Biomedical subjects
Publications and source records attributed to T Alderson.
A composite catalyst comprising a physical mixture of a zeolite and a cobalt/manganese oxide Fischer-Tropsch catalyst decreases the formation of methane in the hydrogenation of carbon monoxide without significantly affecting conversion.
BACKGROUND: Medical students receive increasing amounts of their clinical education in a primary care setting. The educational possibilities of such attachments are still being explored. AIM: To report the evaluation of a small, radical innovation to provide students with a long-term community attachment which integrated with hospital-based education. METHOD: Between 1993 and 1998, 13 medical students completed 15-month attachments with a single general practice in England. The course offered them experience in the major clinical specialties throughout this period. Students were exposed to specialist as well as generalist education in the context of patients with whom they could establish a continuing relationship. The innovation was evaluated by its feasibility, by students' examination results, by analysis of clinical experience, through formal student feedback and by cost. RESULTS: The course was practicable in a particular setting with academic leadership. The students all passed their exams. They had wide, appropriate clinical experience even though the attachment was to a single practice. When they returned to the hospital environment, students did not feel themselves at a disadvantage compared with traditional students. The costs of the course are controversial: placement costs were higher than in the hospital, but those for facilities were lower. CONCLUSION: It is possible to run a course like this successfully. It remains the most radical attempt to share clinical education in the UK between primary and secondary/tertiary care. Further research is required into providing long-term clinical attachments in NHS primary care settings.
The use of artificial urinary sphincter around the urethra or bladder neck for the management of urinary incontinence secondary to intrinsic urethral sphincter deficiency is now well accepted. However, its use around the bowel to serve as a sphincter in urinary pouches is still anecdotal. Its use in experimental models has been met with failure because of ischemic bowel necrosis at the cuff site. To obviate these difficulties, a new technique was devised using a flap of rectus muscle that acted as a cushion between the cuff and the bowel wall. Results in five dogs showed that bowel wall ischemia is avoided with cuff pressure of 51-60 cm applied constantly for four weeks while providing pressure to leak around the closed cuff with a pressure of 62-75 cm water. Further study is needed to confirm the long-term effect of this technique on the bowel wall and the ability of the sphincter to maintain continence.
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The cellular process regulating the post-translational poly(ADP-ribosylation) of various nuclear acceptor proteins is discussed in relation to its significance as a target for cancer chemotherapy; and with particular reference to the mechanism underlying the anti-tumor effects of the cell differentiating agent, hexamethylenebisacetamide. Of special note are the influences which may be exerted on tumor cells expressing certain major types of oncogenically-activated cellular proto-oncogenes (oncogenes). A basis for a pharmacological approach to tumor therapy is further proposed from considerations of the action of a class of anti-tumor agents, the N6-substituted adenosines, by reason of their possible effects on poly(ADP-ribosylation) processing, as well as on other cellular processes of relevance for tumor therapy.
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We have derived sets of human monoclonal antibodies by fusing lymphocytes from cancer patients with a human lymphoid line, LICR-LON/HMy2. Two antibodies, LGL1.1D6 and LLU6.3A4, derived from patients with glioma and bronchial carcinoma respectively, were selected for clinical study on the basis of binding patterns in radioimmunoassays with tumour cell lines and localisation of human tumour xenografts. Highly purified monoclonal antibodies were prepared using bulk supernatants from hybridomas grown in serum free medium. After radiolabelling with 131I, 1 mg antibody was injected intravenously into patients with advanced glioma and carcinoma of the bronchus. Good localisation was obtained in five out of eight patients with glioma and five out of seven patients with carcinoma of the bronchus. Despite the technical difficulties inherent in the production of human monoclonal antibodies this study demonstrates their potential for the clinical localisation of solid tumours.
A novel and unique mechanism for formaldehyde-induced mutagenesis is described which is mediated by the formation of an N6-substituted adenine ribonucleoside analogue, N6-hydroxymethyl adenosine, after an in vitro reaction of formaldehyde with adenosine. This type of ribonucleoside analogue (the deoxyribose derivative is ineffective) exhibits a powerful and remarkable germ-cell-stage-specific mutagenic effect in male Drosophila larvae, apparently by interfering with DNA repair. Circumstantial evidence is presented which indicates that the analogue most probably acts by its utilisation in the synthesis of diadenosine tetraphosphate (Ap4A) to form an antimetabolite(s) of Ap4A which subsequently interferes with Ap4A-mediated intracellular events, amongst which an effect on DNA repair would appear to be its mutagenic mechanism of action.
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A lectin with an affinity for certain sulphated polysaccharides, such as fucoidin and dextran sulphate, has been isolated from the vitelline membrane of hens' eggs and purified to homogeneity as assessed by two-dimensional gel electrophoresis. Polyclonal and monoclonal antibodies have been raised to the lectin and used in indirect immunofluorescence microscopy to localize the agglutinin in the outer layer of the vitelline membrane, where the lectin persists prior to the breakdown of the vitelline membrane. The quantity of lectin extracted from the two layers of the membrane, which have been separated by the method of Bellairs, Harkness & Harkness (1963), correlated well with the results of immunofluorescence microscopy. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis of the two layers of the membrane indicates that each layer has a distinctive polypeptide composition, the outer layer containing in particular lysozyme and avidin. The evidence obtained in this study indicates that the lectin is not involved in adhesion of the blastoderm to the vitelline membrane; neither is it involved in the expression of the blastoderm nor in maintaining the strength of the membrane. The possible roles in promoting transport of solutes across the membrane as well as providing bactericidal properties to the egg are discussed.
We have investigated the ability of various predictive studies to assess which monoclonal antibody (MCA) will be most useful in the immunoscintigraphic localization of metastatic colorectal carcinoma. A set of MCAs was obtained by fusing splenic lymphocytes from rats immunized with membrane preparations from fresh human colorectal cancer. Supernatants from 17 cloned hybridomas were found to bind strongly to colon carcinoma lines by indirect radioimmunoassay. Immunofluorescence using these MCAs on sections of fresh frozen colon carcinoma and normal tissue revealed different staining patterns. Nine MCAs were purified and labelled with 131I. Groups of mice bearing human colorectal tumour xenografts were given radiolabelled MCA and scanned. Six out of the nine MCAs showed tumour localization as determined by rectilinear scanning. Three MCAs which gave good tumour images in mice were selected for clinical evaluation in patients with advanced colorectal cancer. One gave good tumour images, another targeted to bone marrow and the third bound almost exclusively to normal liver. Clinical evaluation is clearly essential in the selection of MCAs for tumour localization.
A putative protective Plasmodium knowlesi antigen, recognized by two monoclonal antibodies which prevent invasion of erythrocytes by merozoites in vitro, is synthesised only by schizonts with 7 or more nuclei, during the last 1.5-2 h of the 24 h erythrocytic cycle of parasite development. The 66 000 MW antigen, which constitutes a minor parasite protein, is processed at the time of schizont rupture and merozoite release, to give rise to two smaller molecules of 44 000 and 42 000 MW. The 44 000 and 42 000 MW antigens and traces of the 66 000 MW antigen are present on the surface of isolated merozoites and the smaller antigens are readily shed. The antigens which are shed are soluble in culture medium and are not readily degraded further. None of the molecules can be detected in newly invaded ring stage parasites, indicating that they are either excluded when the merozoite invades, or if internalised, they rapidly undergo further structural alteration since newly parasitised red cells no longer contain epitopes which react with the inhibitory monoclonal antibodies. This antigen is distinct from other putative protective antigens described in bloodstage malaria parasites.
Two rat monoclonal antibodies (both IgG2a isotype and having closely related specificities) and a pool of rhesus immune IgG, all of which inhibit Plasmodium knowlesi merozoite invasion of rhesus erythrocytes, have been studied before and after proteolytic digestion. The F(ab')2 and Fab fragments of both rat monoclonal antibodies show considerably enhanced inhibition of merozoite invasion as compared with the intact IgG. Inhibition by monovalent fragments indicates that these antibodies are not dependent upon merozoite agglutination and may act by blocking merozoite attachment to the specific red cell receptor. The fact that the inhibitory activities of F(ab')2 and Fab are equally enhanced on a weight basis, as compared with IgG, suggests that the removal of Fc may reduce electrostatic repulsion between antibody and merozoite surface, both of which are negatively charged at neutral pH. By contrast, papain digestion of polyclonal IgG derived from an immunised rhesus pool markedly reduces its inhibitory activity. This suggests that much of the inhibition mediated by polyclonal IgG results from merozoite agglutination and that the specificity of the rat inhibitory monoclonal antibodies is poorly represented in the immune pool. The P. knowlesi antigen reactive with the inhibitory monoclonal antibodies is known to be synthesized as a minor 66 kDa polypeptide during the last 1.5 h. of schizont development and is processed to smaller products (44 and 42 kDa) present on the merozoite surface. The present results suggest that this antigen may have particular interest as a vaccine against P. knowlesi malaria.
Monoclonal antibodies allow the precise definition of molecular components present on tumour cell surfaces. Some human monoclonal antibodies prepared by fusing intratumoral lymphocytes from patients undergoing craniotomy for malignant glioma with cells from a specially derived human lymphoid line (LICR-LON-HMy2) bind to glioma surface components. To study the feasibility of continuous administration of human monoclonal antibodies directed against glioma we designed a chamber which enables hybridoma cells to be cultured in the subcutaneous tissue. This chamber allows antibodies to diffuse out, and nutrients and oxygen necessary for continued cell viability to diffuse in. Cells are unable to traverse the membrane pores of the device, so there is no risk that malignant cells put in the chamber can metastasise. The chamber has now been inserted in one patient with recurrent glioma, in whom the kinetics of internally labelled antibody release has been monitored.
The monoclonal antibody W6/32.1 recognizes a public determinant on the HLA-A, B and C antigens of all tested human haplotypes. Though the antibody does not bind to normal mouse cells of any H-2 haplotype, it does show an unexpected specificity for the T cell leukemia line MBL-2 from a C57BL/6 mouse. It is shown that the murine antigen recognized by W6/32.1 is on an H-2-like molecule which also carries the determinant recognized by the monoclonal antibody B22-249 R1, specific for the H-2Db antigen. Unlike B22-249 R1, however, W6/32.1 does not bind to normal H-2b lymphocytes, nor to a variety of tumor cell lines of the H-2b haplotype. This cross-reaction is specific to W6/32.1, and is not shared by other monoclonal antibodies of similar anti-HLA specificities. Moreover, the affinity of W6/32.1 for its human antigen is substantially higher than for its mouse antigen. We conclude that W6/32.1 fortuitously recognizes a novel determinant on the H-2Db antigen of MBL-2, rather than an extensive region of structural homology shared between HLA and H-2. Thus for cells of the H-2b allotype this determinant is detected only on MBL-2, and by definition is thus an example of a tumor-associated antigen.
Lymphocytes from 180 patients with a variety of malignant diseases were collected and fused with a human myeloma-derived line, LON-LICR-HMy2/CAM1. A total of 162 hybridomas was obtained. Only B lymphocyte markers were found on the surface of the fusion products. Flow cytometric analysis revealed a stably increased DNA content in the hybridoma cells. Some hybridoma supernatants were found to contain new Ig chains. Anti-tumour binding activity was found in 12 supernatants.
Human monoclonal antibodies were produced by fusing intratumoral lymphocytes from patients with malignant gliomas with a human myeloma line. One antibody was selected for further study after screening for binding activity to glioma cell lines. The patient from whom it was derived developed recurrent glioma. 1 mg of antibody was purified, radiolabelled with 131I, and administered intravenously. The distribution of antibody was determined in the blood, CSF and tumour cyst fluid and compared with that of a control human monoclonal immunoglobulin. Antibody localisation in the tumour was observed and confirmed by external scintiscanning.