Biomedical subjects
Publications and source records attributed to L Henderson.
We report a patient with atypical Guillain-Barré syndrome associated with acute rhabdomyolysis. Rhabdomyolysis may be the cause of elevation of creatine kinase sometimes seen in patients with Guillain-Barré syndrome.
The rat carotid body tissue reveals a photometrically measurable haem signal with absorbance maxima at 560 nm, 518 nm and 425 nm, suggesting the presence of a b-type cytochrome; this was confirmed by pyridine haemochrome and CO spectra. The quantity of cytochrome b was estimated to be 310 pmol.mg of protein-1. This haem is capable of H2O2 formation, which can be inhibited by 10 microM-diphenyliodonium (DPI). The hypoxia-induced increase in nervous chemoreceptor discharge and the reduction of FAD and NAD(P)+ were also inhibited by DPI (10 microM). These results suggest that an oxidase such as the NAD(P)H oxidase of neutrophils may act as a pO2 sensor protein in the rat carotid body, probably inducing the pO2 chemoreceptor process by H2O2 formation.
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Two experiments are reported in which high-compatibility reaction time (RT) tasks were performed with, and without, a concurrent secondary task. In both experiments, the secondary task interfered to a greater extent with simple RT than with choice RT. In fact, the effect of adding a secondary task was to eliminate the advantage of simple RT over two-alternative-choice RT. Previous studies of this phenomenon employed a task in which subjects raised a finger when it received tactile stimulation, while engaging in continuous reading aloud. The present experiments show that the effect can be obtained using a different stimulus modality (vision) as well as other responses (vocal) and secondary tasks (shadowing, auditory step-tracking). The paradigm provides a means of isolating preparatory processes that are peculiar to the simple RT task.
Lonidiamine is a novel indazole-carboxylic acid with antitumour properties; it has been studied for potential mutagenicity in a comprehensive battery of tests. In assays for the induction of gene mutations in prokaryotes (Ames test) and eukaryotes (induction of HPRT mutations in CHO cells), negative results were obtained. There was no evidence of the induction of chromosomal damage in cultured mammalian cells in vitro. No mutagenic activity was observed in tests for chromosomal damage in vivo, in somatic cells (micronucleus test) or in germinal cells (dominant lethal test). These negative results are consistent with observations indicating that lonidamine affects cellular energy processes, rather than the mechanisms of cell division. The lack of mutagenic properties suggests that lonidamine may present significant advantages in treatment of some tumours, offering a reduced risk of resistant clones, secondary cancer and heritable genetic damage.
Antisaccades were studied in ten patients with mild to moderate Parkinson's disease and ten age-matched normal controls. Remembered saccades and reflex saccades were assessed for comparison. In the population of patients who showed the previously reported abnormalities of remembered saccades, antisaccades were indistinguishable from those of controls in latency, gain and peak velocity. This finding implies that antisaccades are mediated through pathways which are unaffected by Parkinson's disease, and which are therefore presumably distinct from pathways mediating other voluntary saccades.
As part of the third UKEMS collaborative trial, the induction of mutations in mouse lymphoma L5178Y cells was analysed by an agar cloning method. The method used was based on the published methods of Clive and co-workers and Amacher and co-workers. Mutations at the thymidine kinase (tk) locus were analysed following exposure to ethylmethanesulphonate (EMS) in the absence of S9 mix, benzo[a]pyrene (B[a]P) in the presence of S9 mix and benzidine (BZD) in the absence and presence of S9 mix. Mutations were induced under all these conditions and no difference was found between a 48-h and 72-h expression period. Small and large colonies on trifluorothymidine (TFT) selective plates were expanded and found to be stably resistant to TFT. The effects of varying the S9 level and the composition of the cofactor mix on the mutagenicity of BZD and B[a]P were also analysed. The ability of BZD to induce mutations at the hprt locus was investigated. No mutations were detected either in the presence or absence of S9 mix.
DNA ethylations were measured in four mammalian cell lines, Chinese hamster ovary CHO, mouse lymphoma L5178Y t k+/-, human lymphoblastoid TK6 and Chinese hamster V79, following exposure to [3H]ethyl methanesulphonate. Concurrent estimates of cytotoxicity and gene mutation were also carried out. Total DNA-binding and relative levels of ethylation at N-7 guanine (N-7G), O6 guanine (O6G) and N-3 adenine (N-3A) were essentially the same in all four cell lines. Differences in response to EMS between the cell lines, namely the greater cytotoxicity in TK6 cells, would therefore appear to reflect subsequent handling of the DNA lesions, rather than different levels of DNA ethylation in the cell lines.
Rapid eye movements (saccades) were examined in 7 patients with idiopathic Parkinson's disease (PD) and a matched group of normal control subjects. The effect of instructional and stimulus conditions used to elicit saccades was examined using 3 experimental paradigms. Eye movements directly elicited by a novel peripheral target were unimpaired in patients with PD as compared with control subjects. Saccades to a remembered target location, however, were dysmetric in the PD group and showed a characteristic multistepping pattern. The PD impairment was not caused by a loss of information on target location since their final eye position was close to the target at all eccentricities. Peak velocity, duration, and latency did not distinguish between PD patients and controls. These results support the view that for saccades which are not directly elicited by a visual target there is a neural pathway that can be distinguished from structures involved in the generation of visually elicited (or 'reflexive') saccades. The finding that in PD saccades to a remembered target are selectively impaired suggests that structures in the basal ganglia play a crucial role in this alternative pathway.
In a coincidence timing task, Parkinsonian patients and a control group were instructed to synchronize a keypress with the onset of a visual signal which had been preceded by a regular train of warning signals. Although the Parkinsonian group had previously exhibited slower reactions in a conventional simple reaction-time task, they were able to generate predictive responses that fell as close to the target onset as the controls' but showed greater variability. In a second experiment, Parkinsonian patients and controls made saccadic eye movements to a visual target that stepped at regular intervals between two fixed locations. After a few trials all the subjects tended to make predictive saccades that were initiated before the target excursion. However, the Parkinsonian group were slower to develop this strategy and when they did their saccades became considerably more hypometric than those of the controls. Both groups were able to maintain predictive responding even when the visual target disappeared and responses were paced by a buzzer. We concluded that Parkinsonian patients are capable of initiating predictive responses of the eye and the hand, at least in some circumstances, but such responses tend to be inaccurate in execution. This, in turn, may dispose the Parkinsonian patient against predictive movement.
Aging is associated with the appearance of a selective proteinuria which cannot be attributed to any specific underlying renal disease. The present studies were conducted in conscious, chronically catheterized young (3-4 months), non-proteinuric male rats and old (22-25 months), proteinuric males to determine the mechanism(s) of the proteinuria. Compared with young males, old proteinuric rats had increased blood pressure, reduced glomerular filtration rate (GFR) and renal plasma flow and heavy proteinuria. Fractional clearance of neutral dextran (D) and anionic dextran sulfate (DS) were both significantly increased at the 36 A molecular radius in old rats; the increase in DS fractional clearance being greater than the increase in D fractional clearance. The proteinuria of aging is therefore due to moderate increases in glomerular permeability and, more importantly, to loss of fixed glomerular polyanion. Striking glomerular morphologic changes were also evident in the old rats including thickening of the glomerular basement membrane and extensive glomerular sclerosis.
The nicotinic acetylcholine (ACh) receptor channel mediates synaptic transmission at the neuromuscular junction. During the development of skeletal muscle, ACh receptors undergo changes in distribution, antigenic determinants, degradation rate, and function. Now that these developmental hallmarks have been identified, attention has turned toward understanding both the structural bases for such changes and the role of nerve in triggering these changes. Recently, a much clearer understanding of one of these developmental processes, namely, the alterations in channel function, has emerged through both sensitive patch-clamp measurements and the application of recombinant DNA technology. In light of these new advances, we now reevaluate the processes governing the developmental changes in the functional properties of the ACh receptor.
We have used the T-Lymphocyte cloning technique as a method of monitoring the human population for somatic cell mutant frequency. We present a statistical analysis of the experimental factors which may influence the observed mutant frequency. We have obtained consistently high plating efficiencies of T-cells from the mononuclear cell fraction from donor blood samples (mean of 56%, based on 123 observations from 70 individuals). Nevertheless, an inverse correlation of mutant frequency with plating efficiency was observed, and some experimental factors (serum and interleukin-2 batch, and worker) may have a significant effect on the observed mutant frequency. We discuss the difficulties that these possible effects present in establishment of a reference database and design of long-term studies. No significant effect of donor sex on mutant frequency was observed, but age (1.3% increase per year for normal adults) and smoking (56% increase over normal non-smokers) both significantly increased the mutant frequency. We discuss the utility of the assay for the monitoring of populations for heritable DNA damage, and we compare the results to those obtained with lymphocytes using other endpoints, e.g. chromosome aberrations, micronuclei and sister-chromatid exchange.
We have measured clonal survival following gamma-irradiation of unstimulated (G0) T-lymphocytes from 35 donors, of 11 T-lymphocyte cell lines, of six lymphoblastoid cell lines, and of nine primary fibroblast strains for which we have G0 T-lymphocyte material from the same donor. Amongst the G0 lymphocytes we have results from nine normal donors, from eight cord bloods, from seven ataxia-telangiectasia (A-T) patients and from nine A-T heterozygotes. Although there is some variation between samples, G0 T-lymphocytes from normal donors appear to be slightly more radioresistant than T-lymphocyte lines, with a more shouldered survival curve. From our limited sample, lymphoblastoid cell lines appear to be slightly more radiosensitive than T-lymphocytes. The overall radiosensitivity of primary fibroblasts appears to be broadly similar to that of G0 T-lymphocytes. In nine instances, five A-Ts and four A-T heterozygotes, both G0 T-lymphocytes and primary fibroblasts from the same donor were tested. In five cases there was closely similar radiosensitivity in the two cell types, but in four cases there was some discrepancy. Further work, especially with normal donors, will be required in order to establish how reliably radiosensitivity in other cell types can be predicted from that of G0 T-lymphocytes. In all cell types the hypersensitivity of A-T cells was confirmed. Furthermore, the marginally greater sensitivity of A-T heterozygotes, when compared as a group with normals, was confirmed with G0 T-lymphocytes. Our results also suggest a slightly increased radiosensitivity in G0 T-lymphocytes from some, but not all, cord blood samples.
Sister-chromatid exchange (SCE) frequencies have been measured in lymphocytes and fibroblasts of patients with systemic lupus erythematous (SLE) and healthy controls, and in lymphocytes of control patients with serum anti-nuclear antibodies (ANA) but no other disease manifestations of SLE. The SCEs of SLE lymphocytes were higher than those of the controls but the SCEs of the SLE fibroblasts did not differ from those of the controls. The SCEs of the controls with positive ANA did not differ significantly from those of the healthy controls. There was no correlation between SCE frequencies of the SLE lymphocytes and disease activity determined by many clinical and laboratory measurements. Primary and secondary DNA-repair defects in SLE cells are considered.
A method of detecting 6-thioguanine-resistant lymphocytes by the cloning of T-lymphocytes in microtitre wells is evaluated for its usefulness in population monitoring. Factors shown to affect the cloning efficiency of lymphocytes include the strain and irradiation level of the lymphoblastoid feeder cells and the use of a pre-incubation period in bulk culture without mitogenic stimulus before plating at limiting dilutions. Cord blood samples have markedly lower mutant frequencies than adult blood samples. The adult range was 8.0 X 10(-7) to 1.8 X 10(-5). Seven males and seven females aged between 23 and 47 years were sampled. No effect of sex or age was found. Individual samples which were divided at collection and treated separately did not vary from each other, but repeat samples taken at different times showed up to a 2-fold variation. The application of this method in population monitoring is discussed.
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The effect of diethylstilboestrol-dipropionate on the frequency of SCEs and micronuclei, cytotoxicity, aneuploidy and cell proliferation rates of foetal liver and maternal bone marrow cells following exposure of pregnant mice was measured. An increase in the number of aneuploid and polyploid cells was observed in both tissues. There was no effect on micronuclei frequency, SCE frequency, or cell proliferation rate.