Showing papers by "Newcastle University published in 1997"

Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study.

Abstract: We present clinical data on 558 patients with deletions within the DiGeorge syndrome critical region of chromosome 22q11. Twenty-eight percent of the cases where parents had been tested had inherited deletions, with a marked excess of maternally inherited deletions (maternal 61, paternal 18). Eight percent of the patients had died, over half of these within a month of birth and the majority within 6 months. All but one of the deaths were the result of congenital heart disease. Clinically significant immunological problems were very uncommon. Nine percent of patients had cleft palate and 32% had velopharyngeal insufficiency, 60% of patients were hypocalcaemic, 75% of patients had cardiac problems, and 36% of patients who had abdominal ultrasound had a renal abnormality. Sixty-two percent of surviving patients were developmentally normal or had only mild learning problems. The majority of patients were constitutionally small, with 36% of patients below the 3rd centile for either height or weight parameters.

Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury ( T ) gene family

Abstract: Holt-Oram syndrome is a developmental disorder affecting the heart and upper limb, the gene for which was mapped to chromosome 12 two years ago. We have now identified a gene for this disorder (HOS1). The gene (TBX5) is a member of the Brachyury (T) family corresponding to the mouse TbxS gene. We have identified six mutations, three in HOS families and three in sporadic HOS cases. Each of the mutations introduces a premature stop codon in the TBXS gene product. Tissue in situ hybridization studies on human embryos from days 26 to 52 of gestation reveal expression of TBXS in heart and limb, consistent with a role in human embryonic development.

Quality of life of people with epilepsy: a European study.

Abstract: Purpose: To study the impact of epilepsy and its treatment on people with epilepsy in Europe. We therefore aimed to collect data from as many countries as possible. Methods: Clinical and demographic details and information about psychosocial functioning was collected using self-completed questionnaires mailed to members of epilepsy support groups. Results: Quality of life data was collected from >5,000 patients living in 15 countries in Europe. Over a third of all respondents had frequent seizures, and a fifth believed that their seizures were not well enough controlled by antiepileptic medication. Reported levels of side effects from medication were high. A significant number of respondents reported changing their medication because of side effects or poor control. Respondents reported that epilepsy and its treatment had a significant impact on a number of different aspects of their daily lives. Half of all respondents felt stigmatised by their epilepsy. There were significant differences by seizure type and frequency in the way respondents scored on measures of the perceived impact of their condition, the stigma associated with it and their health status as measured by a generic scale, the SF36. Conclusions: This study confirms the findings of previous smaller-scale studies that reducing side effects and achieving better control of seizures are key to improving the quality of life of people with epilepsy, as is reducing the stigma and handicap associated with it.

Cancer Risk Associated with Germline DNA Mismatch Repair Gene Mutations

Abstract: The autosomal dominant syndrome of Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is due to germline DNA mismatch repair gene mutations in most cases. However, the penetrance of such mutations outwith classical HNPCC kindreds is unknown because families studied to date have been specifically selected for research purposes. Using a population-based strategy, we have calculated the lifetime cancer risk associated with germline DNA mismatch repair gene mutations, irrespective of their family history. We identified 67 gene carriers whose risk to age 70 for all cancers was 91% for males and 69% for females. The risk of developing colorectal cancer was significantly greater for males than for females (74% versus 30%, P= 0.006). The risk of uterine cancer (42%) exceeded that for colorectal cancer in females, emphasising the need for uterine screening. Our findings give further insight into the biological effect of defective DNA mismatch repair. We have demonstrated a systematic approach to identifying individuals at high risk of cancer but who may not be part of classical HNPCC families. The risk estimates derived from these analyses provide a rational basis on which to guide genetic counselling and to tailor clinical surveillance.

A modern introduction to the mathematical theory of water waves

Abstract: Note: Includes bibliography and index Reference Record created on 2004-09-07, modified on 2016-08-08

Delay-dependent robust stability and stabilization of uncertain linear delay systems: a linear matrix inequality approach

Abstract: This paper considers the problems of robust stability analysis and robust control design for a class of uncertain linear systems with a constant time-delay. The uncertainty is assumed to be norm-bounded and appears in all the matrices of the state-space model. We develop methods for robust stability analysis and robust stabilization. The proposed methods are dependent on the size of the delay and are given in terms of linear matrix inequalities.

The ordinary city

Abstract: As debates on globalization have progressed from an earlier phase in which commentators saw the intensification of world-scale flows and processes as the negation of local identities and autonomies, the city has been ‘rediscovered’ as the powerhouse of the globalized economy. Against the view that questions, for example, the continued specificity of the urban in an era increasingly mediated by locationally liberating, advanced telecommunications and rapid transport networks, some strands of urban research assert that cities are becoming more important as the key creative, control and cultural centres within globalizing economic, cultural and social dynamics. Building on these strands, this paper evaluates the assets that cities and metropolitan regions provide in an era of globalization. It attempts to develop an alternative perspective on the city based on the idea that contemporary urban life is founded on the heterogeneity of economic, social, cultural and institutional assets, and concludes by using this perspective to develop implications for urban policy and the quest for social and territorial justice.

Social inequality in coronary risk: central obesity and the metabolic syndrome. Evidence from the Whitehall ii study

Abstract: This report describes the social distribution of central obesity and the metabolic syndrome at the Whitehall II study phase 3 examination, and assesses the contribution of health related behaviours to their distribution. Cross-sectional analyses were conducted utilising data collected in 1991–1993 from 4978 men and 2035 women aged 39–63 years who completed an oral glucose tolerance test. There was an inverse social gradient in prevalence of the metabolic syndrome. The odds ratio (95 % confidence interval) for having the metabolic syndrome comparing lowest with highest employment grade was: men 2.2 (1.6–2.9), women 2.8 (1.6–4.8). Odds ratios for occupying the top quintile of the following variables, comparing lowest with highest grade, were, for waist-hip ratio: men 2.2 (1.8-2.8), women 1.6 (1.1-2.4); post-load glucose: men 1.4 (1.1-1.8), women 1.8 (1.2-2.6); triglycerides: men 1.6 (1.2-2.0), women 2.2 (1.5-3.3); fibrinogen: men 1.7 (1.4-2.3), women 1.9 (1.2-2.8). Current smoking status, alcohol consumption and exercise level made a small contribution (men 11%, women 9%) to the inverse association between socioeconomic status and metabolic syndrome prevalence. In conclusion, central obesity, components of the metabolic syndrome and plasma fibrinogen are strongly and inversely associated with socioeconomic status. Our findings suggest the metabolic syndrome may contribute to the biological explanation of social inequalities in coronary risk. Health related behaviours appear to account for little of the social patterning of metabolic syndrome prevalence.

A unifying construction of orthonormal bases for system identification

Abstract: This paper develops a general and very simple construction for complete orthonormal bases for system identification. This construction provides a unifying formulation of many previously studied orthonormal bases since the common FIR and recently popular Laguerre and two-parameter Kautz model structures are restrictive special cases of the construction presented here. However, in contrast to these special cases, the basis vectors in the unifying construction of this paper can have arbitrary placement of pole position according to the prior information the user wishes to inject. Results characterizing the completeness of the bases and the accuracy properties of models estimated using the bases are provided.

X-linked situs abnormalities result from mutations in ZIC3

Abstract: Vertebrates position unpaired organs of the chest and abdomen asymmetrically along the left–right (LR) body axis. Each structure comes to lie non-randomly with respect to the midline in an overall position designated situs solitus, exemplified in humans by placement of the heart, stomach and spleen consistently to the left. Aberrant LR axis development can lead to randomization of individual organ position (situs ambiguus) or to mirror-image reversal of all lateralized structures (situs in versus)1. Previously we mapped a locus for situs abnormalities in humans, HTX1, to Xq26.2 by linkage analysis in a single family (LR1) and by detection of a deletion in an unrelated situs ambiguus male (Family LR2; refs 2,3). From this chromosomal region we have positionally cloned ZIC3, a gene encoding a putative zinc-finger transcription factor. One frameshift, two missense and two nonsense mutations have been identified in familial and sporadic situs ambiguus. The frameshift allele is also associated with situs inversus among some heterozygous females, suggesting that ZIC3 functions in the earliest stages of LR-axis formation. ZIC3, which has not been previously implicated in vertebrate LR-axis development, is the first gene unequivocally associated with human situs abnormalities.

Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes.

Abstract: Many patients with inherited mitochondrial encephalopathies have one of two pathogenic mutations of mitochondrial DNA (mtDNA): A3243G or A8344G. Individuals who harbour these mutations carry both mutant and wild-type alleles within each cell (heteroplasmy). Despite clear evidence of a direct relationship between the level of mutation and mitochondrial respiratory chain function in vitro, it has been more difficult to demonstrate a clear correlation between clinical phenotype and the level of mutant mtDNA in vivo. To address this issue, we identified 245 individuals who carry either the A3243G or A8344G mutations, and studied the relationship between the incidence of specific clinical features and the level of mutant mtDNA in blood (for A3243G, n = 73; for A8344G, n = 25) and/or skeletal muscle (for A3234G, n = 111; for A8344G, n = 55). Within this study group, the frequency of key clinical features was significantly different for individuals harbouring the A3243G and A8344G mutations. For both mutations, there was a correlation between the frequency of the more common clinical features and the level of mutant mtDNA in muscle. In contrast, we did not observe a correlation between the frequency of clinical features and the level of mutant mtDNA in blood. Therefore, measurement of the level of the A3243G and A8344G mutations in muscle will allow the identification of individuals who are at risk of developing specific complications, thus improving the prognostic advice that can be given to patients and family members who carry these mutations.

Traffic restraint, road pricing and network equilibrium

Abstract: Road pricing is now being advocated as an efficient means of managing traffic demand and of meeting other objectives, such as reducing the environmental impact of road traffic and improving public transport. This paper shows how a network toll pattern could be determined so as to reduce network travel demand to a desirable level. The demand between each origin-destination pair is described as a function of the generalized travel cost. When there is no toll charge, higher values of potential demand might cause congestion and queuing at bottleneck links of the road network. Queuing delay at saturated links may grow to choke off enough potential demand to reduce realized demand to the capacity of the network, thus leading to a queuing equilibrium where travel demand and travel cost match each other. In this paper, we first show how an elastic-demand network equilibrium model with queue could be used to determine this demand-supply equilibrium. We then seek a link toll pattern to remove the wasteful queuing delay, and/or restrain the realized demand to a desirable level to satisfy environment capacity constraints. We also show that the link toll pattern that could hold the traffic demand to a desirable level is not unique, a bi-level programming method is developed to select the best toll pattern among the feasible solutions based on pre-specified criteria.

Theory of Threading Edge and Screw Dislocations in GaN

Abstract: The atomic structures, electrical properties, and line energies for threading screw and threading edge dislocations of wurtzite GaN are calculated within the local-density approximation. Both dislocations are electrically inactive with a band gap free from deep levels. These results are understood to arise from relaxed core structures which are similar to (1010) surfaces.

Glutamate, excitotoxicity and amyotrophic lateral sclerosis.

Abstract: The “glutamate hypothesis” is one of three major pathophysiological mechanisms of motor neurone injury towards which current research effort into amyotrophic lateral sclerosis (ALS) is directed. There is great structural and functional diversity in the glutamate receptor family which results from combinations of 14 known gene products and their splice variants, with or without additional RNA editing. It is possible that motor neurones express a unique molecular profile of glutamate receptors. Abnormal activation of glutamate receptors is one of five main candidates as a final common pathway to neuronal death. In classical acute excitotoxicity, there is influx of Na+ and Cl−, and destabilisation of intracellular Ca2+ homeostasis, which activates a cascade of harmful biochemical events. The concept of secondary excitotoxicity, where cellular injury by glutamate is triggered by disturbances in neuronal energy status, may be particularly relevant to a chronic neurodegenerative disease such as ALS. Data are now beginning to emerge on the fine molecular structure of the glutamate receptors present on human motor neurones, which have a distinct profile of AMPA receptors. Two important molecular features of motor neurones have been identified that may contribute to their vulnerability to neurodegeneration. The low expression of calcium binding proteins and the low expression of the GluR2 AMPA receptor subunit by vulnerable motor neurone groups may render them unduly susceptible to calcium-mediated toxic events following glutamate receptor activation. Eight lines of evidence that indicate a disturbance of glutamatergic neurotransmission in ALS patients are reviewed. The links between abnormal activation of glutamate receptors and other potential mechanisms of neuronal injury, including activation of calcium-mediated second messenger systems and free radical mechanisms, are emphasised. Riluzole, which modulates the glutamate neurotransmitter system, has been shown to prolong survival in patients with ALS. Further research may allow the development of subunit-specific therapeutic targeting of glutamate receptors and modulation of “downstream” events within motor neurones, aimed at protecting vulnerable molecular targets in specific populations of ALS patients.

Prognostic Significance of HER2 and HER4 Coexpression in Childhood Medulloblastoma

Abstract: Recent in vitro studies of the epidermal growth factor receptor (EGFR) family have revealed complex signaling interactions involving the production of ligand-mediated heterodimers synergistic for the transformation of cells in vitro In a series of 70 patients with childhood medulloblastoma, we have used immunohistochemistry and Western blotting analysis to investigate the expression patterns of all four EGFR family members (EGFR, HER2, HER3, and HER4) and heregulin-alpha, a ligand for the HER3 and HER4 receptors The majority of cases expressed two or more receptor proteins; coexpression of the HER2 and HER4 receptors occurred in 54% Expression of the ligand heregulin-alpha was detected in 31% of tumors To investigate whether coexpression results in receptor heterodimerization, we have also performed immunoprecipitation analysis of protein extracts from primary tumors, and we demonstrate various patterns of receptor interaction including between HER2 and HER4 In multivariate 25-year survival analysis with clinicopathological disease features, no individual receptor or heregulin-alpha achieved significance In contrast, when considered together in the multivariate model, coexpression of HER2 and HER4 demonstrated independent prognostic significance (P = 0006) These data suggest the hypothesis that HER2-HER4 receptor heterodimerization is of particular biological significance in this disease, and this report is the first to demonstrate potential clinical significance of EGFR family heterodimerization in human cancer Finally, we have also analyzed expression of the AP-2 transcription factor implicated in the positive regulation of HER2 and HER3 gene transcription in malignant cells and reveal an association between AP-2 expression and not only HER2 and HER3, but also HER4 levels in medulloblastoma primary tumors

Patients' Experiences of Injury as a Result of Epilepsy

Abstract: Summary: Purpose: The increased risk of mortality among people with epilepsy is well documented; people with epilepsy are more likely than the general population to die as a result of an accident. Data about incidence of nonfatal accidents and associated factors are not so readily available, even though such accidents are more common than fatal injuries. We report the proportion of people who sustain various injuries during a seizure and the key variables predicting injury. Methods: Questionnaires were mailed to an unselected, community-based population of patients with epilepsy. The questionnaire included clinical and demographic details, previously validated scales of psychosocial well-being, and questions about seizure-related injuries. Results: Of patients who had had at least one seizure during the previous year, 24% sustained at least one head injury, 16% sustained a burn or scald, 10% a dental injury, and 6% some other fracture. Seizure type, seizure severity, and seizure frequency were key predictors of having sustained at least one of these four seizure-related injuries. Key predictors of budscald were seizure severity, seizure frequency and sex; those of head injury were seizure severity and type; that of dental injury was seizure severity; and those of some other fracture were seizure severity, duration of epilepsy, and three or more drug-related adverse effects. Conclusions: These data help identify significant risk factors associated with seizure-related injuries and so facilitate sensible patient counseling about how the risks of such injuries can be minimized. Key Words: Epilepsy-Accidents-Head injury-Dental injury-Burns.

The representational capacity of the distributed encoding of information provided by populations of neurons in primate temporal visual cortex

Abstract: It has been shown that it is possible to read, from the firing rates of just a small population of neurons, the code that is used in the macaque temporal lobe visual cortex to distinguish between different faces being looked at. To analyse the information provided by populations of single neurons in the primate temporal cortical visual areas, the responses of a population of 14 neurons to 20 visual stimuli were analysed in a macaque performing a visual fixation task. The population of neurons analysed responded primarily to faces, and the stimuli utilised were all human and monkey faces. Each neuron had its own response profile to the different members of the stimulus set. The mean response of each neuron to each stimulus in the set was calculated from a fraction of the ten trials of data available for every stimulus. From the remaining data, it was possible to calculate, for any population response vector, the relative likelihoods that it had been elicited by each of the stimuli in the set. By comparison with the stimuli actually shown, the mean percentage correct identification was computed and also the mean information about the stimuli, in bits, that the population of neurons carried on a single trial. When the decoding algorithm used for this calculation approximated an optimal, Bayesian estimate of the relative likelihoods, the percentage correct increased from 14 correct (chance was 5 correct) with one neuron to 67 with 14 neurons. The information conveyed by the population of neurons increased approximately linearly from 0.33 bits with one neuron to 2.77 bits with 14 neurons. This leads to the important conclusion that the number of stimuli that can be encoded by a population of neurons in this part of the visual system increases approximately exponentially as the number of cells in the sample increases (in that the log of the number of stimuli increases almost linearly). This is in contrast to a local encoding scheme (of 'grandmother' cells), in which the number of stimuli encoded increases linearly with the number of cells in the sample. Thus one of the potentially important properties of distributed representations, an exponential increase in the number of stimuli that can be represented, has been demonstrated in the brain with this population of neurons. When the algorithm used for estimating stimulus likelihood was as simple as could be easily implemented by neurons receiving the population's output (based on just the dot product between the population response vector and each mean response vector), it was still found that the 14-neuron population produced 66 correct guesses and conveyed 2.30 bits of information, or 83 of the information that could be extracted with the nearly optimal procedure. It was also shown that, although there was some redundancy in the representation (with each neuron contributing to the information carried by the whole population 60 of the information it carried alone, rather than 100), this is due to the fact that the number of stimuli in the set was limited (it was 20). The data are consistent with minimal redundancy for sufficiently large and diverse sets of stimuli. The implication for brain connectivity of the distributed encoding scheme, which was demonstrated here in the case of faces, is that a neuron can receive a great deal of information about what is encoded by a large population of neurons if it is able to receive its inputs from a random subset of these neurons, even of limited numbers (e.g. hundreds).

Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids

Abstract: Mitochondrial DNA (mtDNA) is the only extrachromosomal DNA in humans. It is a small (16.5kb) genome which encodes 13 essential peptides of the respiratory chain, two rRNAs and 22 tRNAs. Defects of this genome are now recognized as important causes of disease and may take the form of point mutations or rearrangements1–3. There is no effective treatment for patients with mtDNA mutations4. In the majority of patients with mtDNA defects, both mutant and wild-type molecules are present in the same cell — a phenomenon known as intracellular heteroplasmy. In addition, in the presence of heteroplasmy there is a threshold whereby a certain level of mutant mtDNA is necessary before the disease becomes biochemically and clinically apparent5–7. Based on the presence of heteroplasmy and the recessive nature of these mutations, we believe it will be possible to treat patients by selectively inhibiting the replication of the mutant mtDNA, thereby allowing propagation of only the wild-type molecule. To confirm the validity of such an approach we synthesized peptide nucleic acids (PNAs) complementary to human mtDNA templates containing a deletion breakpoint or single base mutation, both mutatins well documented to cause disease. Using an in vitro replication run-off assay under physiological conditions, the antigenomic PNAs specifically inhibited replication of mutant but not wild-type mtDNA templates. Furthermore, we have shown uptake of these PNAs into cultured human myoblasts. We believe that we have therefore established the potential value of antigenomic PNA therapy for patients with heteroplasmic mtDNA disorders.

Correction of acidosis in hemodialysis decreases whole-body protein degradation.

Abstract: Correction of acidosis in hemodialysis (HD) decreases protein degradation. The effect of the correction of chronic metabolic acidosis in chronic renal failure patients treated with HD was determined from the kinetics of infused L-[1-(13)C]leucine. Six HD patients were studied before (acid) and after (bicarbonate) correction of acidosis (pH: acid 7.36 +/- 0.01, bicarbonate 7.40 +/- 0.01, P

Incorporation of Antibacterial Monomer MDPB into Dentin Primer

Abstract: The polymerizable monomer methacryloyloxydodecylpyridinium bromide (MDPB) shows antibacterial activity when immobilized in a resin-based material. In this study, the antibacterial effect of a dentin primer incorporating MDPB was investigated. The influence of incorporation of MDPB on bond strength to dentin and on the curing performance of the adhesive system was also evaluated. Experimental primers were prepared by addition of MDPB into a proprietary primer at 1, 2, or 5%. Antibacterial effects of experimental primers were compared with those of control primer and two other proprietary primers by an agar disc-diffusion method and bactericidal activity test. Experimental primers produced greater inhibition zones against Streptococcus mutans, Actinomyces viscosus, and Lactobacillus casei than any of three proprietary primers, and inhibition increased as the concentration of MDPB was increased. Bactericidal activity of MDPB-containing primers against Streptococcus mutans was greater than those of the other three primers, with incorporation of MDPB at 5% showing complete killing of bacteria after 30 s contact. No decrease in tensile bond strength was observed for materials containing MDPB. On the contrary, the primer incorporating 1 and 2% MDPB showed higher bond strength than all the others, including the control (p 0.05). These results indicate that incorporation of the antibacterial monomer MDPB enhanced the antibacterial effect of a proprietary dentin primer before curing, and had no adverse influence on bond strength to dentin and curing of the adhesive system.

Calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors: A molecular determinant of selective vulnerability in amyotrophic lateral sclerosis

Abstract: The cause of the selective degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) remains unexplained. One potential pathogenetic mechanism is chronic toxicity due to disturbances of the glutamatergic neurotransmitter system, mediated via alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive glutamate receptors. Functional AMPA receptors consist of various combinations of four subunits (designated GluR1-4). The GluR2 subunit is functionally dominant and renders AMPA receptors impermeable to calcium. Most native AMPA receptors in the mammalian central nervous system (CNS) contain the GluR2 subunit and are calcium impermeable. We have investigated the composition of AMPA receptors expressed on normal human spinal motor neurons by in situ hybridization to determine their likely subunit stoichiometry. Highly significant levels of mRNA were detected for the GluR1, GluR3, and GluR4 subunits. However, GluR2 subunit mRNA was not detectable in this cell group. The absence of detectable GluR2 mRNA in normal human spinal motor neurons predicts that they express calcium-permeable AMPA receptors unlike most neuronal groups in the human CNS. Expression of atypical calcium-permeable AMPA receptors by human motor neurons provides a possible mechanism whereby disturbances of glutamate neurotransmission in ALS may selectively injure this cell group.

Factors Influencing Compliance With Antiepileptic Drug Regimes

Abstract: Failure to comply with drug regimes is prevalent amongst patients with epilepsy and the consequence of this is often an increased risk of further seizures. This paper describes the level of, and influences upon, non-compliance with antiepileptic drug (AED) treatment. A postal questionnaire was sent to an unselected, community-based population of patients with epilepsy. This instrument included questions about patients' AED treatment, any related side-effects, and AED-taking behaviour. Univariate analysis showed that factors associated with compliance were patient age, how important patients felt it was to take drugs as prescribed, whether patients reported feelings of stigma, whether on mono- or polytherapy, whether they were experiencing any side-effects because of AEDs, whether patients had a regular arrangement to see their GP about epilepsy and how easy they found their GP to talk to. Multivariate analysis showed that the strongest predictors of non-compliance were feeling it was not very or not at all important to take AEDs as prescribed, being a teenager, being aged under 60 and being on monotherapy. Further implementation of educational programmes for people with epilepsy would help to improve levels of compliance thereby reducing the risk of unnecessary seizures.