Showing papers by "Medical Research Council published in 1987"

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.

Recombinant antibodies and methods for their production

Abstract: An altered antibody is produced by replacing the complementarity determining regions (CDRs) of a variable region of an immunoglobulin (Ig) with the CDRs from an Ig of different specificity, using recombinant DNA techniques. The gene coding sequences for producing the altered antibody may be produced by site-directed mutagenesis using long oligonucleotides.

Mortality and morbidity from malaria among children in a rural area of The Gambia, West Africa

Abstract: Mortality and morbidity from malaria were measured among 3000 children under the age of 7 years in a rural area of The Gambia, West Africa. Using a post-mortem questionnaire technique, malaria was identified as the probable cause of 4% of infant deaths and of 25% of deaths in children aged 1 to 4 years. The malaria mortality rate was 6.3 per 1000 per year in infants and 10.7 per 1000 per year in children aged 1 to 4 years. Morbidity surveys suggested that children under the age of 7 years experienced about one clinical episode of malaria per year. Calculation of attributable fractions showed that malaria may be responsible for about 40% of episodes of fever in children. Although the overall level of parasitaemia showed little seasonal variation, the clinical impact of malaria was highly seasonal; all malaria deaths and a high proportion of febrile episodes were recorded during a limited period at the end of the rainy season.

Diversity of alpha-fetoprotein gene expression in mice is generated by a combination of separate enhancer elements

Abstract: The 59 flanking region of the mouse alpha-fetoprotein (AFP) gene contains a tissue-specific promoter and three upstream regulatory elements that behave as classical enhancers. At least one of these enhancers is now shown to be required for the tissue-specific expression of the AFP gene when it is introduced into the mouse genome by microinjection of cloned DNA fragments into fertilized eggs. Each enhancer can direct expression in the appropriate tissues, the visceral endoderm of the yolk sac, the fetal liver, and the gastrointestinal tract, but each exerts different influence in these three tissues. These differences may explain the tissue-specific diversity in the levels of expression characteristic of the AFP gene. The postnatal repression of transcription of the AFP gene in both liver and gut, as well as the reinitiation of its transcription during liver regeneration, is mimicked by the introduced gene when it is linked to the enhancer domains together or singly. Thus, the DNA sequence elements responsible for directing the activation of AFP transcription, its repression, and reinduction are contained in a limited segment of DNA within or 59 to the gene (or both) and are operative in the absence of the closely linked albumin gene.

A chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome. A specific entity analysed in 30 patients.

Abstract: We have studied the clinical presentation and course of a chronic inflammatory disease occurring in childhood and observed in 30 patients. The first symptoms were generally present at birth, except in a few patients where they were first noticed in early infancy. All the patients had the association of three main symptoms: neurological, cutaneous and articular. The skin rash was the first symptom observed in all the patients and looked like a chronic non pruritic urticaria varying during the day. The articular manifestations involved knees, ankles and feet, elbows, wrists and hands unaffecting the other joints. They could be mild giving arthritis during flare-ups or severe with major radiological modifications affecting the epiphysis, metaphysis and growth cartilage. The neurological manifestations were characterized by a chronic meningitis and symptoms indicating meningeal irritation: headaches, seizures, spasticity of legs. Most patients had a cerebral atrophy and a low IQ. Sensory organ involvement occurred progressively during the follow-up: ocular inflammation with optic atrophy, deafness and hoarseness. Common morphological features characterized these patients with short stature, head enlargement, saddle back nose and short and thick extremities with clubbing of fingers. The course was that of a chronic inflammatory disease with numerous flare-ups associating fever, splenomegaly and adenomegaly. Except for a high level of eosinophils in blood, CSF and tissues, the biology was non specific and only exhibited features of inflammation. Except for two families, the disease was sporadic. A high frequency of prematurity with features resembling a foetal infection was observed but no proof of a possible causal virus has so far been found so that etiology remains unknown.

Carbohydrates as antigenic determinants of glycoproteins.

Abstract: Antibodies are being used increasingly as reagents in biochemical and biological studies of glycoproteins, for example, in the search for glycoproteins with important roles in embryonic development, cell differentiation and oncogenesis, and as a means of monitoring the biosynthesis and subcellular location of specific glycoproteins such as enzymes and receptors. Crucial for the proper application of antibodies in such experiments is knowledge of the determinants they recognize. A glycoprotein may contain many antigenic determinants, each consisting ofup to seven monosaccharides or amino acids in consecutive sequence (Kabat, 1976) or, in the case of polypeptides, in non-continuous sequence brought together by chain folding (Lerner, 1984; Walter, 1986). Unravelling the specificities contained in conventional (polyclonal) antisera raised against glycoproteins often presents problems due to the mixture of antibodies present with different combining specificities. It is often difficult to distinguish specificities directed against peptide determinants from those directed against carbohydrate structures on a glycoprotein. Monoclonal antibodies have the advantage in this respect since each is a single antibody population with a narrow specificity. As a result ofwork with naturally-occurring monoclonal autoantibodies and the widespread use of hybridomaderived antibodies, there has been an increased awareness of carbohydrates as antigenic determinants of glycoproteins, since it has become apparent that many differentiation antigens ofnormal and neoplastic cells are oligosaccharide determinants of glycoproteins and glycolipids rather than peptide determinants (Feizi, 1985, 1987; Hakomori, 1985). Thus, carbohydrate antigens which were previously the interest of specialist immunochemists are now of wide relevance to both biochemists and cell biologists. We do not intend here to make an exhaustive review of antigens found to date on glycoprotein oligosaccharides; rather we shall discuss some examples of whole cells (haematopoietic and embryonic) and specific glycoproteins (a receptor and a glycosyltransferase) where carbohydrate structures have been found to be major antigenic determinants. We shall also discuss approaches to the study of antigenicity (reactivity with antibodies) and immunogenicity (ability to elicit antibodies) of the oligosaccharides of glycoproteins and the opportunities now available for exploiting antibodies with defined carbohydrate specificities as probes of the structure, tissue distribution and function of glycoprotein oligosaccharides. We also include in this article a hypothesis which considers the biological relevance and possible inter-relationships of three areas of knowledge: (a) the occurrence of the same carbohydrate antigens/structures on diverse and unrelated glycoproteins, (b) marked

Scanning from coarse to fine spatial scales in the human visual system after the onset of a stimulus

Abstract: The manner in which the spatial characteristics of simple discrimination tasks change with time after the onset of a stimulus were examined. The experiments measured the improvements in sensitivity to the length, orientation, curvature, and stereoscopic depth of short lines that accrue with increased exposure durations. These improvements can be consistently interpreted in terms of a change of the spatial scale of analysis from coarse to fine over a period of at least 1000 msec. Variations in visual resolution acuity over the same period are negligible, and it is concluded that the changes in spatial characteristics concern the range of spatial filters in operation. This range progressively shrinks after stimulus presentation.

Borders of parasegments in Drosophila embryos are delimited by the fushi tarazu and even-skipped genes

Abstract: One of the earliest molecular signs of segmentation in Drosophila embryos is the striped expression of some pair-rule genes1 during the blastoderm stage. Two of these genes, fushi-tarazu (ftz) and even-skipped (eve) are expressed during this stage in complementary patterns of seven stripes2–8 which develop and disappear in concert8. Here, we map the cells expressing each of these two pair-rule genes with respect to the 14 stripes of cells expressing the engrailed gene. We find that both ftz and eve generate stripes which have sharp boundaries at the anterior margin, but fade away posteriorly. The anterior boundaries correspond cell by cell with the anterior boundaries of expression of the engrailed gene. We therefore suggest that a key function of early ftz and eve gene activity is the formation of a sharp stable boundary at the anterior margin of each stripe. These boundary lines, rather than the narrowing zonal stripes, would delimit the anterior boundaries of engrailed and other homoeotic genes and thereby subdivide the embryo into parasegments9.

Molecular mapping of the human major histocompatibility complex by pulsed-field gel electrophoresis.

Abstract: Pulsed-field gel electrophoresis and "cosmid walking" have been used to establish a molecular map of the human major histocompatibility complex (MHC). We have isolated approximately equal to 230 kilobases (kb) of genomic DNA in overlapping cosmid clones covering the genes for the second and fourth components of complement (C2 and C4, respectively), factor B, and steroid 21-hydroxylase, and approximately equal to 82 kb of genomic DNA surrounding the genes for the tumor necrosis factors alpha and beta. Single-copy hybridization probes isolated from these cosmid clusters and probes for the known MHC gene loci were hybridized to Southern blots of genomic DNA that had been digested with infrequently cutting restriction endonucleases and separated on pulsed-field gels. The data obtained allowed the construction of a long-range genomic restriction map and indicated that the MHC spans 3800 kb. This map orients the MHC class III gene cluster with respect to the DR subregion; the C2 gene is on the telomeric side of the 21-hydroxylase B gene. In addition we have defined the positions of the genes for the tumor necrosis factors alpha and beta in the human MHC. Genes for the alpha chain of DR and 21-hydroxylase B are separated by at least 300 kb, while the distance between the genes for C2 and tumor necrosis factor alpha is 390 kb. The HLA-B locus lies approximately equal to 250 kb on the telomeric side of the tumor necrosis factor genes.

Plasmodium falciparum malaria and Salmonella infections in Gambian children.

Abstract: Le paludisme sevit a l'etat endemique en Gambie et les formes chimiques sont plus severes chez les enfants de moins de 5 ans. On constate que les septicemies a Salmonelles s'installent peu de temps apres le paludisme

Clinical and laboratory features of de novo acute myeloid leukaemia with trilineage myelodysplasia.

Abstract: Primary myelodysplastic syndromes progress to acute myeloid leukaemia (AML) in about 30% of cases. We have sought evidence of pre-existing trilineage myelodysplasia (TMDS) using the FAB criteria (1982) in 160 consecutive cases of primary de novo AML. TMDS was found in 24 cases (15%) including two of 33 cases of M1 (6%), four of 40 cases of M2 (10%), none of 18 cases of M3, five of 31 cases of M4 (15%), six of 30 cases of M5 (20%), all of six cases of M6 and one of two cases of M7. The median presentation bone-marrow blast-cell count in the 24 AML/TMDS cases was 53% (30-90%) and 82% (45-100%) in the 136 cases of AML without TMDS. 60% of the AML/TMDS bone-marrow aspirates contained fewer than 60% of blasts compared with only 11% of those from AML without TMDS (P less than 0.001). In AML the occurrence of symptomatic cytopenias when the marrow blast-cell count is below 60% and the peripheral blood blast-cell count is below 20% is highly correlated with dysplastic haemopoiesis (P less than 0.001).

Resistance to reinfection after treatment of urinary schistosomiasis

Abstract: The process of reinfection after treatment was studied in a cohort of subjects in a focus of intense Schistosoma haematobium infection. Detailed observations were made at water contact sites of cercarial densities and of water contact by members of the cohort. Individual values of a cumulative index of exposure to infection were calculated using these observations and assumptions which were made about the effect of different water contact activities on the entry of cercariae into the skin. Among groups of subjects with an apparently similar intensity of exposure to infection, reinfection tended to be much heavier in children under 10 years of age than in 10 to 14-year-olds, while only light infections were found in the few adults who became reinfected. This trend for reinfection to decrease with increasing age, after an allowance for variation in exposure, was highly significant (p less than 0.001). These observations suggest that subjects in this area slowly acquire an increasing degree of immunity to the acquisition of S. haematobium infection which is effective in the absence of a mature egg laying infection.

Sex hormones, insulin, lipids, and prevalent ischemic heart disease

Abstract: The relations between estradiol, testosterone, insulin, lipids, and prevalent ischemic heart disease were examined using the cross-sectional data from the Caerphilly Heart Disease Study, a cohort of 2,512 men (aged 45-59 years) surveyed between 1978 and 1982. Endogenous levels of estradiol were associated directly with high density lipoprotein (HDL) cholesterol (r = 0.106, p less than 0.001), but this relation was removed after adjustment for testosterone and insulin levels. Estradiol was not associated with prevalent ischemic heart disease. Endogenous levels of testosterone were associated directly with HDL cholesterol (r = 0.148, p less than 0.001) and inversely with triglyceride (r = -0.217, p less than 0.001). Persons with prevalent ischemic heart disease had significantly lower testosterone levels than persons without ischemic heart disease (mean levels 20.9 vs. 22.0 nmol/liter, p less than 0.01). These relations were confounded by associations with insulin. The associations between testosterone and the lipids persist after adjusting for body mass index, age, and insulin. The association between testosterone and prevalent ischemic heart disease was reduced after adjusting for insulin and/or triglyceride levels. The results suggest that insulin and testosterone may have an interdependent regulatory effect on lipid metabolism. The effect of testosterone on ischemic heart disease appears to be primarily mediated through its association with insulin. Future work on sex hormones and ischemic heart disease will need to account for the effects of insulin.

Nomenclature of metallothionein.

Abstract: The original recommendations concerning the nomenclature of metallothionein were made by the plenum of the First International Meeting on Metallothionein and Other Low Molecular Weight Metal-binding Proteins in 1978 (Nordberg and Kojima, 1979). The present revised version includes amendments to these recommendations as adopted by the Committee on the Nomenclature of Metallothionein appointed at the General Discussion Session of the Second International Meeting on Metallothionein and Other Low Molecular Weight Metal-binding Proteins in 1985.

Cellular heterogeneity and drug resistance in two ovarian adenocarcinoma cell lines derived from a single patient.

Abstract: Two ovarian cell lines were derived from the ascites of a patient before and after the onset of resistance to chemotherapy involving cis-platinum, chlorambucil and 5-fluorouracil. Characterization of these lines shows them to have various features in common and some significant differences. Cytologically the lines cannot be distinguished and they both contain high concentrations of oestrogen receptor. However, they do differ with respect to their growth characteristics, karyotype, glutathione content and sensitivity to cis-platinum. The karyotypes of the 2 lines show several marker chromosomes in common but the resistant line contained a chromosome 8 and a 17 which were absent from the earlier sensitive line. This suggests a clonal origin with subsequent divergence to a heterogeneous population.

Neuroendocrine Responses to Intravenous Tryptophan in Major Depression

Abstract: • The increases in plasma levels of prolactin (PRL) and growth hormone (GH) following intravenous administration of the 5-hydroxytryptamine precursor tryptophan (100 mg/kg) were assessed in 30 depressed patients and 30 control subjects. In depressed patients who lost less than 10 lb, PRL responses were significantly reduced compared with controls. In contrast, the PRL responses of patients with weight loss exceeding 10 lb were significantly greater than those of either controls or the other depressed patients. Growth hormone responses to tryptophan were significantly decreased in patients who lost less than 10 lb. Prolactin, but not GH, responses correlated significantly with the postdexamethasone plasma cortisol concentration; however, an apparent relationship between GH and PRL responses and suicidal behavior was probably due to the common factor of weight loss. The results suggest that depressed patients have different types of abnormal 5-hydroxytryptamine—mediated neuroendocrine responses that correlate with the presence or absence of severe weight loss and cortisol hypersecretion. Further investigations are needed to establish if these abnormalities are central to the depressive disorder or have implications for treatment response.

Effect of high fat diets on energy balance and thermogenesis in brown adipose tissue of lean and genetically obese ob/ob mice.

Abstract: The effects on energy balance and brown adipose tissue thermogenesis of feeding high fat diets of differing fatty acid composition have been investigated in lean and genetically obese (ob/ob) mice Groups of mice were fed either a low fat diet or a high fat diet based on corn oil or beef tallow for 2 wk Energy intake and body weight gain were higher in both lean and obese animals fed the high fat diets than in respective mice fed the low fat diets Carcass energy gain was greater for the obese than for the lean consuming each of the diets Both lean and obese mice had a higher energy gain when fed the beef tallow diet than when fed the corn oil, despite isoenergetic intakes of the two diets The thermogenic activity of brown adipose tissue, assessed from measurements of cytochrome oxidase activity and mitochondrial guanosine 5'-diphosphate (GDP) binding, were greater in both lean and obese mice fed the corn oil diet than in those fed the low fat diet However, GDP binding and cytochrome oxidase activities in lean or obese mice fed the beef tallow diet were not different from those of mice of the same genotype fed the low fat diet These results indicate that in both lean and obese (ob/ob) mice energy deposition and the stimulation of brown adipose tissue thermogenesis during the voluntary hyperphagia induced by feeding high fat diets are influenced by the fatty acid composition of the diet A diet rich in polyunsaturated fatty acids appears to result in preferential stimulation of the thermogenic activity of brown adipose tissue, particularly in the ob/ob mouse

Monoclonal integration of HTLV-I proviral DNA in patients with strongyloidiasis

Abstract: The relationship between strongyloidiasis and HTLV-I was investigated in Okinawa, an area where both conditions are endemic. Thirty-six patients with strongyloidiasis were seropositive for HTLV-I and suffered from several related clinical complications. Fourteen of these patients (39%) were shown to have monoclonal integration of HTLV-I proviral DNA in their blood lymphocytes, a condition designated as "smouldering" adult T-cell leukaemia (ATL). Monoclonal integration of proviral DNA correlated with an increased CD4/CD8 ratio and the presence of abnormal lymphocytes in the peripheral blood, and with a trend for greater severity of the parasitic infection. Although the immunodeficiency caused by HTLV-I could predispose to hyperinfestation by Strongyloides, it is also possible that both the parasitic and the retroviral infestations are important co-factors leading to the development of ATL.

Prosody and the development of comprehension

Abstract: Four studies are reported in which young children's response time to detect word targets was measured. Children under about six years of age did not show the response time advantage for accented target words which adult listeners show. When semantic focus of the target word was manipulated independently of accent, children of about five years of age showed an adult-like response time advantage for focussed targets, but children younger than five did not. It is argued that the processing advantage for accented words reflects the semantic role of accent as an expression of sentence focus. Processing advantages for accented words depend on the prior development of representations of sentence semantic structure, including the concept of focus. The previous literature on the development of prosodic competence shows an apparent anomaly in that young children's productive skills appear to outstrip their receptive skills; however, this anomaly disappears if very young children's prosody is assumed to be produced without an underlying representation of the relationship between prosody and semantics.

Epidemiology of sarcoidosis in the Isle of Man--2: Evidence for space-time clustering.

Abstract: The case-control test for space-time clustering developed by Pike and Smith was applied to 96 cases of sarcoidosis diagnosed in the Isle of Man from 1962 to 1983. There were significantly more links between cases separated by time intervals of less than 10 years and distances of less than 100 metres than between the others. Analysis of the type of links indicated that clusters consisted of pairs whose contact was by place of residence or work. More linked cases were diagnosed less than three years apart than would be expected by chance. These findings lend support to the idea that sarcoidosis is a communicable disease.