Showing papers by "Medical Research Council published in 1988"

From Neuropsychology to Mental Structure

Abstract: As a cognitive neuropsychologist, Tim Shallice considers the general question of what can be learned about the operation of the normal cognitive system from the study of the cognitive difficulties arising from neurological damage and disease. He distinguishes two types of theories of normal function - primarily modular and primary non-modular - and argues that the problems of making valid inferences about normal function from studies of brain-damaged subjects are more severe for the latter. He first analyzes five well-researched areas in which some modularity can be assumed: short-term memory, reading, writing, visual perception, and the relation between input and output language processing. His aim is to introduce the methods about normal function mirror ones derived directly from studies of normal subjects and indeed at times preceded them. He then more theoretically examines these inferences, from group studies and individual case studies to modular and non-modular systems. Finally, he considers five areas where theories of normal function are relatively undeveloped and neuropsychology provides counterintuitive phenomena and guides to theory-building: the organization of semantic systems, visual attention, concentration and will, episodic memory, and consciousness.

Cognitive Psychology and Emotional Disorders

Abstract: The Cognitive Approach to Emotional Disorders. The Information-processing Paradigm. Cognitive Impairments. Attention to Emotional Stimuli, I: Causes and Correlates. Attention to Emotional Stimuli, II: Mechanisms Underlying Bias. Memory. Thoughts and Images. Judgement. Schemata. Nonconscious Processing. Theoretical Overview. References. Indexes.

The role of strong syllables in segmentation for lexical access

Abstract: A model of speech segmentation in a stress language is proposed, according to which the occurrence of a strong syllable triggers segmentation of the speech signal, whereas occurrence of a weak syllable does not trigger segmentation. We report experiments in which listeners detected words embedded in nonsense bisyllables more slowly when the bisyllable had two strong syllables than when it had a strong and a weak syllable; mint was detected more slowly in mintayve than in minlesh. According to our proposed model, this result is an effect of segmentation: When the second syllable is strong, it is segmented from the first syllable, and successful detection of the embedded word therefore requires assembly of speech material across a segmentation position. Speech recognition models involving phonemic or syllabic receding, or based on strictly left-toright processes, do not predict this result. It is argued that segmentation at strong syllables in continuous speech recognition serves the purpose of detecting the most efficient locations at which to initiate lexical access.

Cognitive Vulnerability to Persistent Depression

Abstract: The account of cognitive vulnerability to depression offered by Beck's cognitive model is summarised. As this account currently lacks consistent empirical support, an alternative, related, account is presented. This proposes that, once a person is initially depressed, an important factor that determines whether their depression remains mild or transient, or becomes more severe and persistent, is the nature of the negative cognitive processes and constructs that become active and accessible in the depressed state. These interact with the nature of environmental difficulties, available social support, and biological factors, to determine whether a depression-maintaining cognitive-affective vicious cycle will be set up. Results from studies specifically designed to test predictions from this account have yielded positive results. Findings consistent with the hypothesis have also been obtained in other prospective studies which have shown that cognitive measures, administered in the depressed state, ...

Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia.

Abstract: There has been considerable debate over whether asymptomatic neonatal hypoglycaemia results in neurological damage. In a detailed multicentre study of 661 preterm infants hypoglycaemia was found to be common. Moderate hypoglycaemia (plasma glucose concentration less than 2.6 mmol/l) occurred in 433 of the infants and in 104 was found on three to 30 separate days. There was considerable variation among the centres, implying differences in decisions to intervene. The number of days on which moderate hypoglycaemia occurred was strongly related to reduced mental and motor development scores at 18 months (corrected age), even after adjustment for a wide range of factors known to influence development. When hypoglycaemia was recorded on five or more separate days adjusted mental and motor developmental scores at 18 months (corrected age) were significantly reduced by 14 and 13 points respectively, and the incidence of neurodevelopmental impairment (cerebral palsy or developmental delay) was increased by a factor of 3.5 (95% confidence interval 1.3 to 9.4). These data suggest that, contrary to general belief, moderate hypoglycaemia may have serious neurodevelopmental consequences, and reappraisal of current management is urgently required.

The mas oncogene encodes an angiotensin receptor

Abstract: The class of receptors coupled to GTP-binding proteins share a conserved structural motif which is described as a 'seven-transmembrane segment'1 following the prediction that these hydrophobic segments form membrane-spanning α-helices. Identified examples include the mammalian opsins2, α1-, α2-, β1- and β2-adrenergic receptors3, the muscarinic receptor family4,5, the 5-HT1C-receptor6, and the substance-K receptor7. In addition, two mammalian genes have been identified that code for predicted gene products with sequence similarity to these receptors, but whose ligand specificity is unknown namely, G21 (ref. 8) and the mas oncogene9. The mas oncogene shows the greatest sequence similarity to the substance-K receptor, and on this basis it was predicted that it would encode a peptide receptor with mitogenic activity which would act through the inositol lipid signalling pathways10,11. The mas oncogene product was transiently expressed in Xenopus oocytes, and stably expressed in a transfected mammalian cell line. The results demonstrate that the mas gene product is a functional angiotensin receptor.

Fitting Smoothed Centile Curves to Reference Data

Abstract: Methode d'ajustement de courbes centiles lissees a des donnees de reference, basee sur la famille de transformation de Box et Cox

Spatial and temporal distribution of energy

Abstract: Studies of the spatial and temporal distribution of microscopic radiation doses lead to potentially important questions regarding conventional approaches to radiation protection. The short ranges of alpha-particle and Auger-electron emissions from radionuclides lead to uncertainties in assessing their hazards. The conventional extrapolations from intermediate doses to low doses and dose rates are questioned by observed dose-rate effects in the so-called "initial slope," by the total lack of data for single tracks in cells and by the possibility of multiple-cell effects. At all subcellular levels, even down to DNA, high linear-energy-transfer (LET) radiations can produce unique initial damage, different from that possible with low-LET radiations, and therefore may even, in principle, produce unique final biological effects. This questions simple extrapolations from low- to high-LET radiations and the application of universal quality factors to diverse effects. Further understanding of these questions could lead, in future, to substantial increases or decreases in estimations of risk.

Use of a three-stage continuous culture system to study the effect of mucin on dissimilatory sulfate reduction and methanogenesis by mixed populations of human gut bacteria.

Abstract: A mixed culture of human fecal bacteria was grown for 120 days in a three-stage continuous culture system. To reproduce some of the nutritional and pH characteristics of the large gut, each vessel had a different operating volume (0.3, 0.5, and 0.8 liter) and pH (6.0, 6.5, and 7.0). A mixture of polysaccharides and proteins was used as carbon and nitrogen sources. Measurements of H2, CH4, S2-, sulfate reduction rates, sulfate-reducing bacteria (SRB), and volatile fatty acids were made throughout the experiment. After 48 days of running, porcine gastric mucin (5.8 g/day) was independently fed to vessel 1 of the multichamber system. The mucin was extensively degraded as evidenced by the stimulation of volatile fatty acid production. In the absence of mucin, sulfate-reducing activity was comparatively insignificant and methanogenesis was the major route for the disposal of electrons. The reverse occurred upon the addition of mucin; sulfate reduction predominated and methanogenesis was completely inhibited. This was attributed to release of sulfate from the mucin which enabled SRB to outcompete methanogenic bacteria for H2. SRB stimulated by mucin were acetate-utilizing Desulfobacter spp., lactate- and H2-utilizing Desulfovibrio spp., and propionate-utilizing Desulfobulbus spp. When the mucin pump was switched off, the multichamber system reverted to a state close to its original equilibrium. These data provide further evidence that sulfated polysaccharides such as mucin may be a source of sulfate for SRB in the human large gut.

Emotional Disturbance and the Specificity of Autobiographical Memory

Abstract: Williams and Broadbent (1986) found that patients who had recently attempted suicide showed not only biased latencies to retrieve autobiographical memories, but were more over-general in their responses, especially in response to positive cues. That is, they were likely to give memories referring to people, places, or activities where a time period was not referred to or was greater than one day. Further research is reported which replicates and extends the phenomenon of over-general recall. First, a further sample of overdose patients shows the same tendency to give general rather than specific memories. Secondly, ex-patients who have taken an overdose between 3 and 14 months prior to the testing occasion remain significantly more over-general in their memories than normal controls, but show a normal pattern of being relatively more specific in response to positive than to negative cue words. The phenomenon is discussed in relation to a “descriptions” framework which suggests that to encode or r...

Occurrence of sulphate-reducing bacteria in human faeces and the relationship of dissimilatory sulphate reduction to methanogenesis in the large gut.

Abstract: Sulphate-reducing bacteria (SRB) were enumerated in 40 faecal samples obtained from two different human populations in the United Kingdom and rural South Africa. Species able to metabolize acetate, lactate, propionate, butyrate, H2/CO2, succinate, pyruvate, valerate, ethanol and a glutamate/serine/alanine mixture were found in faeces from both populations. Although a variety of nutritionally and morphologically distinct species of SRB belonging to the genera Desulfotomaculum, Desulfobacter, Desulfomonas and Desulfobulbus were identified, Desulfovibrio types always predominated. Significant numbers of SRB were present only in faecal samples from subjects whose breath methane excretion was low or undetectable. Reduced or absent methanogenesis in the presence of SRB was confirmed in fermentation studies with faecal slurries. Fourteen of 20 (70%) British faecal samples contained SRB and the remainder produced methane. The reverse was the case with 20 rural black South Africans, where only three (15%) of the samples had significant levels of SRB; the remaining 85% produced methane. These results suggest that to a large extent, dissimilatory sulphate reduction and methanogenesis are mutually exclusive in the human large gut.

The mechanism of chromosomal translocation t(11;14) involving the T-cell receptor C delta locus on human chromosome 14q11 and a transcribed region of chromosome 11p15.

Abstract: A chromosomal translocation t(11;14) (p15;q11) is described in a human acute T-cell leukaemia of immature phenotype (CD3-, CD4-, CD8-). The translocation occurs at a T-cell receptor joining J delta segment, 12 kb upstream of the constant C delta gene and 98 kb upstream of the C alpha gene at chromosome band 14q11. Nucleotide sequencing shows that both J delta and C delta are very conserved between mouse and man. The region of chromosome 11 involved in the translocation is transcriptionally active and produces a 4-kb mRNA. The DNA sequence at the chromosome 11 junction shows a perfect match to a recombinase signal sequence implying that this translocation occurred by recombinase error. The occurrence of the translocation breakpoint at the C delta locus, normally rearranged in immature T cells, and the structure of the translocation junctions suggests that the translocation occurred during an attempt at normal rearrangement of the J delta segment in an early thymocyte.

Carbohydrate structures of the human-immunodeficiency-virus (HIV) recombinant envelope glycoprotein gp120 produced in Chinese-hamster ovary cells.

Abstract: The present paper describes the structures of the N-linked oligosaccharides of the human-immunodeficiency-virus (HIV) envelope glycoprotein gp120 (cloned from the HTLV-III B isolate and expressed as a secreted fusion protein after transfection of Chinese-hamster ovary cells), which is known to bind with high affinity to human T4-lymphocytes. Oligosaccharides were released from peptide by hydrazinolysis, fractionated by paper electrophoresis, high-performance lectin-affinity chromatography and Bio-Gel P-4 column chromatography, and their structures determined by sequential exoglycosidase digestions in conjunction with methylation analysis. The glycoprotein was found to be unique in its diversity of oligosaccharide structures. These include high-mannose type and hybrid type, as well as four categories of complex-type chains: mono-, bi-, tri- and tetra-antennary, with or without N-acetyl-lactosamine repeats, and with or without a core-region fucose residue. Among the sialidase-treated oligosaccharides, no less than 29 structures were identified as follows: (formula; see text) where G is galactose, GN is N-acetylglucosamine, M is mannose, F is fucose, and '+/- ' means that residues are present in a proportion of chains. The actual number of oligosaccharide structures is much greater, since before desialylation there was evidence that, among the hybrid and complex-type chains, all but 6% contained sialic acid at the C-3 position of terminal galactose residues, and partially sialylated forms of the bi- and multi-antennary chains were present. Detailed evidence for the proposed oligosaccharide sequences will be published as a supplementary paper [T. Mizuochi, M. W. Spellman, M. Larkin, J. Solomon, L. J. Basa & T. Feizi (1988) Biomed. Chromatogr., in the press].

Contribution of the microflora to proteolysis in the human large intestine

Abstract: Protease activities in human ileal effluent were approximately 20-fold greater than in normal faeces. Comparative studies with faeces from a person who did not have a pancreas suggested that a substantial proportion of the proteolytic activity in normal faeces was of bacterial origin. Thimerosal, iodoacetate, EDTA and cysteine significantly inhibited proteolysis in faeces, but not in small intestinal contents, showing that cysteine and metalloproteases were produced by bacteria in the large gut. These results, together with results from studies using p-nitroanilide substrates, demonstrated that faecal proteolysis was both qualitatively and quantitatively different from that in the small intestine. Studies with pure cultures of proteolytic gut bacteria indicated that the cell-bound proteases of Bacteroides fragilis-type organisms were likely to contribute significantly towards proteolytic activity associated with the washed cell fraction and washed particulate fraction of faeces. Extracellular proteases were formed by Streptococcus faecalis ST6, Propionibacterium acnes P6, Clostridium perfringens C16, Cl. bifermentans C21 and Cl. sporogenes C25. Inhibition results suggested that these bacteria, and similar organisms, may be partly responsible for the extracellular proteolytic activity found in the cell-free supernatant fraction of faeces.

Criteria for estimating likelihood of difficulty of endotracheal intubation with the Macintosh laryngoscope.

Abstract: Many anatomical factors in difficult intubation at direct laryngoscopy have been evaluated. Lateral radiographs were taken of nineteen patients in whom tracheal intubation proved particularly difficult, and fourteen patients whose intubation was reasonably straightforward. Stepwise discriminant analysis was used to select the best measurements for distinguishing between the difficult and straightforward groups. The variables which together are most reliable in predicting likely difficulty in intubation are reduced atlanto-occipital extension, reduced mandibular space, and lastly, increased antero-posterior thickness of the tongue. A formula and graph have been derived to relate these variables with likelihood of difficulty, and a method has been described of applying this information at the bedside, without using X-ray examination, to estimate the likelihood of difficulty in intubating a new patient. Eighteen months' experience of the application of this clinical evaluation have so far found it reliable.

Permethrin-treated bed nets (mosquito nets) prevent malaria in Gambian children

Abstract: The incidence of clinical attacks of malaria was significantly less in Gambian children aged 1-9 years who slept in villages where all the bed nets (mosquito nets) were treated with permethrin than in children who slept in control villages with placebo-treated nets. Significant differences in changes in spleen size and in packed cell volume were also observed between the 2 groups during the course of a rainy season. No side effect was noted. Treatment of bed nets with insecticide is a form of malaria control that is well suited to community participation and can readily be incorporated into primary health care programmes. Insecticide-treated nets may be more effective in areas of seasonal or low intensity transmission than in areas with heavy perennial challenge.

Competition for hydrogen between sulphate-reducing bacteria and methanogenic bacteria from the human large intestine.

Abstract: Sulphate-reducing activity in human faecal slurries was followed by measuring sulphide production. Sulphate-reducing bacteria (SRB) were found to outcompete methanogenic bacteria (MB) for the mutual substrate hydrogen in faecal slurries from methane- and non-methane-producing individuals mixed together. When molybdate (20 mmol/l) was added to these slurries, sulphate reduction was inhibited and methanogenesis became the major route of electron disposal. Sulphide production was stimulated by the addition of 20 mmol/l sulphate in non-methanogenic but not in methanogenic slurries. In methanogenic slurries that contained the methanogen inhibitor 2-bromoethanesulphonic acid (BES), hydrogen accumulated whilst sulphide levels were unaffected, confirming the absence of SRB in methanogenic faeces. The addition of nitrate (10 mmol/l) to faecal slurries completely inhibited methanogenesis but only slightly reduced sulphate reduction. The sulphated mucopolysaccharides, chondroitin sulphate and mucin, strongly stimulated sulphide production in non-methanogenic faecal slurries only, suggesting that these substances may be a potential source of sulphate in the large gut.

Relation between velocity and curvature in movement: equivalence and divergence between a power law and a minimum-jerk model.

Abstract: Unconstrained hand movements typically display a decrease in hand speed around highly curved sections of a trajectory It has been suggested that this relation between tangential velocity and radius of curvature conforms to a one-third power law We demonstrate that a one-third power law can be explained by models taking account of trajectory costs such as a minimum-jerk model Data were analyzed from 6 subjects performing elliptical drawing movements of varying eccentricities Conformity to the one-third power law in the average was obtained but is shown to be artifactual It is demonstrated that asymmetric velocity profiles may result in consistent departures from a one-third power law but that such differences may be masked by inappropriate analysis procedures We introduce a modification to the original minimum-jerk model by replacing the assumption of a Newtonian point-mass with a visco-elastic body Simulations with the modified model identify a basis for asymmetry of velocity profiles and thereby predict departures from a one-third law commensurate with the empirical findings

Becoming a skilled reader

Abstract: 1. Introduction 2. The Skilled Adult Reader 3. Language Development beyond the age of five 4. Learning to Read Words 5. Learning to understand text 6. Educational Implications Afterword Bibliography Name Index Subject Index

Serial evaluation of vasopressin release and thirst in human pregnancy. Role of human chorionic gonadotrophin in the osmoregulatory changes of gestation.

Abstract: Serial studies were designed to characterized changes in osmoregulation throughout gestation. Eight women underwent a 2-h infusion of hypertonic saline before conception, during gestational weeks 5-8, 10-12, and 28-33, and then 10-12 wk postpartum. Basal plasma osmolality (Posmol) was already significantly decreased by 5-8 wk (P less than 0.001) and remained 10 mosmol.kg-1 below nonpregnant values throughout pregnancy. The apparent threshold for AVP release (defined as the abscissal intercept of the regression line relating plasma AVP [PAVP] to Posmol) was also decreased significantly throughout gestation, as was the osmotic threshold for thirst (derived from analogue scales relating desire to drink to Posmol). The decrement in osmotic thirst threshold appeared to precede that for AVP release, and consistent with this 24-h urine volumes were significantly greater at 5-8 wk gestation (P less than 0.05). The slopes of each regression equation defining PAVP vs. Posmol (whose r values ranged from 0.79 to 0.99), very reproducible before and after pregnancy, were similar at 5-8 and 10-12 wk, but were markedly reduced in the third trimester (P less than 0.001). These volunteers had randomly undergone an additional infusion before conception (both tests in the luteal phase of the menstrual cycle) when 10,000 IU of human chorionic gonadotrophin (hCG) had been given intramuscularly over a 5-d period. Serum hCG values between 0.2 and 3.3 U.ml-1 were lower than usually seen in pregnancy, but the osmotic thresholds for AVP release and thirst decreased by 3 and 4 mosmol.kg-1, respectively (P less than 0.05). Finally we studied a patient with a molar pregnancy in whom thresholds for hormone release and thirst were both decreased to values resembling normal gestation and remained so for approximately 6 wk postevacuation, only normalizing when hCG had virtually disappeared from her serum. In contrast, thresholds increased within the first two puerperal weeks in two women with normal pregnancies. These data demonstrate (a) osmotic thresholds for both AVP release and thirst decrease within the very first gestational weeks; (b) increment in PAVP per unit increase in Posmol is reduced late in gestation; and (c) hCG may be involved in the osmoregulatory changes of pregnancy.

Physical and Biochemical Studies of Streptococcus mutans Sediments Suggest New Factors Linking the Cariogenicity of Plaque with its Extracellular Polysaccharide Content

Abstract: Cultures of Streptococcus mutans MFe28 (serotype h) were grown with differing extracellular polysaccharide (EPS) content. Biochemical and physicochemical characteristics considered relevant to caries were measured. Acid production parameters measured in a pH-stat were: Vm = 0.76 ± 0.14 μmol/g/sec (wet weight); apparent Km (acid production) = 100 μmol/L; molar yield = 1.97 ± 0.25 mol acid/mol glucose. Acid anion inhibition of acid production was also noted. Buffering by the pure washed bacterial residue required approx. 112 μmol of baselg (wet weight) of residue to change the pH from 4 to 6.5, and this dropped almost to zero as the EPS content increased to 100%. Diffusion coefficients (D) in the residues were independent of EPS content over a wide range. When the effusion method was used, De (glucose) and De (acetate) were (3.26 ± 0.6) and (5.05 ± 0.8) x 10-6 cm2lsec, respectively. The extracellular fluid fraction, measured by inulin exclusion, increased from 0.33 for the pure bacteria to 0.78 for the pure...

Molecular pathology of scrapie-associated fibril protein (PrP) in mouse brain affected by the ME7 strain of scrapie.

Abstract: Scrapie-associated fibrils (SAF) are disease-specific structures found in extracts of the brains of animals affected with scrapie. These structures are pathological aggregates of a normal host protein (PrP). Abnormal post-translational modification of PrP has been suggested to explain its aberrant properties in scrapie-affected brains and although there is a form of PrP in SAF indistinguishable in size from the protein in uninfected brain, lower-molecular-mass variants of PrP are also found in SAF fractions. We report the characterisation of the multiple forms of PrP found in SAF fractions purified from mouse brain affected by the ME7 strain of scrapie. The quantitively major forms of PrP in SAF prepared without the use of proteinase K have the amino-terminal sequence Lys-Lys-Arg-Pro-Lys-Pro-Gly-Gly-, identical to that predicted for the amino-terminus of normal mouse brain PrP. However N-terminal cleavage of some PrP does occur in vivo within a domain of repetitive sequences at sites similar to but distinct from those cut by proteinase K in vitro. This suggests the conformation of the protein in aggregates in vivo does not differ extensively from that in detergent-treated SAF in vitro. We conclude that the size diversity of PrP in SAF is only partly due to N-terminal proteolysis and is independent of the proteolysis that occurs if proteinase K is used in the purification of SAF. Apart from proteolytic changes in the structure of PrP, we found a novel, as yet unidentified, amino-acid derivative of the arginine residue at position 3 in mouse PrP, which may predispose PrP to form SAF.