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Biomedical subjects

G M Brown

Publications and source records attributed to G M Brown.

At least 145 records · Page 8Linked to original sources
PubMed1991

Increased metacarpal bone mass following 18 months of slow-acting antirheumatic drugs for rheumatoid arthritis.

Osteoporosis in RA is mediated by numerous inflammatory substances. This study was undertaken to see if SAARD could modify the rate of metacarpal bone loss in RA. Combined cortical thickness (CCT) measured at the midshaft of the right second metacarpal was used to calculate bone mass (CA%) using a digitizer. Eighty-one subjects were studied, all of whom had at least three sets of hand X-rays, the last of which was approximately 18 months following initiation of SAARD therapy. There were 12 males and 69 females. The mean age at time of starting therapy was 51 (SD 12) years while the mean duration of disease at the time was 7.6 (SD 8) years. The mean time to referral for SAARD from the general clinic was 2.5 (SD 3) years. The percentage fall in bone mass prior to therapy was 2.51%/day compared to a gain of 0.6%/day after therapy (P less than 0.05). Forty-nine patients were aged over 50 years while 32 were 50 years or younger at the time of study. Comparison showed that in the pretreatment period, the rate of change in CCT and CA% was not significantly dependent age (P less than 0.1). During that therapy, the rate of change in CCT and CA% significantly different in the two age groups. Patients aged over 50 years continued to lose bone, but at a slower rate (P less than 0.05). Patients aged 50 years or less either stopped losing or gained metacarpal bone mass during the study period (P less than 0.005). The time to referral for SAARD and disease duration (comparable in the two age groups) did not have a significant effect on changes in CA% during therapy. Change in bone mass could be predicted by change in disease activity. We conclude that SAARD have a significant sparing effect on metacarpal osteoporosis in RA. This positive effect is masked by the overwhelming influence of age (and menopause) and could be missed. Metacarpal osteoporosis seems a pathophysiologically more useful measure of radiological change in RA than erosions or joint space narrowing.

Aging↗
PubMed1991

Urinary 6-sulphatoxymelatonin, an index of pineal function in the rat.

The objective of this study was to apply the radioimmunoassay for 6-sulphatoxymelatonin (aMT6s) to rat urine, and use it to study the source of aMT6s. The radioimmunoassay was found to have acceptable within- and between-assay variation, excellent specificity, and good parallelism between the standard and unknown. Because urine is highly contaminated we assessed whether preliminary purification was required and established that it was unnecessary. Using this assay a 24-hr rhythm in 6-sulphatoxymelatonin output was seen in pools of urine harvested at 3-hr intervals from Wistar rats on LD 12:12. The nocturnal rise in aMT6s was abolished by constant light. In contrast pinealectomy lowered aMT6s output significantly throughout both dark and light. This study confirms previous studies indicating that the pineal is the major source of 6-sulphatoxymelatonin. It is concluded that urinary 6-sulphatoxymelatonin as measured by radioimmunoassay is a valid measure of pineal gland activity in the rat.

Animals↗
PubMed1991

Persistent biological reactivity of quartz in the lung: raised protease burden compared with a non-pathogenic mineral dust and microbial particles.

This study assessed the potential harmfulness of particles in the lung by measuring their ability to elicit and maintain an inflammatory response and to damage lung tissue. It compared the inflammogenicity of two nondurable, biological particulates (Corynebacterium parvum and zymosan) with a pathogenic mineral dust (quartz) and a nonpathogenic dust (titanium dioxide) by dosing rats via the intratracheal route and measuring the consequent alveolitis. The magnitude and duration of the inflammatory response were assessed by measuring the total number of leucocytes and the percentage of neutrophils obtained by bronchoalveolar lavage. Two key functional parameters of the lavaged leucocytes--ability to degrade fibronectin and production of plasminogen activator--were also measured. A marked inflammatory response had occurred by one day after instillation, characterised by increases in total leucocyte numbers and percentage of neutrophils in the bronchoalveolar lavages, with all four test materials. In all but the quartz exposed animals, the inflammation subsided rapidly thereafter, approaching control levels by 15 days after injection; in the quartz exposed animals the alveolitis persisted for up to 30 days. All of the inflammogens generated chemotaxins in rat serum in vitro and so, by analogy, might also be expected to generate chemotactic activity in alveolar lining fluid which could contribute to the generation of an inflammatory response. The cellular inflammatory response was accompanied by a concomitant increase in the proteolytic activity of the bronchoalveolar lavage leucocytes but production of plasminogen activator remained unchanged. In vitro exposure to the inflammogens had no effect on the proteolytic activity against fibronectin or on the plasminogen activator activity of bronchoalveolar leucocytes.

Animals↗
PubMed1991

Substance abuse and schizophrenia: effect on symptoms but not on neurocognitive function.

The authors compare symptoms and neuropsychological test performance in DSM-III schizophrenic patients who reported prior substance abuse (N = 38) with those in patients who reported no such abuse (N = 25) to determine the impact of substance abuse on the psychopathology of schizophrenia. Positive and negative symptom scores were derived from the Schedule for Affective Disorders and Schizophrenia. Sixty neuropsychological measures drawn from commonly used tests of intelligence, memory, learning, fluency, and problem solving were calculated. Separate analyses were performed on patients in a psychotic episode who were free of neuroleptics (N = 27) and on those taking maintenance neuroleptics (N = 36). Among unmedicated patients, those who reported prior substance abuse had significantly higher thought disorder scores. Among neuroleptic-medicated patients, hallucination and delusion scores were significantly higher in the patients who reported prior substance abuse. The substance abuse followed withdrawal from social relations and preceded the onset of positive symptoms. None of the neuropsychological tests discriminated between abusers and nonabusers.

Adult↗
PubMed1991

Leukocyte-mediated epithelial injury in ozone-exposed rat lung.

Both epithelial injury and inflammation are characteristic findings in the centriacinar regions of the lungs of rats exposed to ozone. In humans such effects could lead to long-term lung damage and disease. In animals, neoplastic change in the lungs after exposure to ozone has been described previously. The possible relationships between inflammatory cell recruitment, epithelial injury, and hyperplasia, with special regard to the important role of repair processes in leading to increased incidence of tumors in some species, have been addressed in the present study. We have previously described that leukocytes from lungs inflamed by different agents can injure epithelial cells in vitro. We have suggested that this leukocyte-mediated epithelial injury could enhance epithelial turnover in ozone-exposed lungs and so enhance the likelihood of tumor development. We, therefore, set out to test the hypothesis that bronchoalveolar leukocytes from ozone-exposed lungs can injure epithelial cells in vitro. PVG rats were exposed to 0.2, 0.4, 0.6, and 0.8 parts per million2 (ppm) ozone for seven hours per day for up to four days. On the morning following the last exposure, bronchoalveolar lavage was used to sample the bronchoalveolar leukocytes and the following parameters were assessed: total number, differential leukocyte count, production of oxidants, ability to degrade fibronectin, and ability to injure epithelial cells. In addition to these parameters, which were measured at all concentrations and time points in limited experiments, we also assessed macrophage size in short-term culture and inflammation in histological sections of lungs. Total number of lavageable cells was not affected by ozone inhalation. However, the percentage of macrophages decreased with ozone treatment and the percentage of neutrophils increased on days 1 and 2 at 0.6 and 0.8 ppm ozone. There was no significant effect of ozone exposure on the ability of neutrophils to degrade fibronectin or injure epithelial cells. Production of superoxide anion in response to stimulation with phorbol myristate acetate was significantly decreased by exposure to 0.6 ppm ozone, as described in previous studies. Macrophages from the lungs of rats exposed to ozone were larger than control macrophages.

Animals↗
PubMed1990

There are two major types of skeletal keratan sulphates.

High-field 1H-n.m.r.-spectroscopic studies supported by chemical carbohydrate analyses show that skeletal keratan sulphates (KS-II) of bovine origin may be sub-classified into two groups. Keratan sulphate chains from articular and intervertebral-disc cartilage (KS-II-A) contain two structural features, namely alpha(1----3)-fucose and alpha(2----6)-linked N-acetyl-neuraminic acid residues, that are absent from keratan sulphates from tracheal or nasal-septum cartilage (KS-II-B).

Animals↗
PubMed1990

Refinement of triclinic lysozyme: I. Fourier and least-squares methods.

X-ray diffraction data to 1.5 A resolution have been collected for triclinic crystals of hen egg white lysozyme. The triclinic model was derived from the tetragonal one by the rotation function and refined initially by Fo-Fc and differential difference syntheses against 2 A resolution data. Refinement was continued by differential difference cycles against the 1.5 A data until R was reduced to 0.220. Although the initial refinement was rapid, it was subsequently a matter of attrition, leading to a complete recheck of the data and the discovery of systematic error which affected primarily the high-resolution data. Refinement was continued against the corrected 2 A data by block-diagonal least squares. After five cycles the refinement was terminated at R = 0.254 because of the imminent availability of a preferred refinement program. Problems with the protein model, the solvent, and the interaction of the scale and thermal parameters are discussed. The experiences gained in this study are summarized.

Fourier Analysis↗
PubMed1990

Treatment of humoral hypercalcemia of malignancy in rats with inhibitors of carbonic anhydrase.

The enzyme carbonic anhydrase has been suggested as a critical participant in osteoclast-mediated bone resorption. In humoral hypercalcemia of malignancy (HHM) intense osteoclastic bone resorption is principally responsible for the observed hypercalcemia. We therefore undertook to examine the effect of the carbonic anhydrase inhibitor acetazolamide on the hypercalcemia induced by the H500 Leydig cell tumor in Fisher rats, a well-described model of HHM. Acetazolamide treatment for 10 h at 10 mg/h resulted in a significant fall in serum calcium in the five drug-treated animals (14.2 +/- 0.9 to 11.5 +/- 0.1 mg/dl, p less than 0.05). Conversely, the six animals infused with vehicle alone showed a significant rise in serum calcium (12.5 +/- 0.5 to 13.8 +/- 0.1 mg/dl, p less than 0.05). At the end of the infusion, the acetazolamide-treated animals had a significantly lower mean serum calcium than those receiving vehicle alone (11.5 +/- 0.1 versus 13.8 +/- 0.1, p less than 0.05). There was no significant change in serum phosphorus, urine calcium, urine phosphorus, or nephrogenous cyclic AMP excretion between the two groups. Acetazaolamide and HTS 5-(3-hydroxybenzoyl)-2-thiophenesulfonamide, another carbonic anhydrase inhibitor, both significantly inhibited in vitro bone resorption induced by 5 X 10(-9) M 36Tyr(1-36)-PTHrP-amide (PTHrP, parathyroid hormone-related protein). Acetazolamide also inhibited the resorption induced by 10(-8) M (1-141)-PTHrP and 2.5 X 10(-9) M (1-74)-PTHrP. We conclude that acetazolamide is effective in lowering the serum calcium in animals with humoral hypercalcemia of malignancy. The data are consistent with the hypothesis that the mechanism of action for this effect is direct inhibition of osteoclast-mediated bone resorption.

Acetazolamide↗
PubMed1990

Impaired chemotactic responses of bronchoalveolar leukocytes in experimental pneumoconiosis.

Rats were exposed to clouds of the following pneumoconiotic dusts: quartz, coal-mine dust, and chrysotile asbestos at 10 or 50 mg/m3 for 8, 32, and 75 days; for comparison, rats were also exposed to the non-pathogenic dust titanium dioxide (TiO2). The bronchoalveolar leukocytes (macrophages and neutrophils) from dust-exposed and control rats were obtained by lavage and tested for their ability to migrate toward zymosan-activated serum. Varying amounts of neutrophils were present depending on the ability of the dust to cause inflammation and the length of exposure. There was a marked loss of chemotactic ability in leukocytes from rats inhaling the pneumoconiotic dusts compared with controls; TiO2-exposed leukocytes had some impairment of chemotaxis, but this was substantially less than that found with the pneumoconiotic dusts. The loss of chemotactic activity did not correlate with the percentage of neutrophils in the lavage cells except when there were very high levels of neutrophils, and there was substantial impairment of chemotaxis with negligible numbers of neutrophils, showing that macrophage chemotaxis was impaired. A phagocytic burden within the leucocytes was not sufficient alone to inhibit chemotaxis, nor was the loss of chemotactic activity due to occupied receptors, since incubation failed to restore chemotaxis. Loss to chemotactic activity by leukocytes from pneumoconiotic dust-exposed lung could be an important factor in the development of pneumoconiosis.

Animals↗
PubMed1990

Nocturnal melatonin and cortisol secretion in newly admitted psychiatric inpatients. Implications for affective disorders.

Melatonin secretion has been suggested as a marker of both circadian and noradrenergic dysfunction in affective disorders. Seventy-two newly admitted psychiatric inpatients [49 with major depressive disorder (MDD), 12 with schizophrenia, and 11 with intermittent depressive disorder (IDD)] underwent neuroendocrine screening at 0200, 0800, 1600 and 2300 hours prior to and the day following dexamethasone administration. All groups showed a drop in cortisol following dexamethasone. Dexamethasone nonsuppression was found in 20 of 49 patients with MDD, in none of the schizophrenics and in none of those with intermittent depressive disorder. Mean melatonin levels decreased significantly after the administration of dexamethasone across all four groups. Overall, the schizophrenic group had a significantly greater mean melatonin level than each of the other three groups, whereas the three depressive groups did not differ significantly from one another. Only at 2300 hours did both the schizophrenic group and the MDD patients with normal dexamethasone suppression show significantly greater melatonin levels than the MDD patients with dexamethasone nonsuppression or the IDD group. The observed trend for a low circadian melatonin profile in IDD patients with superimposed personality disorders is puzzling.

Adult↗
PubMed1990

Secretion of plasminogen activator inhibitor by normal rat pleural leukocytes in culture.

The normal balance between coagulation and fibrinolysis in the pleural cavity is poorly understood despite the critical role of the pleura in the movement of the lungs. To determine the fibrinolytic activity and the interaction between plasminogen activators and their inhibitors in the normal pleural space, we tested normal rat pleural leukocytes, principally macrophages and mast cells, and their supernatants, for activity in an [125I]fibrin degradation assay. It was found that pleural leukocytes did not release plasminogen activator, but the leukocytes and their supernatants inhibited the plasminogen-dependent fibrinolysis caused by both alveolar leukocytes and mesothelial cells. Further experiments demonstrated that pleural leukocytes produce a protein inhibitor primarily against urokinase-induced fibrinolysis in culture and that macrophages are the main source of the inhibitor. The lysate of mast cell-enriched population exhibited high plasminogen activator activity while no such activity could be determined in macrophage-enriched lysate. These data show that normal rat pleural leukocytes contain plasminogen activator inside the cells and synthesize a urokinase-type plasminogen activator inhibitor in culture that may be important in the fibrinolysis/coagulation balance in the pleural space.

Animals↗
PubMed1990

Sulphatoxy melatonin: an index of depression in anorexia nervosa and bulimia nervosa.

Urinary excretion of the principal melatonin metabolite, sulphatoxy melatonin (aMT6s), was assessed both during the day and during the night in 38 female eating disorder patients (anorexia nervosa, n = 17; bulimia nervosa, n = 12; anorexia nervosa + bulimia nervosa, n = 9) and 14 female control subjects. Correlations between nocturnal serum melatonin and urinary aMT6s were also obtained. All patient groups and the controls showed a preservation of diurnal rhythm with elevated nocturnal urinary aMT6s values and no significant difference in amplitude between groups. However, patients with concurrent major depression had significantly lower levels of daytime and nighttime urinary aMT6s than the nondepressed group. Weight did not influence these findings. Correlations between nocturnal serum melatonin levels and urinary aMT6s were high for control subjects (r = 0.77) and moderate for the patient groups (r = 0.31). This may reflect differences in the rate of excretion of melatonin between patients and controls.

Anorexia Nervosa↗
PubMed1990

Dose-response profiles of plasma growth hormone and vasopressin after clonidine challenge in man.

The objective of the study was to determine dose-response relationships of growth hormone, vasopressin, blood pressure, heart rate, and behavioral responses to clonidine. Ten healthy male volunteers were tested with each of three doses of clonidine (0.7, 1.4, and 2.1 micrograms/kg) with at least 1 week between tests. All doses gave a significant growth hormone response with a peak at 50 min. The high dose gave a significantly higher response than either the medium dose or the low dose, which did not differ from each other. Within individual subjects, there was a consistency of response to the different doses; thus, three of the volunteers had responses of 5 ng/ml or higher to the low dose. Those three subjects had higher growth hormone peaks after the highest dose than did six other subjects. Vasopressin showed a drop following clonidine after the two higher doses. Systolic blood pressure dropped following clonidine, showing a significantly greater drop for the medium and high doses than for the low dose. Diastolic blood pressure also showed a drop, but responsiveness did not differ between doses. There was significant dryness of mouth produced by clonidine, but no difference between doses. There was a significant sedative effect following clonidine which was greater for the high dose than for the medium or low dose. The finding that some subjects had a growth hormone peak of 5 ng/ml or greater after the low dose supports the hypothesis that use of a low dose strategy may be useful in confirming supersensitivity in conditions where increased responsiveness is suspected. The lack of difference between blood pressure responses to the medium and high doses of clonidine--doses that have different effects on growth hormone--supports the hypothesis that differences in responsiveness of presynaptic and postsynaptic alpha 2-adrenergic receptors exist.

Adult↗
PubMed1990

Alveolitis caused by exposure to coal mine dusts: production of interleukin-1 and immunomodulation by bronchoalveolar leukocytes.

Two kinds of coal mine dust, low rank with high quartz (bituminous) and high rank with low quartz (anthracite), were assayed for ability to induce alveolitis and to stimulate interleukin-1 release from normal alveolar macrophages in vitro. Dust-elicited bronchoalveolar leukocytes were also assessed for their effects on macrophage-depleted splenocyte mitogenesis and their ability to produce interleukin-1. Quartz and titanium dioxide were used for comparison as toxic and inert dusts, respectively. Both coal mine dusts caused substantial release of interleukin-1 from normal alveolar macrophages in vitro and the levels were higher than those caused by quartz. Bituminous coal mine dust provoked acute but rapidly subsiding macrophage/neutrophil alveolitis which was greater than that provoked by titanium dioxide; anthracite caused less alveolitis than titanium dioxide and quartz caused large scale, persistent alveolitis. Whole bronchoalveolar leukocytes, including polymorphonuclear neutrophils, elicited by exposure to dust, were less inhibitory to lymphocyte mitogenesis than normal alveolar macrophages and bituminous coal mine dust-induced neutrophils were augmentary to lymphocyte mitogenesis; macrophages from inflamed lungs were, on the whole, inhibitory to lymphocyte mitogenesis. Alveolar macrophages from bituminous coal mine dust- or titanium dioxide-exposed lungs showed increased ability to release interleukin-1 on stimulation in vitro. These findings suggest that bronchoalveolar leukocytes elicited by coal mine dust could modulate immunity by means of interleukin-1 release and enhancement of lymphocyte proliferation.

Animals↗
PubMed1990

Contrasting bronchoalveolar leukocyte responses in rats inhaling coal mine dust, quartz, or titanium dioxide: effects of coal rank, airborne mass concentration, and cessation of exposure.

The aim of this study was to determine the bronchoalveolar leukocyte response to airborne coal mine dust; quartz and titanium dioxide were used as positive and negative controls, respectively. Groups of rats were exposed to airborne mass concentrations of 10 and 50 mg/m3 of the dusts for 7 hr/day, 5 days/week and their bronchoalveolar space was lavaged at time points between 2 and 75 days of exposure, to assess the leukocyte response. This study revealed time-dependent and airborne mass concentration-dependent recruitment of neutrophils and macrophages into the bronchoalveolar region with coal mine dust inhalation but no real difference in the magnitude of the response between coal mine dusts from collieries mining coal of different rank and quartz content although the maximum quartz content in the dusts used was 6%. The inflammatory response was much less than that produced by quartz, at similar airborne mass concentrations, and more than that produced by titanium dioxide which was, in general, a poor inflammogen in the rat lung. Groups of rats were exposed to the airborne dusts for 32 or 75 days, then removed from the exposure chambers, and allowed to recover by breathing room air for a further 64 days. During this recovery period there was marked progression of the leukocyte response with quartz and persistence of the response with coal mine dust. Chronic recruitment of leukocytes to the lungs of individuals inhaling coal mine dust is likely to be an important factor in the development of coal workers' pneumoconiosis.

Administration, Inhalation↗