Showing papers by "Medical Research Council published in 1990"

Psychosocial Resilience and Protective Mechanisms

Abstract: The concept of mechanisms that protect people against the psychological risks associated with adversity is discussed in relation to four main processes: reduction of risk impact, reduction of negative chain reactions, establishment and maintenance of self-esteem and self-efficacy, and opening up of opportunities. The mechanisms operating at key turning points in people's lives must be given special attention.

Human memory : theory and practice

Abstract: Why Do We Need Memory? Perceiving and Remembering. How Many Kinds of Memory? The Evidence for STM. The Role of Memory in Cognition - Working Memory. Visual Memory and the Visuo-spatial Sketchpad. Attention and the Control of Memory. When Practice Makes Perfect. Organizing and Learning. Acquiring Habits. When Memory Fails. Retrieval. Recollection and Autobiographical Memory. Where Next? Connectionism Rides Again. Knowledge. Memory, Emotion and Cognition. Understanding Amnesia. Treating Memory Problems. Consciousness. Implicit Knowledge and Learning. Implicit Memory and Recollection.

SCAN. Schedules for Clinical Assessment in Neuropsychiatry.

Abstract: After more than 12 years of development, the ninth edition of the Present State Examination (PSE-9) was published, together with associated instruments and computer algorithm, in 1974. The system has now been expanded, in the framework of the World Health Organization/Alcohol, Drug Abuse, and Mental Health Administration Joint Project on Standardization of Diagnosis and Classification, and is being tested with the aim of developing a comprehensive procedure for clinical examination that is also capable of generating many of the categories of the International Classification of Diseases, 10th edition, and the Diagnostic and Statistical Manual of Mental Disorders, revised third edition. The new system is known as SCAN (Schedules for Clinical Assessment in Neuropsychiatry). It includes the 10th edition of the PSE as one of its core schedules, preliminary tests of which have suggested that reliability is similar to that of PSE-9. SCAN is being field tested in 20 centers in 11 countries. A final version is expected to be available in January 1990.

Differing patterns of striatal 18F‐dopa uptake in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy

Abstract: Using positron emission tomography (PET), we studied regional striatal 18F-dopa uptake in 16 patients with L-dopa-responsive Parkinson's disease (PD), 18 patients with multiple system atrophy, and 10 patients with progressive supranuclear palsy. Results were compared with those of 30 age-matched normal volunteers. The patients with PD showed significantly reduced mean uptake of 18F-dopa in the caudate and putamen compared to controls, but while function in the posterior part of the putamen was severely impaired (45% of normal), function in the anterior part of the putamen and in the caudate was relatively spared (62% and 84% of normal). Mean 18F-dopa uptake in the posterior putamen was depressed to similar levels in all patients. Unlike patients with PD, the patients with progressive supranuclear palsy showed equally severe impairment of mean 18F-dopa uptake in the anterior and posterior putamen. Caudate 18F-dopa uptake was also significantly lower in patients with progressive supranuclear palsy than in patients with PD, being depressed to the same level as that in the putamen. Mean 18F-dopa uptake values in the anterior putamen and caudate in patients with multiple system atrophy lay between PD and progressive supranuclear palsy levels. Locomotor disability of individual patients with PD or multiple system atrophy correlated with decline in striatal 18F-dopa uptake, but this was not the case for the patients with progressive supranuclear palsy. We conclude that patients with PD have selective nigral pathological features with relative preservation of the dopaminergic function in the anterior putamen and caudate, whereas there is progressively more extensive nigral involvement in multiple system atrophy and progressive supranuclear palsy.(ABSTRACT TRUNCATED AT 250 WORDS)

Human protectin (CD59), an 18,000-20,000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers.

Abstract: Human cells are relatively resistant to lysis by the homologous complement system. Here we describe the mechanism of action of a recently discovered and widely distributed 18,000-20,000 molecular weight (MW) membrane glycoprotein (CD59), which appears to act as a major protective element against complement-mediated lysis (hence called protectin). When incorporated into heterologous erythrocyte membranes, protectin efficiently prevented cell lysis by human serum. Neutralization with antibody of the naturally occurring protectin on human erythrocytes or on nucleated K562 cells increased their susceptibility to lysis by homologous complement. During complement activation, protectin became incorporated into the membrane attack complex (MAC). By interacting with newly exposed regions in the C5b-8 complex and in aggregating C9 it limited the number of C9 molecules associating with the C5b-8 complex to a C8:C9 ratio of 1:1.5 instead of a normal average of 1:3.5. The results demonstrate directly that protectin is a powerful inhibitor of complement cytolysis and acts by inhibiting the C5b-8 catalysed insertion of C9 into the lipid bilayer.

Peak treadmill running velocity during the VO2 max test predicts running performance.

Abstract: Twenty specialist marathon runners and 23 specialist ultra‐marathon runners underwent maximal exercise testing to determine the relative value of maximum oxygen consumption (VO2max), peak treadmill running velocity, running velocity at the lactate turnpoint, VO2 at 16 km h‐1, % VO2max at 16 km h‐1, and running time in other races, for predicting performance in races of 10–90 km. Race time at 10 or 21.1 km was the best predictor of performance at 42.2 km in specialist marathon runners and at 42.2 and 90 km in specialist ultra‐marathon runners (r=0.91–0.97). Peak treadmill running velocity was the best laboratory‐measured predictor of performance (r = ‐ 0.88—0.94) at all distances in ultra‐marathon specialists and at all distances except 42.2 km in marathon specialists. Other predictive variables were running velocity at the lactate turnpoint (r= —0.80—0.92); % VO2max at 16 km h‐1 (r=0.76–0.90) and VO2max (r=0.55—0.86). Peak blood lactate concentrations (r=0.68–0.71) and VO2 at 16 km h‐1 (r=0.10–0....

Modeling the perception of concurrent vowels: vowels with different fundamental frequencies.

Abstract: If two vowels with different fundamental frequencies ( f0’s) are presented simultaneously and monaurally, listeners often hear two talkers producing different vowels on different pitches. This paper describes the evaluation of four computational models of the auditory and perceptual processes which may underlie this ability. Each model involves four stages: (i) frequency analysis using an ‘‘auditory’’ filter bank, (ii) determination of the pitches present in the stimulus, (iii) segregation of the competing speech sources by grouping energy associated with each pitch to create two derived spectral patterns, and (iv) classification of the derived spectral patterns to predict the probabilities of listeners’ vowel‐identification responses. The ‘‘place’’ models carry out the operations of pitch determination and spectral segregation by analyzing the distribution of rms levels across the channels of the filter bank. The ‘‘place–time’’ models carry out these operations by analyzing the periodicities in the wavef...

Leukemia Following Chemotherapy for Ovarian Cancer

Abstract: An international collaborative group of cancer registries and hospitals identified 114 cases of leukemia following ovarian cancer. We investigated the possible etiologic role of chemotherapy, radiotherapy, and other factors, using a case-control study design, with three controls matched to each case of leukemia. Chemotherapy alone was associated with a relative risk of 12 (95 percent confidence interval, 4.4 to 32), as compared with surgery alone, and patients treated with both chemotherapy and radiotherapy had a relative risk of 10 (95 percent confidence interval, 3.4 to 28). Radiotherapy alone did not produce a significant increase in risk as compared with surgery alone. The risk of leukemia was greatest four or five years after chemotherapy began, and the risk was elevated for at least eight years after the cessation of chemotherapy. The drugs cyclophosphamide, chlorambucil, melphalan, thiotepa, and treosulfan were independently associated with significantly increased risks of leukemia, as was the combination of doxorubicin hydrochloride and cisplatin. Chlorambucil and melphalan were the most leukemogenic drugs, followed by thiotepa; cyclophosphamide and treosulfan were the weakest leukemogens, and the effect per gram was substantially lower at high doses than at lower doses. The extent to which the relative risks of leukemia are offset by differences in chemotherapeutic effectiveness is not known.

Visual control of balance in cerebellar and parkinsonian syndromes.

Abstract: The role of vision in the control of balance in patients with Parkinson's disease (PD) and cerebellar disease (CD) was studied by measuring body sway with eyes open, closed, and in response to visual stimuli generated by discrete lateral displacements of a moveable room which enclosed the subjects. In response to room movement, normal subjects swayed by an amount intermediate between sway with eyes open and eyes closed and their response attenuated on repetition of the movement, a process depending on shifting from predominantly visual to proprioceptive control. CD patients swayed more than controls with eyes open or closed and as shown by high ‘Romberg quotients’ (eyes closed/eyes open sway ratio) were able to use visual information to control much of their unsteadiness. CD patients had a normal attenuation of response to repetition of the room movement. PD patients had normal sway with eyes open or closed but their responses to room movement were abnormal, being proportionately larger and failing to attenuate during successive stimuli. The results indicate that cerebellar lesions seem largely to spare the visuopostural loop and also spare the ability to shift from a visual to a proprioceptive control of postural sway. In contrast, the findings in PD suggest that the visuopostural loop is hyperactive and that its influence cannot easily be de-emphasized when visual information is misleading. The latter finding suggests that basal ganglia participation in posture is concerned with the reweighting of the various sensorimotor loops controlling posture in the process of adapting to novel situations.

Linkage of a nasopharyngeal carcinoma susceptibility locus to the HLA region.

Abstract: The frequency of nasopharyngeal carcinoma is nearly 100-fold higher in southern Chinese than in most European populations. Earlier studies have suggested that an increased risk of nasopharyngeal carcinoma is associated with specific haplotypes in the HLA region: relative risks slightly over twofold were found for haplotypes A2, Bw46 and the antigen B17. We now report a linkage study based on affected sib pairs which suggests that a gene closely linked to the HLA locus confers a greatly increased risk of nasopharyngeal carcinoma. The maximum likelihood estimate is of a relative risk of approximately 21. The relationship between this suspected disease susceptibility gene (or genes) and known viral and environmental aetiological factors remains to be elucidated.

Physiology and ecology of the sulphate-reducing bacteria.

Abstract: All plants, animals and bacteria require sulphur for the synthesis of proteins. The biological transformation of sulphur in natural environments is a nutrient cycling process comprising both aerobic and anaerobic components (Postgate 1984). In its highest oxidation state, sulphur exists as the sulphate ion (SO:-) which is reduced to sulphide (Sz-) by most bacteria, fungi and plants before incorporation into amino acids. This process is termed assimilatory sulphate reduction and is purely a biosynthetic process. However, any sulphur compound with an oxidation state above that of sulphide ( 2) can potentially function as an electron acceptor for the oxidation of carbon substrates by biological processes (Goldhaber & Kaplan 1974). For example, during dissimilatory sulphate reduction, the sulphate ion is utilized as an oxidant for the degradation of organic material. An equivalent amount of sulphide is formed per mole of sulphate reduced (Berner 1974): 2CH,O + SO:-+ H,S + 2HCO;

The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott-Aldrich syndrome.

Abstract: The X chromosome-linked scurfy (sf) mutant of the mouse is recognized by the scaliness of the skin from which the name is derived and results in death of affected males at about 3-4 weeks of age. Consideration of known man-mouse homologies of the X chromosome prompted hematological studies, which have shown that the blood is highly abnormal. The platelet and erythrocyte counts are both reduced and become progressively lower relative to normal as the disease progresses. There is gastrointestinal bleeding, and most animals appear to die of severe anemia. By contrast, the leukocyte count is consistently raised. Some animals showed signs of infection but it is not yet clear whether there is immunodeficiency. Other features include the scaly skin and apparently reduced lateral growth of the skin, conjunctivitis, and diarrhea in some animals. The mutant resembles Wiskott-Aldrich syndrome in man, which is characterized by thrombocytopenia, eczema, diarrhea, and immunodeficiency. The loci of the human and mouse genes lie in homologous segments of the X chromosome, although apparently in somewhat different positions relative to other gene loci. Scurfy differs from Wiskott-Aldrich syndrome in that scurfy males are consistently hypogonadal.

Influence of cigarette smoking on the levels of DNA adducts in human bronchial epithelium and white blood cells.

Abstract: The presence of carcinogen-DNA adducts in human tissues is evidence of exposure to carcinogens and may be an indicator of cancer risk. DNA was isolated from non-tumorous bronchial tissue of 37 cigarette smokers, 8 former smokers and 8 non-smokers and analyzed for the presence of aromatic and/or hydrophobic DNA adducts in the 32P-post-labelling assay. Adducts were detected as bands of radioactive material when 5'-32P-labelled deoxyribonucleoside 3',5'-bisphosphates were chromatographed on polyethyleneimine-cellulose tlc plates, and the patterns indicated the formation of adducts by a large number of compounds. Adduct levels detected in DNA from non-smokers, former smokers and current smokers were 3.45 +/- 1.62, 3.93 +/- 1.92 and 5.53 +/- 2.13 adducts/10(8) nucleotides, respectively. The differences in adduct levels between smokers and former and non-smokers were statistically significant (p less than 0.01); and among the smokers, significant correlations were found between adduct levels and both daily cigarette consumption and total cigarette consumption (daily consumption X number of years smoked). DNA was also isolated from the peripheral-blood leukocytes of 31 heavy smokers (greater than 20 cigarettes/day) and 20 non-smokers and analyzed by 32P-post-labelling. Adduct levels in the smokers' samples were not significantly different from levels in the non-smokers' samples (2.53 +/- 1.31 and 2.12 +/- 1.44 adducts/10(8) nucleotides, respectively). Thus, evidence for carcinogen exposure was found in human bronchial epithelium, a target tissue for tobacco-induced tumour formation, but not in peripheral-blood cells, indicating possible limitations in the use of the latter as a surrogate, non-target tissue source of DNA for monitoring human exposure to inhaled carcinogens.

Herpes simplex virus type 1 UL28 gene product is important for the formation of mature capsids.

Abstract: The herpes simplex virus type 1 temperature-sensitive (ts) DNA-positive mutant ts1203 has been characterized. The ts lesion in ts1203 was located by marker rescue within the coding region of gene UL28. Nuclei of cells infected with ts1203 at the non-permissive temperature (NPT) contained large numbers of capsids with a uniform morphology. These capsids lacked DNA but had a defined internal structure. No full capsids were detected at the NPT, suggesting that ts1203 was unable to package viral DNA. In this respect ts1203 is similar to ts1201 which has a defect in gene UL26. The capsids made by ts1203 at the NPT, however, contained a more compact internal structure than those of ts1201. In addition, ts1203 capsids were dispersed throughout the nucleus whereas ts1201 capsids were frequently found clustered together in large arrays. Southern blot and sedimentation analyses of viral DNA confirmed that ts1203 had an encapsidation defect and showed that most of the mutant DNA at the NPT was of a high M r. The effect of the ts1203 mutation could not be reversed in the absence of de novo protein synthesis by transferring mutant-infected cells from the NPT to the permissive temperature.

Effect of different carbohydrates on growth, polysaccharidase and glycosidase production by Bacteroides ovatus, in batch and continuous culture.

Abstract: Bacteroides ovatus was grown in batch culture on 12 different carbon sources (five polysaccharides, seven monosaccharides and disaccharides). Specific growth rates were determined for each substrate together with polysaccharidase and glycosidase activities. Growth rates on polymerized carbohydrates were as fast or faster than on corresponding simple sugars, demonstrating that the rate of polysaccharide depolymerization was not a factor limiting growth. Bacteroides ovatus synthesized a large range of polymer-degrading enzymes. These polysaccharidases and glycosidases were generally repressed during growth on simple sugars, but arabinose was required for optimal production of alpha-arabinofuranosidase. Polysaccharidase and glycosidase activities were measured in continuous cultures grown with either xylan or guar gum under putative carbon limitation. With the exception of beta-xylosidase, activities of the polymer-degrading enzymes were inversely related to growth rate. This correlated with polysaccharide utilization which was greatest at low dilution rates. These results show that Bact. ovatus is highly adapted for growth on polymerized carbohydrate in the human colon and confirm that the utilization of polysaccharides is partly regulated at the level of enzyme synthesis.

Secretion of immunoglobulin M assembly intermediates in the presence of reducing agents

Abstract: There are several demonstrations that misfolded or unassembled proteins are not transported along the secretory pathway, but are retained intracellularly, generally in the endoplasmic reticulum. For instance, B lymphocytes synthesize but do not secrete IgM, and only the polymeric form of IgM is secreted by plasma cells. The C-terminal cysteine of the mu heavy chain of secreted IgM (residue 575) is involved in the intracellular retention of unpolymerized IgM subunits. Here we report that the addition of reducing agents to the culture medium, at concentrations which do not affect cell viability, terminal glycosylation, or retention of proteins in the endoplasmic reticulum through the KDEL mechanism, induces secretion of IgM assembly intermediates by both B and plasma cells. Free joining (J) chains, which are not normally secreted by plasma cells unless as part of IgM or IgA, are also secreted in the presence of reducing agents. We propose a role for free thiol groups in preventing the unhindered transport of proteins through the secretory pathway. Under the scheme, assembly intermediates interact through their thiol groups between themselves and/or with unknown proteins of the endoplasmic reticulum. Such interactions may be prevented by altering the intracellular redox potential or by site-directed mutagenesis of the relevant cysteine residue(s).

Aflatoxin-albumin adducts in human sera from different regions of the world.

Abstract: An immunoassay now permits the determination of human exposure to aflatoxin at an individual level and consequently allows a better assessment of the role of aflatoxin, and its interaction with hepatitis B virus infection, in the aetiology of liver cancer. Measurements of aflatoxin bound to serum albumin in children and adults from various African countries show that between 12 and 100% contain aflatoxin-albumin adducts, with levels up to 350 pg AFB1-lysine equivalent/mg albumin. In Thailand, lower levels and prevalence of this adduct were observed, while no positive sera were detected from France or Poland. Data are presented showing that exposure to this carcinogen can occur throughout life and the relevance of these observations to the understanding of the multifactorial aetiology of liver cancer in these countries is discussed.

Parathyroid Hormone Reversibly Suppresses the Differentiation of Osteoprogenitor Cells into Functional Osteoblasts

Abstract: The effects of PTH on osteoprogenitor cell differentiation have been analyzed by quantifying its effects on bone nodule formation in an in vitro assay. Fetal rat calvaria cells were plated at 3 x 10(4) cells/35-mm dish, and cultures were maintained for 17-23 days in alpha-Minimal Essential Medium containing ascorbic acid, Na beta-glycerophosphate, and 10% fetal bovine serum. Continuous exposure to PTH at concentrations from 1 pM to 1 nM (2 x 10(-5) to 2 x 10(-2) IU/ml) caused a dose-dependent inhibition of bone nodule formation. Half-maximal inhibition occurred at 0.05 nM, and total inhibition at 1 nM, concentrations much lower than those required to elicit a significant cAMP response in rat calvaria cells. PTH at the concentrations used did not affect cell growth or saturation density. While continuous exposure to 1 nM PTH eliminated bone nodule formation, a single 48-h pulse administered at any time during the 17-day culture period had no effect. When 1 nM PTH was added on day 1 and removed at different times during the culture period, a time-related release from inhibition was observed. Cultures exposed to 1 nM PTH until nodules had developed in the corresponding control cultures and then switched to medium without added PTH rapidly formed clusters of differentiated osteoblasts and nodules within 3 days. PTH added at different times during the culture period and present continuously there-after suppressed formation of new nodules, the magnitude of the effect being a function of the duration of exposure. The results show that PTH at physiological concentrations is a potent suppressor of osteoblast differentiation and that its effect occurs at a late stage in the differentiation of osteoprogenitor cells, probably preventing differentiation of preosteoblasts into osteoblasts.