Biomedical subjects
Publications and source records attributed to S Wood.
A cosmid library for human chromosome 8 has been constructed from flow-sorted chromosomes in the vector sCos-1. This library is 85% human and has been arrayed into 210 microtiter plates representing four genome equivalents. Cosmids have been isolated with 10 of 11 probes representing nine different loci from chromosome 8.
Two cosmids isolated from a flow-sorted chromosome 8 library by hybridization with pSW50 (D8S7) were screened for GT microsatellite sequences. Both contained a positive 900-bp Hind III-Xba I fragment. Sequencing revealed a complex dinucleotide repeat. Flanking oligonucleotide primers were synthesized, and the polymerase chain reaction products produced by these primers were typed within the CEPH panel of families. A two-allele polymorphism was identified that is in linkage disequilibrium with a previously described insertion-deletion polymorphism at this locus.
The human complement system is an important early host defense against infection. Entamoeba histolytica activates the complement system but is resistant to killing by complement C5b-9 complexes deposited on the membrane surface. Our aim was to identify components of the amebic plasma membrane that mediate resistance to human complement C5b-9 by screening for neutralizing monoclonal antibodies. A monoclonal antibody was identified that abrogated amebic resistance to C5b-9, and the mAb was shown to recognize the parasite's galactose-specific adhesin. The purified adhesin bound to C8 and C9 and conferred C5b-9 resistance to sensitive ameba upon reconstitution; these activities of the adhesin were inhibited by the antiadhesin mAb. The E. histolytica adhesin shared sequence similarities and antigenic cross-reactivity with CD59, a membrane inhibitor of C5b-9 in human blood cells, suggesting both molecular mimicry and shared complement-inhibitory functions.
In order to determine the factors influencing outcome following craniotomy for trauma in patients over the age of 65 and to establish criteria for surgical intervention, the authors carried out a retrospective analysis of the hospital and general practice records of all head injury patients over the age of 65 who underwent a craniotomy for evacuation of a post-traumatic haematoma within 7 days of injury at Frenchay Hospital during a 10-year period (1980-89). Outcome was measured using the Glasgow Outcome Scale and patients were allotted to a good outcome group (good recovery or moderate disability but independent) or a poor outcome group (severe disability, vegetative state of death). There were 35 men and 31 women with a mean age of 72.5 years (range 65-85 years). The mortality rate was 61% and 9% of patients survived in a severely disabled or vegetative state. All 20 (30%) patients with a good outcome had a Glasgow Coma Score (GCS) of 5 or more immediately before surgery. All 18 (27%) patients with a GCS of 4 or less and all 22 (33%) patients with unilateral or bilateral pupillary dilatation had a poor outcome. Outcome was significantly worse in the older patients (75-85 years) compared with the younger patients (65-74 years) and in those patients requiring craniotomy within 24 hours of injury, but the mechanism of injury (fall or road traffic accident), the presence or absence of skull fractures and limb fractures and the pre-operative CT scan appearances did not influence outcome. This study confirms the high probability of poor outcome following surgical evacuation of traumatic intracranial haematomas for elderly head-injured patients with pupillary dilatation or extensor motor responses. Craniotomy under these circumstances is not justified.
In the Nottingham District Health Authority we found that one in 943 babies born between 1983-1986 have a sensorineural or mixed hearing impairment (at 50 dB HL or greater in the better ear averaged over the frequencies 0.5, 1, 2, 4 kHz) that is either congenital or progressive in nature. If this figure is broken down between non-neonatal intensive care unit babies and neonatal intensive care unit (NICU) graduates, we find that one in 174 NICU graduates have a hearing impairment compared with one in 1278 non-NICU babies. Excluding from the non-NICU baby population those with a known family history of hearing impairment, and those with a known relevant syndrome at birth, there is a 10.2 to 1 odds ratio for babies in NICU to have such hearing impairments compared to this restricted 'normal' baby population. In addition NICU babies with a hearing impairment were considerably more likely to have another disability (odds ratio 8.7 to 1). Acquired sensorineural or mixed impairments comprised about 9% of the children with impairments by 3 years of age. Twenty per cent of the patients seen at the Children's Hearing Assessment Centre (CHAC) with better-ear impairment of 95 dB HL or greater had acquired hearing impairments. The mean age of referral for congenital hearing impairments was found to be a function of severity and NICU status. For children with better-ear hearing impairments of 80 dB HL or greater, the mean and median ages of referral were both 8 months (s.d. 4 months).
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An in vivo system has been established to investigate v-myc-induced hematopoietic neoplasia in mice. A Moloney murine leukemia virus (Mo-MLV)-derived recombinant retrovirus containing v-myc was used to infect immature bone marrow cells, and these cells were then transplanted into lethally irradiated recipients. All provirus-positive reconstituted mice were found to develop hematopoietic proliferative disorders and, in certain cases, overt leukemia--myeloblastic, myelomonocytic and T lymphocytic. In all cases expression of v-myc was high and the disease type did not correlate with the level of expression. We have isolated immortalized monocytes, myeloid progenitors and T lymphocytes from several of these mice and shown tumorigenicity in secondary syngeneic recipients. This system provides a model for investigating the progression from a pre-leukemic disease to malignancy. In addition, we describe a recombinant v-myc-containing retrovirus that directs high-level v-myc expression from the Mo-MLV promoter in all the hematopoietic cell types examined.
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Studies of the absorption and fluorescence properties of the chaperone protein groEL (cpn60) from Escherichia coli show that tryptophan is present, in contrast to the proposed amino acid sequence of the protein (Hemmingsen, S.M. et al. (1988) Nature 333, 330-334). By determining a suitable value for the specific absorption coefficient of the protein at 280 nm, it has been shown that the content of the aromatic amino acids corresponds to a single tryptophan and (most probably) seven tyrosines per subunit (Mr 57,200).
OBJECTIVES: To document the circumstances and care of patients with schizophrenia who had recently been discharged from local psychiatric inpatient services, and to establish the extent to which misgivings about community care might be justified. DESIGN: Cross sectional surveys with review of case notes. Follow up interviews with questionnaires administered one year after discharge. SETTING: Two inner London districts (West Lambeth and Lewisham) with high levels of social deprivation and at different stages of developing community services. PATIENTS: 90 and 50 patients in the two services respectively, aged 18 to 65, who satisfied the Research Diagnostic Criteria for schizophrenia and who were discharged from inpatient services. MAIN OUTCOME MEASURES: Diagnosis elicited by present state examination, global social disability rating, use of services during the three months before interview. RESULTS: 89 of the 140 patients (64%) had been ill for five or more years, yet few were former long stay inpatients. 55% (50/91; 95% confidence interval 45% to 65%) of those interviewed had current psychotic mental states and 22% (27/124; 16% to 31%) were functioning socially at very poor or severely maladjusted levels. 86% (107/124) were unemployed. The majority of patients had seen a mental health or social service professional, yet only 16% (20/124) were in specialised accomodation (excluding hospitals) and only 23% (17/73) of those eligible had used day care. Small numbers of people had experienced homelessness (two) or imprisonment (four over six months). CONCLUSIONS: Many schizophrenic patients leaving local psychiatric inpatient care have active symptomatology and profound social disabilities. Community care was characterised by high rates of contact with service professionals but little supported accommodation or day activity. This group of clients may require dedicated provision, which would actively encourage them to use services protected from the demands of those with less severe illness.
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When Bacillus stearothermophilus LDH dimer is incubated with increasing concentrations of the denaturant guanidinium chloride, three distinct unfolded states of the molecule are observed at equilibrium [Smith, C. J., et al. (1991) Biochemistry 30, 1028-1036]. The kinetics of LDH refolding are consistent with an unbranched progression through these states. The Escherichia coli chaperonin, GroEL, binds with high affinity to the completely denatured form and more weakly to the earliest folding intermediate, thus retarding the refolding process. A later structurally defined folding intermediate, corresponding to a molten globule form, is not bound by GroEL; neither is the inactive monomer. The complex between GroEL and denatured LDH is destabilized by the binding of magnesium/ATP (Mg/ATP) or by the nonhydrolyzable analogue adenylyl imidodiphosphate (AMP-PNP). From our initial kinetic data, we propose that GroEL exists in two interconvertible forms, one of which is stabilized by the binding of Mg/ATP but associates weakly with the unfolded protein. The other is destabilized by Mg/ATP and associates strongly with unfolded LDH. The relevance of these findings to the role of GroEL in vivo is discussed.
An increasing number of hereditary diseases are becoming amenable to diagnosis by analysis of DNA as the responsible genes are located and identified. Gel electrophoresis of DNA fragments plays a central role in the diagnosis of hereditary disease. Electrophoretic separation of differently sized fragments enables the characterization or typing of normal variants which are known to be genetically linked to disease genes. For some diseases it is possible to directly detect mutations by DNA electrophoresis. Deletion mutants may be detected by a restriction fragment of altered size or by a failure to amplify a coding region with the polymerase chain reaction. Carriers of small deletions, involving a few base pairs, may be identified by DNA amplification which produces heteroduplexes that show characteristic, anomalous electrophoretic migration. Mutations that alter restriction sites also alter the sizes of restriction fragments. Common disease mutations that alter a single base pair may be detected using a pair of reactions with normal and mutant oligonucleotides under conditions where a perfect match is necessary for hybridization, amplification or ligation. Alternatively a mismatched oligonucleotide primer may be designed to generate a restriction site with either the normal or mutant allele, following DNA amplification. Finally a number of techniques are available that are useful as screening tools for novel mutations.
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