizosaccharomyces pombe

Abstract: Checkpoints that respond to DNA structure changes were originally defined by the inability of yeast mutants to prevent mitosis following DNA damage or S-phase arrest. Genetic analysis has subsequently identified subpathways of the DNA structure checkpoints, including the reversible arrest of DNA synthesis. Here, we show that the Cds1 kinase is required to slow S phase in the presence of DNA-damaging agents. Cds1 is phosphorylated and activated by S-phase arrest and activated by DNA damage during S phase, but not during G1 or G2. Activation of Cds1 during S phase is dependent on all six checkpoint Rad proteins, and Cds1 interacts both genetically and physically with Rad26. Unlike its Saccharomyces cerevisiae counterpart Rad53, Cds1 is not required for the mitotic arrest checkpoints and, thus, defines an S-phase specific subpathway of the checkpoint response. We propose a model for the DNA structure checkpoints that offers a new perspective on the function of the DNA structure checkpoint proteins. This model suggests that an intrinsic mechanism linking S phase and mitosis may function independently of the known checkpoint proteins.

Cortical correlate of the Piper rhythm in humans.

Abstract: Brown, Peter, Stephan Salenius, John C. Rothwell, and Riitta Hari. Cortical correlate of the Piper rhythm in humans. J. Neurophysiol. 80: 2911–2917, 1998. The electromyogram (EMG) of healthy humans...

Selective Innervation of Neostriatal Interneurons by a Subclass of Neuron in the Globus Pallidus of the Rat

Abstract: A subpopulation of neurons in the globus pallidus projects to the neostriatum, which is the major recipient of afferent information to the basal ganglia. Given the moderate nature of this projection, we hypothesized that the pallidostriatal projection might exert indirect but powerful control over principal neuron activity by targeting interneurons, which comprise only a small percentage of neostriatal neurons. This was tested by the juxtacellular labeling and recording of pallidal neurons in combination with immunolabeling of postsynaptic neurons. In addition to innervating the subthalamic nucleus and output nuclei, 6 of 23 labeled pallidal neurons projected to the neostriatum. Both the firing characteristics and the extent of the axonal arborization in the neostriatum were variable. However, light and electron microscopic analysis of five pallidostriatal neurons revealed that each neuron selectively innervated neostriatal interneurons. A large proportion of the boutons of an individual axon (19-66%) made contact with parvalbumin-immunoreactive interneurons. An individual parvalbumin-immunoreactive neuron (n = 27) was apposed on average by 6.7 boutons (SD = 6.1) from a single pallidal axon (n = 2). Individual pallidostriatal boutons typically possessed more than one symmetrical synaptic specialization. In addition, 3-32% of boutons of axons from four of five pallidal neurons contacted nitric oxide synthase-immunoreactive neurons. Descending collaterals of pallidostriatal neurons were also found to make synaptic contact with dopaminergic and GABAergic neurons of the substantia nigra. These data imply that during periods of cortical activation, individual pallidal neurons may influence the activity of GABAergic interneurons of the neostriatum (which are involved in feed-forward inhibition and synchronization of principle neuron activity) while simultaneously patterning neuronal activity in basal ganglia downstream of the neostriatum.

Functional organization of spatial and nonspatial working memory processing within the human lateral frontal cortex.

Abstract: The present study used functional magnetic resonance imaging to demonstrate that performance of visual spatial and visual nonspatial working memory tasks involve the same regions of the lateral prefrontal cortex when all factors unrelated to the type of stimulus material are appropriately controlled. These results provide evidence that spatial and nonspatial working memory may not be mediated, respectively, by mid-dorsolateral and mid-ventrolateral regions of the frontal lobe, as widely assumed, and support the alternative notion that specific regions of the lateral prefrontal cortex make identical executive functional contributions to both spatial and nonspatial working memory.

Respiratory syncytial virus infection in tropical and developing countries

Abstract: Little is known about the epidemiology of respiratory syncytial virus (RSV) infection in tropical and developing countries; the data currently available have been reviewed. In most studies, RSV was found to be the predominant viral cause of acute lower respiratory tract infections (ALRI) in childhood, being responsible for 27-96% of hospitalised cases (mean 65%) in which a virus was found. RSV infection is seasonal in most countries; outbreaks occur most frequently in the cold season in areas with temperate and Mediterranean climates and in the wet season in tropical countries with seasonal rainfall. The situation on islands and in areas of the inner tropics with perennial high rainfall is less clear-cut. The age group mainly affected by RSV in developing countries is children under 6 months of age (mean 39% of hospital patients with RSV). RSV-ALRI is slightly more common in boys than in girls. Very little information is available about the mortality of children infected with RSV, the frequency of bacterial co-infection, or the incidence of further wheezing after RSV. Further studies on RSV should address these questions in more detail. RSV is an important pathogen ill young children in tropical and developing countries and a frequent cause of hospital admission. Prevention of RSV infection by vaccination would have a significant impact on the incidence of ALRI in children in developing countries.

The National Diet and Nutrition Survey: People Aged 65 Years and Over

Abstract: Commissioned by the Ministry of Agriculture, Fisheries and Food, the Department of Health and carried out by Social and Community Planning Research and MRC Dunn Nutrition Unit, the dental hospitals of the Universities of Newcastle and Birmingham and the Department of Epidemiology of the University of London, this research forms part of the National Diet and Nutrition Survey. Set up in 1992 the surveys cover representative groups of the population and examine the diet of the over‐65s in terms of actual dietary intake, habits, energy and nutrient intakes, physical measurements. Regional and socio‐economic comparisons are made.

Adaptive Markov Chain Monte Carlo through Regeneration

Abstract: Markov chain Monte Carlo (MCMC) is used for evaluating expectations of functions of interest under a target distribution π. This is done by calculating averages over the sample path of a Markov chain having π as its stationary distribution. For computational efficiency, the Markov chain should be rapidly mixing. This sometimes can be achieved only by careful design of the transition kernel of the chain, on the basis of a detailed preliminary exploratory analysis of π. An alternative approach might be to allow the transition kernel to adapt whenever new features of π are encountered during the MCMC run. However, if such adaptation occurs infinitely often, then the stationary distribution of the chain may be disturbed. We describe a framework, based on the concept of Markov chain regeneration, which allows adaptation to occur infinitely often but does not disturb the stationary distribution of the chain or the consistency of sample path averages.

Chromosomal Instability in the Descendants of Unirradiated Surviving Cells after α -Particle Irradiation

Abstract: We have demonstrated chromosomal instability in the clonal descendants of hemopoietic stem cells after irradiating murine bone marrow with α-particles However, because cells that are irradiated by α-particles are defined by a Poisson distribution of individual particle traversals, there is an inevitable proportion of unirradiated cells in the surviving population The calculated expected proportions of irradiated and nonirradiated cells indicate that the number of clonogenic cells transmitting chromosomal instability is greater than the number expected to be hit and survive To investigate further this discrepancy, we studied the effects of interposing a grid between the cells and the α-particle source so that the surviving population consists predominantly of untraversed stem cells Comparison with the same irradiation conditions without the grid reveals that the same level of instability is induced The data confirm that α-particles induce chromosomal instability but instability is demonstrated in the progeny of nonirradiated stem cells and must be due to unexpected interactions between irradiated and nonirradiated cells This untargeted effect has important implications for mechanistic studies of radiation action and for assessment of radiation risk