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Biomedical subjects

A J Bell

Publications and source records attributed to A J Bell.

At least 19 recordsLinked to original sources
PubMed1995

Treatment of B-cell lymphomas with combination of bispecific antibodies and saporin.

We report the use of a bispecific F(ab')2 antibody to target the ribosome-inactivating protein saporin to the surface antigen CD22 in the treatment of low-grade, end-stage, B-cell lymphoma. Four patients were treated. Toxic effects were minimal (grade I), with mild fever, weakness, and myalgia for 1-2 days after treatment. One patient showed an antibody response to mouse Fab' and saporin. All patients showed rapid and beneficial responses to treatment with improvements in most disease sites and in peripheral blood cytopenia. The responses were short-lived (less than 28 days) but further study of this targeting system is warranted.

Antibodies, Bispecific↗
PubMed1995

Double-blind, placebo-controlled investigation of the effect of combined phototherapy/low intensity laser therapy upon experimental ischaemic pain in humans.

BACKGROUND AND OBJECTIVE: This study assessed the putative analgesic effect of combined monochromatic light/laser irradiation at low intensity (660-950 nm; 31.9 J/cm2; pulsed at 16 or 73 Hz). STUDY DESIGN/MATERIALS AND METHODS: The investigation was completed under double-blind conditions using a standardised form of the submaximal effort tourniquet technique. Healthy male volunteers naive to the experimental conditions (n = 45) attended on two occasions for the purposes of pain induction, the first during which baseline data were obtained and on a second occasion during which they were randomly allocated to one of two treatments or a placebo condition. For the treatment conditions, irradiation was applied to the ipsilateral Erb's point at the parameters stated; for the placebo condition, sham "irradiation" was delivered using a dummy unit. Pain was measured using computerised visual analogue scales and McGill Pain Questionnaires (MPQ) to assess "current pain intensity" and "worst pain experienced," respectively. RESULTS: Analysis of variance and appropriate post hoc tests demonstrated only a weak (but significant) hypoalgesic effect compared to placebo (P < 0.05) in the treatment group irradiated at 16Hz for the sensory component of the MPQ; other comparisons were found to be nonsignificant. CONCLUSIONS: These results do not provide convincing evidence for the hypoalgesic potential of combined monochromatic light/laser irradiation, at least at the parameters used here, and thus indicate the necessity of additional work to investigate this modality further in order to assess the potential benefit, if any, of such treatment in the clinical setting.

Analgesia↗
PubMed1995

An information-maximization approach to blind separation and blind deconvolution.

We derive a new self-organizing learning algorithm that maximizes the information transferred in a network of nonlinear units. The algorithm does not assume any knowledge of the input distributions, and is defined here for the zero-noise limit. Under these conditions, information maximization has extra properties not found in the linear case (Linsker 1989). The nonlinearities in the transfer function are able to pick up higher-order moments of the input distributions and perform something akin to true redundancy reduction between units in the output representation. This enables the network to separate statistically independent components in the inputs: a higher-order generalization of principal components analysis. We apply the network to the source separation (or cocktail party) problem, successfully separating unknown mixtures of up to 10 speakers. We also show that a variant on the network architecture is able to perform blind deconvolution (cancellation of unknown echoes and reverberation in a speech signal). Finally, we derive dependencies of information transfer on time delays. We suggest that information maximization provides a unifying framework for problems in "blind" signal processing.

Algorithms↗
PubMed1994

Identification of the poly-L-proline-binding site on human profilin.

Profilin is a ubiquitous protein that has been implicated in the signaling pathway leading to cytoskeletal rearrangement in cells. An unusual property of profilin is its high binding affinity for poly-L-proline (PLP). This binding property is conserved in the profilins from diverse species with little sequence homology. We have monitored the binding of PLP to profilin by fluorescence and nuclear magnetic resonance spectroscopies. NMR spectroscopy has identified several residues whose amide nitrogen and amide hydrogen chemical shifts are significantly perturbed by binding of PLP. The affected residues are located at various locations throughout profilin's primary structure; however, mapping the location of the affected residues onto the recently determined three-dimensional solution structure of human profilin indicates that the effects of PLP binding are highly localized. Poly-L-proline binds profilin at the hydrophobic interface between profilin's NH2- and COOH-terminal helices and the upper face of its antiparallel beta-sheet. In contrast, residues located on the opposite side of the profilin structure are unaffected. The extent of the potential interaction surface of the PLP-profilin complex suggests that as few as 6 contiguous prolines would be sufficient for binding profilin. Examination of sequence data bases indicates that stretches of prolines of this length and longer occur in numerous regulatory proteins, suggesting that the ability of profilin to bind polyproline may be an important component of its signaling capabilities.

Amino Acid Sequence↗
PubMed1994

Mechanisms in removal of tumor by antibody.

We report two preliminary trials of antibody treatment of B-cell lymphoma. Advanced lymphoma was treated with chimeric FabFc2, in which mouse Fab' gamma is linked to two human Fc gamma 1 fragments so as to recruit natural effectors to tumor targets. Terminal lymphoma was treated with bispecific antibody (BsAb) which recruits the ribosome-inactivating protein saporin. These different mechanisms led to interesting differences in patterns of tumor clearance. Eight patients were treated with chimeric antibody of two specificities, each at 12 mg/kg: anti-CD37, plus either anti-CD38 or anti-CD19 according to tumor phenotype. On completion of the 3-wk treatment, residual plasma antibody had a half-life exceeding 10 d. Tumor cells in blood disappeared rapidly. However significant reductions in solid masses occurred in only three patients, becoming apparent 3-4 wk after beginning treatment and then continuing slowly. Five patients were treated with preformed immune complexes of saporin and F(ab' gamma)2 BsAb. Although doses of saporin reached 10 mg weekly, contact with the tumor can only have been fleeting: plasma antibody was undetectable (< 0.5 micrograms/mL) 48 h after infusion, whereas the saporin disappeared even faster and was undetectable (< 4 ng/mL) at 24 h. Tumor cells disappeared from the blood more slowly than occurred with chimeric antibody. In contrast shrinkage of extravascular tumor was more rapid, and occurred in all patients, but proved less durable.

Antibody Specificity↗
PubMed1994

Long-term outcome of post-partum psychiatric illness requiring admission.

Among 65 women admitted to a mother and baby unit within 6 months post-partum, 53 were followed up for an average of 8.8 years. Women who had no previous history of psychiatric illness or who had experienced previous puerperal illness only, did significantly better at follow-up. The majority of these women had presented with a clinical picture of major depression. Past psychiatric history is confirmed as an important prognostic indicator in post-partum illnesses.

Adolescent↗
PubMed1994

Effects of low intensity infrared laser irradiation upon conduction in the human median nerve in vivo.

The current investigation, for which ethical permission was obtained, was designed to assess the putative neurophysiological effects of low intensity (9.6 J/cm2) laser (830 nm) irradiation upon conduction latencies in the human median nerve in vivo. Antidromic nerve conduction studies were performed on the non-dominant arms of healthy human volunteers (n = 51), who were each assigned to one of a variety of laser, placebo or control groups under randomized, blinded conditions. Analysis of negative peak latency differences using analysis of variance showed small (approximately 0.4 ms) but significant increases in latencies as a result of direct laser irradiation, and, where two-site recording was used, distal to the site of irradiation. No such differences were seen in the other experimental groups. These results show that laser irradiation applied to intact skin at the parameters used here may produce a direct, localized effect upon conduction in underlying nerves.

Adult↗
PubMed1993

Relaxation study of the backbone dynamics of human profilin by two-dimensional 1H-15N NMR.

The dynamic properties of 111 backbone HN sites in uncomplexed human profilin, a protein of 139 residues, have been characterized by two-dimensional inverse-detected 1H-15N NMR spectroscopy. Heteronuclear (1H)-15N nuclear Overhauser effects and 15N longitudinal and transverse relaxation rates have been analyzed in terms of model-free spectral density functions and exchange contributions to transverse relaxation rates. Relatively high mobilities on the nanosecond time-scale are observed for Asp26 and Ser27, which form part of a loop connecting beta-strands A and B, and for Thr92 through Ala95, which are in a loop connecting beta-strands E and F. Significant exchange contributions, indicative of motions on the microsecond to millisecond time-scale, have been obtained for 30 residues. These include Leu77, Asp80 and Gly81 of a loop between beta-strands D and E, Ser84 and Met85 of beta-strand E, Gly121 of a loop connecting beta-strand G and the C-terminal helix, and Gln138, which is next to the C-terminal residue Tyr139. Some of the regions showing high flexibility in profilin are known to be involved in poly-L-proline binding.

Amino Acid Sequence↗
PubMed1993

Characterization of the three-dimensional solution structure of human profilin: 1H, 13C, and 15N NMR assignments and global folding pattern.

Human profilin is a 15-kDa protein that plays a major role in the signaling pathway leading to cytoskeletal rearrangement. Essentially complete assignment of the 1H, 13C, and 15N resonances of human profilin have been made by analysis of multidimensional, double- and triple-resonance nuclear magnetic resonance (NMR) experiments. The deviation of the 13C alpha and 13C beta chemical shifts from their respective random coil values were analyzed and correlate well with the secondary structure determined from the NMR data. Twenty structures of human profilin were refined in the program X-PLOR using a total of 1186 experimentally derived conformational restraints. The structures converged to a root mean squared distance deviation of 1.5 A for the backbone atoms. The resultant conformational ensemble indicates that human profilin is an alpha/beta protein comprised of a seven-stranded, antiparallel beta-sheet and three helices. The secondary structure elements for human profilin are quite similar to those found in Acanthamoeba profilin I [Archer, S. J., Vinson, V. K., Pollard, T. D., & Torchia, D. A. (1993), Biochemistry 32, 6680-6687], suggesting that the three-dimensional structure of Acanthamoeba profilin I should be analogous to that determined here for human profilin. The structure determination of human profilin has facilitated the sequence alignment of lower eukaryotic and human profilins and provides a framework upon which the various functionalities of profilin can be explored. At least one element of the actin-binding region of human profilin is an alpha-helix. Two mechanisms by which phosphatidylinositol 4,5-bisphosphate can interfere with actin-binding by human profilin are proposed.

Amino Acid Sequence↗
PubMed1993

Assessment of reperfusion in myocardial infarction by body surface electrocardiographic mapping.

To determine the efficacy of body surface potential mapping to detect and quantify reperfusion in acute infarction, 66 patients were studied by repeated body surface potential mapping before and after administration of the thrombolytic agent. The QRS and ST-segment were analyzed and compared to the arterial patency as assessed by arteriography within 10 days. The infarct-related vessel was patent in 50 patients and occluded in the remaining 16. In 6 of the 15 patients in whom thrombolytic therapy was started within 2 hours of the onset of chest pain the ST-segment changed from that of an acute infarction pattern to that of a normal pattern, and the QRS pattern either remained normal or recovered prior to discharge. In two additional patients the QRS pattern returned to normal prior to discharge from the hospital. In the 51 patients with later thrombolytic therapy (> or = 2 hours) the degree of ST elevation and depression decreased more than either the control infarction group (36 inferior and 73 anterior patients) or the group in whom reperfusion attempts were unsuccessful, but the pattern of the map remained that of an infarction. The QRS maps showed that in the first 48 hours recovery of potential was insufficient to distinguish those with successful thrombolysis. Early reperfusion could be detected by body surface potential mapping and the eventual damage predicted from the degree of change in the QRS map. Later reperfusion could be surmised but not quantified.

Electrocardiography↗
PubMed1993

Electrical current paths in acute pericarditis.

The electrocardiographic changes accompanying pericarditis consist of ST elevation in most of the leads of the 12-lead electrocardiogram. The source of this ST elevation is thought to be local inflammatory changes in the epicardium underlying the inflamed pericardium. The current from this area of ST elevation must return to some unaffected region of the heart and this should be associated with a region of ST depression. This current path from the external epicardial surface has been postulated to flow back into the endocardium through the great vessels and atria. To test this hypothesis, 18 patients with pericarditis were studied by body surface potential mapping and inverse epicardial potential distributions were computed. The resultant maps were compared to those of normal people and patients with acute anterior infraction. Epicardial maps from patients with pericarditis showed a region of current flow into the heart over the great vessels and atria in all 18 patients. This pattern was not seen in normal patients or infarction patients and was consistent with the mechanism resulting in ST elevation in pericarditis being one of current flowing from the epicardium out into the thorax and back into the heart through the great vessels and atria.

Acute Disease↗
PubMed1993

Lithium-induced parathyroid dysfunction: a case report and review of the literature.

OBJECTIVE: Twenty-six cases of lithium-induced hyperparathyroidism have been reported in the literature. This article describes an additional case that illustrates current management recommendations. DESIGN: Case report. Clinical presentation and proposed mechanisms of the suspected drug-induced effect are discussed. CONCLUSIONS: Serum calcium concentrations should be determined before and periodically during long-term lithium carbonate therapy. Discontinuation of therapy in patients who develop lithium-induced parathyroid dysfunction generally corrects calcium and parathyroid hormone concentrations. Surgery is indicated in patients with complications of hyperparathyroidism.

Adult↗
PubMed1992

Prevalence of overweight and obesity in Down's syndrome and other mentally handicapped adults living in the community.

To find out the prevalence of overweight and obesity in the mentally handicapped, 183 subjects living in the community were studied; 58 of whom had Down's syndrome. It was found that 70.58% of males and 95.83% of females with Down's syndrome, and 49.29% males and 62.96% females from other mentally handicapped subjects, were categorized as overweight and obese, compared with 40% of males and 32% females in that category from normal population.

Adult↗
PubMed1991

Preliminary studies for an immunotherapeutic approach to the treatment of human myeloma using chimeric anti-CD38 antibody.

Multiple myeloma is a disease in which conventional chemotherapy has only limited value, but which may be ideal for treatment with passive antibody against a suitable cell surface antigen on the neoplastic plasma cell. The CD38 antigen is known to be present on the majority of neoplastic plasma cells, and this was confirmed by detailed examination of bone marrow aspirates from three patients. Strong expression of CD38 was confined to cells which, by the criteria of light-scattering profiles and possession of cytoplasmic Ig, were plasma cells. The vast majority of neoplastic plasma cells appeared to be involved. Using a cell line as a model, it was found that the CD38 antigen acts as a target for a chimeric antibody prepared from the antibody OKT10. The chimeric antibody consists of the Fab portion of the mouse monoclonal antibody linked by a stable thioether bond to an Fc molecule derived from human IgG1, thereby forming mouse Fab-human Fc. In contrast to the parent antibody, the chimeric molecule mediates antibody-dependent cellular cytotoxicity (ADCC) very efficiently with human blood mononuclear effector cells, and is effective at low concentration. Also, even though the CD38 antigen is present on natural killer cells, there appears to be little deleterious action of the antibody on effector cell function. The antibody also failed to affect the growth of progenitor cells of the granulocyte/macrophage or erythroid lineages present in normal bone marrows, despite the suspicion that these cells express the antigen. Other advantages of the CD38 molecule are that it is not found in the serum of patients with myeloma, and it does not appear to modulate in vitro. Fourteen patients with florid myeloma and on various chemotherapeutic regimes had an undiminished capacity to mediate ADCC with the chimeric antibody, when compared with normal individuals. The maintenance of ADCC activity, coupled with the known suppression of the antibody response in these patients, augers well for treatment with chimeric antibody.

ADP-ribosyl Cyclase↗
PubMed1991

Red cell aplasia in myelodysplastic syndrome.

Six cases of red cell aplasia occurring in patients with myelodysplastic syndromes (MDS) showed a diversity of clinical course and prognosis. In some patients red cell aplasia may have represented an evolution of MDS while in others autoimmune destruction of erythoblasts may have been the mechanism. A proliferative phase is seen in many of these patients, the clinical importance of which is uncertain.

Aged↗