Biomedical subjects
Publications and source records attributed to C Haworth.
Most emergency presentations by vulnerable road users were the result of collisions that did not involve a motor vehicle. Many injuries occurred off-road without police attendance. Hence, reliance on official police records would underestimate the magnitude and scope of these injuries. Suggestions to provide a safer road environment are given.
Pre-B cell acute lymphoblastic leukaemia (cALL) commonly occurs in young patients and although successful conventional therapies are available (such as cytotoxic drugs and bone marrow transplantation) for a proportion of patients (approximately 30%) these are ultimately unsuccessful. Recurrence of disease is a result of the failure of the immune system to recognize these abnormal cells and down-regulation of crucial molecules required for cognate CD4(+) T cell recognition has been postulated as a means of immune escape. In this study we show that an embryonic kidney cell line (293 cells) transfected with CD154 (40 L.1) are capable of not only maintaining the viability of primary ALL cells in culture but can also up-regulate the expression of a number of crucial molecules involved in antigen recognition. We show that 40 L.1 cell stimulation of primary ALL cell cultures can not only enhance the allogeneic and autologous MLR response to such cells but will also induce CTL effectors which are capable of lysing wild-type autologous ALL cells. It is therefore conceivable that such an approach could be used to generate an active anti-tumour response in patients, following conventional therapy, reducing the incidence of recurrence.
The present study details the design and demonstrates function for a series of reagents and methods to allow the detection of exposure to antigens specific for Porcine endogenous retrovirus (PERV). The detection of PERV is carried out by the means of a variety of immunological screening methods including, indirect immunofluorescence, Western blotting and enzyme linked immunosorbent assay (ELISA) for the detection of antibodies in serum specific for PERV gag and env antigens. Alternatively, PERV-specific antisera for gag and env can be used to detect viral antigen in serum or other samples. PERV env peptides with potential specificity for the known PERV types are also described. Antisera against the peptides can be used to detect PERV antigens directly or to characterise viral type. Using electron microscopy coupled with labelled PERV-gag-specific antisera it was possible to visualise PERV virions.
Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML, MIM 601399) is an autosomal dominant disorder characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukaemia (AML). Informative recombination events in 6 FPD/AML pedigrees with evidence of linkage to markers on chromosome 21q identified an 880-kb interval containing the disease gene. Mutational analysis of regional candidate genes showed nonsense mutations or intragenic deletion of one allele of the haematopoietic transcription factor CBFA2 (formerly AML1) that co-segregated with the disease in four FPD/AML pedigrees. We identified heterozygous CBFA2 missense mutations that co-segregated with the disease in the remaining two FPD/AML pedigrees at phylogenetically conserved amino acids R166 and R201, respectively. Analysis of bone marrow or peripheral blood cells from affected FPD/AML individuals showed a decrement in megakaryocyte colony formation, demonstrating that CBFA2 dosage affects megakaryopoiesis. Our findings support a model for FPD/AML in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukaemia.
OBJECTIVE: To investigate the usefulness of immunological tests in the diagnosis of HIV infection in young symptomatic children (< 15 months of age). DESIGN: Tests were evaluated in HIV-infected (HIV antibody- and PCR-positive) patients and non-infected individuals. SETTING: Hospitalised patients in a referral centre (Red Cross War Memorial Children's Hospital, Cape Town). PATIENTS: All admissions under 15 months of age who had HIV antibody requested were eligible, provided there was sufficient serum (150 microliter) for further study. Overall, there were 201 symptomatic cases and 49 healthy controls. Twenty of the symptomatic cases were HIV antibody-positive and 19 of these were HIV-infected on the basis of a positive PCR for HIV viral product. RESULTS: Of the tests we evaluated (total IgG, IgM, IgA and rheumatoid factors of the same classes), raised total IgG level (cut-off 18 g/I or above) was the most useful. We used a commercial radial immunodiffusion plate which was found to have excellent reproducibility (inter-assay coefficient of variation 3.2%). The test detected 16 of 19 infected infants (sensitivity 84%, negative predictive value 98%). With the exception of the finding of oral thrush (odds ratio 7; P < 0.001), the clinical signs at presentation did not distinguish those who were HIV antibody-positive from those who were negative. CONCLUSIONS: In our study of hospital admissions, the finding of elevated IgG and HIV antibody was diagnostic of HIV infection. (The positive predictive value of the combination was 100%.) Likewise, the presence of raised IgG levels and oral candidosis had a high specificity for HIV infection (98%) but the sensitivity was low (37%). Measurement of total IgG levels by radial immunodiffusion is simple, relatively inexpensive (< 10% of the cost of PCR), helpful in diagnosing HIV infection in symptomatic infants and able to be performed in areas with minimal laboratory back-up.
OBJECTIVE: To determine whether intravenously administered iron supplements would improve the hematologic response to recombinant erythropoietin in stable preterm infants. METHODS: Forty-two preterm infants (<33 weeks' gestation, birth weight < 1500 gm, hematocrit <38%) were treated with recombinant human erythropoietin (Eprex), 600 U/kg per week, and randomly assigned to receive either an oral preparation of ferrous lactate (elemental iron, 12 mg/kg per day) or an intravenous preparation of iron sucrose (6 mg/kg per week). RESULTS: Hematocrits, reticulocyte counts, and transfusions were similar in the oral group (OG) and the intravenous group (IVG). However, markedly higher serum ferritin concentrations were noted in the IVG (p <0.001), and by completion of the study the arithmetic mean values were 265 +/- 127 microg/L versus 137 +/- 65 microg/L in the IVG and the OG, respectively. The numbers of hypochromic erythrocytes increased in both groups during the study but were significantly higher in the OG (p = 0.04). Mean daily weight gain in the IVG (27 +/- 6.4 gm/day) was greater than in the OG (22.9 +/- 4.78 gm/day; p = 0.04). CONCLUSIONS: High doses of both orally administered iron and intravenously administered iron sucrose appear to supply sufficient iron for erythropoiesis in stable infants. Storage iron may become depleted after oral supplementation. The intravenous preparation appears to be safe and maintains serum ferritin concentrations, and it may be indicated for patients with low ferritin levels and for those not established on enteral feedings.
In a double-blind placebo-controlled study we showed a 3-fold decrease in blood transfusions (BTFs) given to preterm infants with anaemia of prematurity who received recombinant erythropoietin. However, only 50% of placebo recipients required a BTF. Data from the placebo group indicated that either mean daily weight gain < or = 7.5 g/day before study entry or haematocrit < or = 50% at birth was associated with BTFs (P < 0.001). We calculated that giving erythropoietin to patients in the treatment group with either of these variables prevented 24 of 28 BTFs and that it would cost R184 to prevent 1 BTF. The cost of each BTF was R187 (blood filtered to remove white cells and reduce cytomegalovirus transmission). Therefore, the costs of the two treatments were similar, but as the risk of transmitting infection is lower with erythropoietin, we recommend its use in selected preterm infants.
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Strongyloidiasis in immunocompromised patients is typically associated with a fulminant clinical course and little eosinophilia. We describe an immunocompromised patient with strongyloidiasis in whom the infection was only minimally symptomatic in association with a dramatic increase in eosinophil count.
Twelve patients undergoing IL-2 and flavone acetic acid (FAA) combination immunotherapy for advanced melanoma were studied throughout treatment for the induction of measurable levels of bioactive TNF, GM-CSF and IL-6 in their serum. This was to assess the extent of secondary cytokine induction in these patients and the possible role of such cytokines in both the toxic and therapeutic responses. The nature of the treatment schedule enabled these cytokines to be measured in response to FAA alone, FAA/IL-2 and FAA alone following IL-2/FAA activation of target cells. A small rise in the serum levels of these cytokines was seen on the initial course of FAA/IL-2 but this was minor compared to the marked elevation in levels 2-8 h following the initiation of the third course of FAA given with or without IL-2 and at a time point which coincided with maximum toxicity in those patients who experienced it. These results show that FAA alone can induce cytokine release from primed target cells. This may be associated with the therapeutic effect and/or toxicity of the agent.
A prospective, blinded study was done to examine the effects of acute bolus and chronic continuous intrathecal baclofen on genitourinary function in 10 patients with severe spasticity due to spinal cord pathology. Genitourinary function was assessed by symptom questionnaires and urodynamic studies performed after a bolus dose of baclofen and 6 to 12 months after continuous intrathecal baclofen. Results were compared to placebo for acute bolus testing or to pre-continuous intrathecal baclofen values. In all patients with irritative voiding and urge incontinence uninhibited bladder contractions were eliminated. Of 3 patients with an indwelling urethral catheter for incontinence due to detrusor hyperreflexia 1 was converted to intermittent self-catheterization. Whereas bladder capacity, compliance, sensation and voiding pressures were not different after continuous intrathecal baclofen, when a mean of all patients was compiled, a 72% increase in capacity and 16% improvement in compliance were observed in subjects without cervical spinal cord pathology. Detrusor-sphincter dyssynergia was abolished in 40% of the patients. Continuous intrathecal baclofen may represent a novel approach to the management of patients with a neurogenic bladder who have decreased bladder compliance and detrusor hyperreflexia not controlled by oral medications.
The increased risk of neoplasia following cytotoxic therapy for both malignant and nonmalignant disease is well known. Sister chromatid exchange (SCE) frequencies in patients receiving such chemotherapy are often elevated, and the persistence of high levels after treatment may provide an indicator for susceptibility to secondary neoplasia. The cytostatic drug razoxane has been used for the treatment of psoriasis, acute myeloid leukemia (AML), and colorectal carcinoma. Prolonged use of this drug, however, has been associated with the subsequent development of AML and, up to November 1987, 16 cases of acute leukemia following razoxane treatment have been reported. We report the SCE frequencies for 34 patients with colorectal carcinoma who were receiving or had previously been treated with razoxane. Our results show no significant increase in SCE levels in the razoxane group compared with either normal controls or untreated patients.
Granulocyte-macrophage colony-stimulating factor (GM-CSF), in addition to being a growth factor for granulocytes and macrophages, is an activator of cells of the monocyte/macrophage lineage and induces HLA class II expression and cytokine synthesis in these target cells. Macrophage activation and class II expression are prominent features in rheumatoid arthritis (RA) joints, but the mechanism of their stimulation is not understood, since interferon-gamma, the major stimulus of class II expression, is not usually detectable at the protein level in synovial cell culture supernatants. We have, therefore, studied GM-CSF expression in cultures of cells derived from joints affected by RA and osteoarthritis (OA), and show that GM-CSF is produced spontaneously both by RA synovial cells and to a lesser extent by OA synovial cells in the absence of extrinsic stimuli. GM-CSF production continues for the 5-day duration of the culture period. Using neutralizing antibodies to tumor necrosis factor (TNF)-alpha we demonstrated that GM-CSF production in RA synovial cell cultures is dependent on the continued presence of active TNF-alpha. This result supports our concept that continued activation of the cytokine network is a marked feature of RA, and that TNF-alpha plays a pivotal role in this network, by regulating the production of other pro-inflammatory cytokines, such as interleukin 1, as demonstrated previously, and GM-CSF.
Cytokines are protein mediators involved in inflammation, the immune response, cell growth, repair and fibrosis. All of these processes are ongoing in active autoimmune diseases such as rheumatoid arthritis (RA), and so it would be expected that many cytokines would be actively produced in RA joints or Graves' disease (GD) thyroid glands. The cDNA cloning of cytokines has permitted the generation of pure recombinant molecules, and of newer more sensitive assays, and spurred the rapid development of knowledge in this field. Here we review the molecular strategies devised to study the possible role of cytokines in the pathogenesis of RA and GD, and describe some of the initial results. After 'cataloguing' the relative abundance of various cytokines, we sought to discover which cytokines are of major importance in pathogenesis. For that purpose we used neutralizing anti-cytokine antibodies and found that TNF alpha is one of the major signals regulating the production of IL-1 in the RA but not in the osteoarthritic (OA) joint. In order to further understand the dynamics of the cytokine network, the localization of the cytokine-producing cells by immunostaining and in situ hybridization has also been performed. The latter techniques are particularly valuable for attempting to establish the role of the target cell, such as thyroid epithelium, in the pathogenesis of disease. Cytokines act on cells via binding to high-affinity receptors. The last two years has been the cDNA cloning of many molecules encoding cytokine receptor chains, and it is now possible to begin to evaluate the other half of the cytokine pathway. Taken together, there are now exciting opportunities for the molecular dissection of the cytokine events occurring in auto-immune tissues.
Cytokines are protein mediators that play a part in inflammation, the immune response, cell growth, repair, and fibrosis. All of these are continuing processes in active rheumatoid arthritis (RA), and so it would be expected that many cytokines would be actively produced in RA joints. Here, the molecular strategies devised to study the possible role of cytokines in the pathogenesis of RA, are reviewed and some of the initial results described. The relative abundance of various cytokines is 'catalogued' and then attention is turned to an attempt to discover which cytokines are of major importance in the pathogenesis. Neutralising antibodies to cytokines were used for that purpose, and it was found that tumour necrosis factor alpha (TNF alpha) is one of the major signals regulating the production of interleukin-1 in the RA, but not in the osteoarthritic joint. To understand further the dynamics of the cytokine network localisation of the cytokine producing cells by immunostaining--for example, TNF alpha, is currently being established.
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The number of cytokine molecules identified and cloned grows almost weekly. Studies using pure preparations have shown that single entities, e.g. TGF beta and IL-1 act on a wide variety of target cells whereas other cytokines, e.g. G-CSF have a more restricted target cell population. The outcome of stimulation of a cell by a cytokine depends on the target cell type, the presence of other coexisting cytokines and, as the release of cytokines may be targeted in the direction of the stimulus, the orientation of producer and target cells. These modulating phenomena may enable a small number of cytokines to specifically define a much larger number of responses, so that maximum 'value' is obtained from the successful evolution of cytokine and receptor molecules. The current nomenclature has little regard for this, the names of cytokines often deriving from the first property observed in vitro. In many cases these are not the most important properties of the molecule and can be misleading, e.g. transforming growth factor beta, which is growth inhibitory in some systems; the antiviral action of interferon gamma is relatively minor compared to its role as a macrophage activation factor; and interleukin-1 is produced by, and acts on, many cells outside the lymphohaemopoietic system. In addition, although there is often a high degree of homology, the repertoire of activities may vary between species. For example, IL-5 is a growth factor for eosinophils, both in humans and mice, however, in the mouse it also acts as a B-cell differentiation factor--a property which has been less easy to identify in human IL-5.(ABSTRACT TRUNCATED AT 250 WORDS)