Showing papers by "St Thomas' Hospital published in 1985"

Direct evidence that reverse cholesterol transport is mediated by high-density lipoprotein in rabbit.

Abstract: Mammalian cells obtain cholesterol for membrane synthesis mostly via the receptor-mediated endocytosis of low-density lipoprotein (LDL)1. Macrophages and vascular endothelium additionally have receptors that recognize certain modified forms of LDL (for example, acetyl-LDL)2,3. The process by which cholesterol returns from peripheral cells to hepatocytes (reverse cholesterol transport) has not been established; although tissue culture studies have favoured high-density lipoprotein (HDL) as the principal vehicle4,5, the in vivo evidence for this is meagre. When cholesterol-loaded macrophages are incubated in medium containing plasma, cholesterol moves from the cells to HDL and is then esterified by lecithin/cholesterol acyltransferase6. The accumulation of cholesteryl esters in the particles increases their size and decreases their density; enrichment with apoprotein E (apo E) also occurs, producing a decrease in electrophoretic mobility7,8. We now report that similar changes occur in the circulating HDL of rabbits, when their peripheral tissues are loaded with cholesterol by intravenous (i.v.) injection of acetylated or native human LDL. This result suggests that HDL is involved in reverse cholesterol transport in vivo.

Luminance and darkness detectors in the olivary and posterior pretectal nuclei and their relationship to the pupillary light reflex in the rat. I. Studies with steady luminance levels.

Abstract: In order to identify the pretectal nucleus which contains pupillomotor cells in the rat, cells were sought which were sensitive to changes in luminance level at the eye. Two types were found: Luminance detectors which showed a graded increase in firing with increase in luminance, and darkness detectors which showed a graded increase in firing rate with graded dimming of luminance intensity. All luminance detectors were located in the olivary pretectal nucleus, whereas darkness detectors were located in the posterior pretectal nucleus. Consensual pupil responses were recorded in conscious normal and sympathectomised rats using an infra-red sensitive T.V. pupillometer. Pupil diameter varied 2mm in an approximately linear fashion over six log units range in luminance intensity. Sympathectomy produced a general constriction of the pupil, but the overall response to light was unaffected. The changes in pupil size occurred over the same range of luminance that the firing rates of both luminance and darkness detectors changed. The olivary pretectal nucleus may therefore be involved in pupilloconstruction in the light, and the posterior pretectal nucleus, with pupillodilation in the dark.

Nodular prurigo—a clinicopathological study of 46 patients

Abstract: In a study of 46 patients with nodular prurigo (NP), potential metabolic causes of pruritus, such as anaemia, hepatic dysfunction, uraemia and myxoedema, were present in 50%. Focal causes of pruritus were important in 37% and included insect bites, venous stasis, folliculitis and nummular eczema. Psycho-social disorders were recorded in over 50% of patients and were considered relevant in 33%. Clinical and histological appearances ranged from classical NP to chronic lichenified eczema. Neural hyperplasia was not a prominent feature.

Maternal zinc and intrauterine growth retardation

Abstract: The levels of zinc in plasma, erythrocytes, polymorphonuclear (PMN) and mononuclear (MN) white cells were measured after delivery in women giving birth to appropriate-for-gestational-age (AGA) babies (group I mothers), or small-for-gestational-age (SGA) babies (group II mothers) and in non-pregnant controls. Mean maternal plasma zinc and albumin levels 24-48 h after delivery were lower than in controls, but PMN and MN zinc levels were unchanged. PMN zinc levels were lower than those of MN cells. PMN and MN zinc levels were significantly lower in group II mothers than in group I, irrespective of smoking habits. There were no racial differences in peripheral white cell zinc levels. PMN, and to a lesser degree MN, zinc levels were lower in smoking than in non-smoking mothers. Erythrocyte zinc did not correlate with other zinc measurements nor with the size of the babies. Fetal erythrocyte zinc levels were one-third of maternal levels. A combination of smoking and/or low PMN zinc levels selects 85% of mothers having small-for-gestational-age babies.

Plasma free testosterone--is an index sufficient?

Abstract: Only about 50% of women who are clinically hirsute have a raised total plasma testosterone concentration; in those cases where the total testosterone is normal the free testosterone may, in fact, be raised. Since the measurement of free testosterone is tedious, workers have used an androgen index or a calculated free testosterone concentration from the measurements of total testosterone and sex-hormone-binding globulin. We have examined the correlation between measured free testosterone, a derived free testosterone and an androgen index in hirsute women, normally menstruating women and non-hirsute women on oral contraceptive therapy. These three measures of the free testosterone concentration in blood gave similar results in all cases.

Infarct size limitation by the xanthine oxidase inhibitor, allopurinol, in closed-chest dogs with small infarcts

Abstract: The present study was designed to evaluate the ability of allopurinol to limit infarct size following permanent coronary occlusion in the greyhound. Coronary occlusion was produced by injecting 2.5 mm plastic beads into the coronary artery of the closed chest dog. Non-perfused myocardium, the area at risk, was visualised by autoradiography of l41Cerium labelled microspheres which were infused immediately following coronary embolization. The treated dogs (n = 12) received 400 mg of allopurinol orally one day before surgery. A 25 mg·kg−1bolus was administered (iv) immediately before occlusion, and repeated every 8 h. 11 dogs served as controls. After 24 h, the dogs were killed and the hearts were sliced into 5.0 mm transverse sections. The infarcted myocardium was visualised by triphenyl tetrazolium chloride staining. The percentage of the risk zone which evolved to infarct was calculated. This percentage was 18.1 ± 3.95% in the allopurinol group vs 58.4 ± 2.81% in the control group (p<0.001). We conclude that allopurinol is a potent drug for the limitation of infarct size in the dog with permanent coronary occlusion.

Radiation and Platinum Drug Interaction

Abstract: Platinum drugs have chemical as well as biochemical and biological effects on cells, all of which may interact with radiation effects. They inhibit recovery from sublethal and potentially lethal radiation damage. They produce a pattern of chromosome aberrations analogous to that from alkylating agents. Cellular sensitivity to platinum is increased when glutathione levels are reduced, just as is radiosensitivity. There is a pattern of drug sensitivity throughout the phases of the cell cycle which is different from that for radiosensitivity. The ideal platinum drug-radiation interaction would achieve radiosensitization of hypoxic tumour cells with the use of a dose of drug which is completely non-toxic to normal tissues. Electron-affinic agents are employed with this aim, but the commoner platinum drugs are only weakly electron-affinic. They do have a quasi-alkylating action however, and this DNA targeting may account for the radiosensitizing effect which occurs with both pre- and post-radiation treatments. Because toxic drug dosage is usually required for this, the evidence of the biological responses to the drug and to the radiation, as well as to the combination, requires critical analysis before any claim of true enhancement, rather than simple additivity, can be accepted. The amount of enhancement will vary with both the platinum drug dose and the time interval between drug administration and radiation. Clinical schedules may produce an increase in tumour response and/or morbidity, depending upon such dose and time relationships.

Cerebral disease in systemic lupus erythematosus.

Abstract: Cerebral disease in systemic lupus erythematosus (SLE) has proved a challenge to the clinicians, pathologists, and laboratory investigators. The true frequency of neuropsychiatric abnormalities in SLE is difficult to estimate because of the marked variability in presentation and severity [44]. It is sometimes difficult, too, to distinguish between neurological symptoms due to cerebral disease caused by SLE, and neurological complications of SLE, such as uraemia. There is no widely accepted test for diagnosing cerebral disease in SLE. Further, there is no single cerebral lesion able to account for all the neuropsychiatric abnormalities of the disease or no lesion that is pathognomonic for SLE [24, 46 I. In the light of these problems, it is not surprising that the pathogenesis of cerebral disease in SLE is unknown. Over the past two decades, however, there have been a variety of clinical, pathological, and laboratory studies that have provided a better understanding of these disorders. We shall discuss some of these studies to provide an overview of cerebral disease in SLE and of proposed pathogenic mechanisms.

The effect of hypoglycaemia on visual function: a clinical and electrophysiological study.

Abstract: Disturbance of vision commonly accompanies hypoglycaemia. This study was designed to investigate the nature of the visual disturbance, the blood glucose threshold at which the disturbance occurred and the physiological basis. Measurements were made of the corrected visual acuity, colour vision (100 Hue test), visual evoked potentials (VEP), electroencephalography (EEG) frequency analysis and psychometry (digit recall) during stepwise induction of controlled hypoglycaemia produced by an intravenous insulin infusion. Six male volunteers and five insulin-dependent diabetic subjects were studied. During hypoglycaemia corrected visual acuity was unchanged. Colour vision was significantly impaired. Baseline VEP were normal in both groups but significantly prolonged during hypoglycaemia (mean increment 10.8 ms) and increased by greater than 5 ms in nine out of 11 subjects. Quantitative EEG analysis demonstrated slowing with a power density spectral shift from fast alpha to slow alpha, theta and delta which correlated with VEP latency and amplitude changes. The findings have clinical implications. A deterioration in colour vision is likely to impair the ability to read reagent strips by eye. VEP measurements in diabetic patients are likely to be misleading if hypoglycaemia is present; EEG changes are a sensitive index of cortical dysfunction during hypoglycaemia and provide a theoretical basis for developing a portable device to detect early hypoglycaemia.

Zinc in the Fetus and Newborn

Abstract: The growing fetus and infant are at risk of becoming deficient of zinc, an adequate supply of which is essential for normal growth and development. Mild maternal zinc depletion was strongly associated with intrauterine growth retardation. Low levels of zinc in maternal plasma and poor placental perfusion reduced the materno-fetal transfer of zinc. Mean maternal dietary intake of zinc was 60% recommended daily allowance and mothers of small-for-gestational-age (SGA) babies consumed significantly less zinc than mothers of appropriate-for-gestational-age babies. In addition, iron/folate supplements, which are often routinely prescribed during pregnancy, despite dietary intakes of iron and folate being adequate, significantly decreased the oral bio-availability of zinc in pregnant women. Zinc supplementation may be beneficial to women at risk of delivering SGA babies. Zinc requirements and interactions are also important to consider when designing mineral supplements for preterm babies, infant formulae and food fortification in developing countries.

Acid maltase deficiency in adults. Diagnosis and management in five cases.

Abstract: Five patients with adult onset acid maltase deficiency are described. All patients had developed their initial pelvic girdle symptoms late in the second or early in the third decade and some years later developed signs of respiratory insufficiency. Typically they were tall, had weak and wasted paraspinal and gluteal muscles with lower limb weakness. All were orthopnoeic with marked diaphragmatic weakness. In all patients characteristic glycogen vacuoles were seen in peripheral blood lymphocytes. Muscle biopsy was characteristic in only 1 out of 4 cases and showed minimal or nonspecific features in 3. The diagnosis was confirmed by enzyme assay in muscle and cultured fibroblasts. Long-term domiciliary ventilatory support (25 patient-years) using a rocking bed or intermittent positive pressure respiration with a tracheostomy has allowed a return to work in all patients, with their clinical condition remaining stable.

Epidural fentanyl in labour. An evaluation of the systemic contribution to analgesia.

Abstract: In a randomized double-blind trial in the first stage of labour, 20 patients given fentanyl 80 micrograms in the epidural test dose of bupivacaine, were compared with 20 patients receiving an intravenous infusion designed to produce comparable plasma fentanyl concentrations, at the same time as their epidural test dose. Despite slightly higher plasma fentanyl concentrations in the intravenous fentanyl group, epidural fentanyl produced analgesia which was more complete, more rapid in onset and slightly longer lasting. Supplementary doses of bupivacaine were needed to produce analgesia in 75% of the intravenous and 30% of the epidural fentanyl group. It is clear that epidural fentanyl produces satisfactory pain relief when added to the epidural test dose, but that the presence of fentanyl in the systemic circulation makes a negligible contribution to analgesia.

Luminance detectors in the olivary pretectal nucleus and their relationship to the pupillary light reflex in the rat. II. Studies using sinusoidal light.

Abstract: The luminance detectors in the olivary pretectal nucleus, which are likely candidates mediating the pupillary light reflex, responded to all frequencies of sinusoidally modulated light up to 12-25 Hz. At low frequencies (0.05-4.0 Hz) the luminance detectors responded with modulated firing to different stimulation rates. The modulation depth of the cell response increased with the increase in stimulation frequency up to 20 Hz, then rapidly fell. There was a delay between the peak intensity of the stimulus and the peak firing of cell response of about 30-40 ms. The amplitudes of the consensual pupil responses to the same sinusoidal stimulus, on the other hand, decreased with an increase in frequency and no discernible response was recorded above 2 Hz. The pupil responses were little affected by sympathectomy. The differences in the frequency response characteristics of luminance detectors and the pupil were attributed to the sluggish dynamic properties of the pupil muscles. This was demonstrated using an electronic model of the iris muscle which modified the responses of the luminance detectors giving output waveforms broadly resembling pupil responses to square and sinusoidally modulated lights.

Familial primary cutaneous amyloidosis.

Abstract: SUMMARY Primary cutaneous amyloidosis is uncommon in Europeans. A British family is described in which an extremely rare variant was inherited as an autosomal dominant. The subtlety of physical signs in this family contrasted with the severity of the associated pruritus. Transepidermal elimination of amyloid was a characteristic histological feature.

Human chorionic gonadotropin and human placental lactogen in extragonadal tumors an immunoperoxidase study of ten non‐germ cell neoplasms

Abstract: The immunoperoxidase localization of the alpha and beta subunits of human chorionic gonadotropin (hCG) and of human placental lactogen (hPL) was studied in ten extragonadal nontrophoblastic tumors associated with raised serum levels of one or more of these placental proteins. Three of the tumors were bronchial carcinomas, one was a gastric carcinoma, two were malignant carcinoids (one bronchial and one gastric), two were pancreatic islet cell carcinomas, and two were metastatic carcinomas with an unknown primary site. The maximum alpha subunit serum level was 33,000 ng/ml (gastric carcinoid), the maximum hCG/hCG-beta level was 705,000 ng/ml, and the maximum hPL level was 50 ng/ml (both in the gastric carcinoma). An indirect immunoperoxidase technique and rabbit polyclonal affinity-purified antibodies and peroxidase conjugates were used on formalin-fixed, paraffin-embedded sections. Five blocks (eight cases) or six blocks (two cases) from various sites were obtained from each patient at surgery and/or autopsy. Positive stains for hCG/hCG-beta were seen in six of seven tumors (25/37 blocks) with raised levels, for the alpha subunit in nine of nine tumors (30/47 blocks), and for hPL in two of five tumors (4/26 blocks). Only a relatively minor number of the cells were positive, and within the same case, there was considerable site-to-site variation in the number of positive cells. Large bizarre cells contained hCG/hCG-beta as well as the alpha subunit, if it was demonstrated in the same tumor as the beta subunit. Otherwise, the alpha subunit was found in small unremarkable cells. Giant cells that were smaller than those positive for hCG/hCG-beta contained in hPL. In some serial sections, hCG-alpha, hCG/hCG-beta, and hPL were segregated in different cell populations, supporting the concepts of their separate genetic control.

Combined effect of misonidazole and glutathione depletion by buthionine sulphoximine on cellular radiation response.

Abstract: Chinese hamster cells (V79) and glutathione-proficient (GSH+/+) and glutathione-deficient (GSH-/-) human fibroblasts were treated with a glutathione (GSH)-depleting agent buthionine sulphoximine (BSO) and the hypoxic radiosensitizer misonidazole (MISO), separately or in combination Subsequently, the cells were exposed to X-rays Determination of the yield of single-strand DNA breaks (ssb) immediately after irradiation indicated no effect of BSO or MISO treatment when radiation exposure was made aerobically Assuming that ssb determined immediately after irradiation reflects mainly the effect of radical processes, the results obtained with BSO and MISO, singly and in combination, agreed well with the predictions of a modified version of the 'competition model' using V79 and GSH+/+ cells Some results obtained with GSH-/- cells could not be so explained

Acute biphenotypic leukaemia (myeloid and null-ALL type) supervening in a myelodysplastic syndrome.

Abstract: Summary. An acute leukaemia was seen in a 72–year-old patient with a myelodysplastic syndrome (MDS) of 14 months duration, who had been treated only with steroids. The morphological appearance of the blast cells suggested a poorly differentiated cell type. Surface marker analysis, including double staining studies, showed the coexistence of a population of null acute lymphoblastic leukaemia (ALL) blast cells together with acute myeloid leukaemia type cells. No chromosomal alterations were detected. The change from a chronic MDS to an acute leukaemia of mixed (myeloid and null ALL) type suggests either transformation of a pre-existing abnormal clone or de novo appearance of two separate leukaemic clones.

The effects of silica on lymph nodes and vessels—a possible mechanism in the pathogenesis of non-filarial endemic elephantiasis

Abstract: Non-filarial tropical elephantiasis, which occurs in certain volcanic areas of the world, has been postulated to be an obstructive lymphopathy due to the fibrogenic effects of silica absorbed through the plantar skin of bare-footed people. Animal experiments involving the direct intralymphatic injection of fine silica particles have been carried out in order to assess the extent to which this substance can engender lymphatic obstruction and to determine its main site of action. Intralymphatic silica provoked an immediate and intense macrophage reaction with later fibrosis both within lymph vessels and to a lesser extent within lymph nodes. Lymphography indicated that the consequent obstruction resulted more from the effects of silica on vessels than on nodes.

Plasma apolipoprotein B metabolism in familial type III dysbetalipoproteinaemia.

Abstract: Lipoprotein metabolism was studied in eleven patients with Type III hyperlipoproteinaemia, one with normolipidaemic dysbetalipoproteinaemia and eight controls. Apolipoprotein B kinetics in very low density, intermediate density and low density lipoproteins (VLDL, IDL and LDL) was investigated. Fractional catabolic rates (FCRs) of VLDL-apo B and IDL-apo B were lower (P less than 0.005 and P less than 0.001) in the patients: 0.064 +/- 0.018 and 0.059 +/- 0.006 h-1 respectively, (mean +/- SEM), compared with 0.219 +/- 0.035 and 0.243 +/- 0.028 h-1. Synthetic rates (SRs) of IDL-apo B varied widely from 1.5 mg kg-1 day-1 in the subject with normolipidaemic dysbetalipoproteinaemia to 2.8-25.2 mg kg-1 day-1 in Type III. The mean time for conversion of IDL-apo B to LDL-apo B was prolonged, 18.7 h compared with 3.8 h in the controls (P less than 0.001). LDL-apo B pool size and SR were lower in the patients (P less than 0.05 for both). Two patients treated with gemfibrozil showed reduced hyperlipidaemia and decreased SR of VLDL-apo B and IDL-apo B. Dysbetalipoproteinaemia is associated with pronounced impairment of IDL and VLDL-remnant catabolism, lipoprotein levels reflecting an interaction between this defect and SR of these lipoproteins.