Structural aspects of skeletal keratan sulphates.
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Animals↗
Biomedical subjects
G M Brown
Publications and source records attributed to G M Brown.
Fluctuation of blood melatonin concentrations with age: result of changes in pineal melatonin secretion, body growth, and aging.
Melatonin in the systemic circulation of rats fluctuates with age, and the causes for such changes were investigated. Male rats (aged 7 days, 16 days, 18 days, 20 days, 30 days, 48 days, 60 days, and greater than 17 months) were adapted under a lighting regime of 12L:12D for at least 7 days. Pineals and blood samples from the trunk or confluens sinuum were collected in the dark period. Melatonin in tissues was extracted, identified, and determined by gas chromatography-mass spectrometry (GC-MS) and/or radioimmunoassay. Tissue melatonin levels obtained by radioimmunoassay correlated closely with those quantified by GC-MS. Thus, the melatonin radioimmunoassay used is a reliable assay method for melatonin in the plasma and pineal of the rat. Plasma melatonin in the confluens sinuum of rats exhibited episodic release superimposed on a basal release pattern. It was suggested that there are two pools of melatonin in the pineal gland, a readily releasable pool and a bound pool. The mean plasma levels of melatonin in the confluens sinuum of rats increased with age with the highest level recorded at 60 days old and declined to a lower level at greater than 17 months old. The above age-related changes, being similar to the alterations in pineal melatonin levels with growth and aging, suggest that, under our experimental conditions, levels of pineal melatonin increase or decrease with its secretory rate. In developing rats, the age-related increase in the rate of secretion of pineal melatonin as reflected by increases in melatonin levels in the confluens sinuum or pineal melatonin content before adulthood is different from the changes in melatonin levels in the systemic circulation which showed an early developmental rise, followed by an active period and then a prepubertal decline. However, when the body weight was taken into consideration, changes in the levels of pineal melatonin content per 100 gm body weight or the calculated blood melatonin levels (plasma melatonin in the confluens sinuum/body:head ratio) correlated well with the fluctuation of serum melatonin in the systemic circulation. Thus, the developmental changes in the concentrations of melatonin in the general circulation are the result of 1) changes in the rate of pineal melatonin secretion and 2) increase in the dilution factor because of increase in body size. In old rats, levels of plasma melatonin in the confluens sinuum and pineal melatonin content decreased indicating a decline in the rate of pineal melatonin secretion.(ABSTRACT TRUNCATED AT 400 WORDS)
Age Factors↗
Inflammation in the lungs of rats after deposition of dust collected from the air of wool mills: the role of epithelial injury and complement activation.
In a previous study assessing respiratory symptoms in individuals employed in wool textile mills in the north of England relations between symptoms of chronic bronchitis, breathlessness and wheeze, and rhinitis and current exposure to airborne mass concentration of dust were shown. As preliminary steps in defining the potential hazard associated with dust from the air of wool mills the ability of inspirable dust, collected from the air of wool textile mills, to cause inflammation when injected into the lungs of rats was determined. Dusts were collected from the beginning of wool processing (opening) in one factory and from the middle (combing) and late (backwinding) stages of the process in two other factories. Ability of the dusts to cause inflammation was assessed by instillation into the lungs of rats followed by bronchoalveolar lavage. All the dusts caused some inflammation which peaked on day 1 and did not persist beyond one week. A distinctive aggregation response of mononuclear cells in the lavage, however, had a different time course, peaking at day 7. An attempt was made to determine how the wool mill dusts caused inflammation and experiments showed that the dusts themselves had no inherent chemotactic activity but that they did have a pronounced ability to generate chemotaxins in serum and so could activate complement in lung fluid. In addition, dust collected from ledges in the mills had the ability to injure epithelial cells in vitro which could also contribute to inflammation. A role for endotoxin in the inflammatory activity of the dusts was not discounted and a leachate of the dust had the ability to cause inflammation when injected into the lungs of rats. Wool mill dust is likely to be a complex mixture of materials and these experiments represent a preliminary approach to understanding the biological activity of the whole unfractionated dust and further studies are in progress to define more accurately the toxic material(s) in the dust.
Animals↗
Regional brain metabolism during auditory hallucinations in chronic schizophrenia.
Regions of the brain involved in language and attention were studied using [18F]-fluorodeoxy-glucose in PET. In nine chronic DSM-III schizophrenic patients who had persistent auditory hallucinations, ten who had recovered from hallucinations and ten normal controls. In none of the regions examined was metabolic activity significantly different in hallucinating patients compared with that in other groups. However, a pattern of seven significant correlations of metabolic activity between language regions and between frontal and parietal cortex characterised the hallucinating but not the other groups. Three of the seven correlations were significantly greater in hallucinating patients than in the two other groups, and six were greater in hallucinating patients than controls. Metabolism in Broca's region and its right-hemisphere homologue correlated positively and significantly in the hallucinating group, as it did in anterior cingulate and left superior temporal areas, and in right frontal and parietal areas. Hallucination ratings correlated with metabolism in the anterior cingulate region.
Adult↗
Autologous fibroblast implantation. Feasibility and potential problems in gene replacement therapy.
Autologous implants of genetically modified fibroblasts may be an ideal approach to gene replacement therapy. However, primary fibroblasts have limited life span and their use for gene therapy is questionable. We have developed a rat model to evaluate the feasibility of this approach. Primary fibroblasts initiated from rat skin biopsies were transfected with plasmid DNA. The transkaryotic fibroblasts were implanted into the original rat donors. A plasmid-encoded gene product, human growth hormone, was detected in the donor rats' circulation but less than 1% of the expected amount was recovered. Implantation at intraperitoneal, intramuscular or subcutaneous sites were effective in delivering the novel gene product. Fluctuating levels of human growth hormone were detected for over 6 months but their determination was rendered unreliable due to interference by extremely high titers of antibodies developed against the human growth hormone. In some cases, the antibody titer continued rising for more than 6 months, indicative of the continued presence of the antigen. One of the recipients developed two intra-abdominal fibrosarcomas that were shown to be derived from the implanted cells. In conclusion, this model demonstrates that autologous fibroblast implantation is a feasible approach to delivering novel gene products lasting for several months. Strong and prolonged immuno-reaction against the gene product will occur if the recipient's immune system is naive to the replacement product, as would occur in patients with CRM- mutations. The potential for neoplastic development from the implanted fibroblasts should prompt further evaluation of the long-term safety in gene replacement therapy.
Animals↗
Chronopharmacological actions of the pineal gland.
In all mammalian species studied to date, the pineal gland shows a pronounced circadian rhythm with high activity at night and very low activity in daytime, as reflected in the output of its hormone, melatonin. The pineal is one of the few organs which can synthesize melatonin and, under normal circumstances, is virtually the only source of circulating melatonin. Pineal activity is tightly controlled by the light/dark cycle, in such a manner that melatonin can convey information to the organism on the length of the dark phase of the photoperiod. In seasonal breeding species, the 24 hour pattern of secretion of melatonin shows seasonal changes which are crucial for determining the timing of seasonal changes in bodily function. In man, alterations in pineal function are of significance in jet-lag, shift work and in affective disorder.
Aging↗
Nutritional assessment in rheumatoid arthritis.
The nutritional status was assessed in a group of 220 patients with rheumatoid arthritis from three communities (coloured 89 patients, white 88 and black 43). The triceps skinfold (TSF) thickness, upper arm muscle circumference (UAMC), body mass index (BMI) and percentage of ideal body weight (% IBW) were measured and the serum albumin value determined. The mean age of the coloured patients was 49.8 years, white 57.7 years and black 44.8 years. Forty-five patients (20.5%) had a reduction of one or more anthropometric measurements (TSF, UAMC and/or %IBW) and a further 6 patients (2.7%) had a reduction of the serum albumin value alone. These 51 patients were considered to be malnourished and had a higher mean erythrocyte sedimentation rate and more severe functional disability than the remainder of the patients. The prevalence of malnutrition was lower if diagnosed only on abnormality of the TSF, UAMC and %IBW, since 25 patients (11.4%) had a reduction of only one measurement, 12 (5.5%) had a reduction of 2 and 8 (3.6%) had a reduction of all three measurements. Obesity (BMI greater than 30) was noted in 10.5% and there were no differences in the functional disability, disease activity and use of steroid therapy in the obese patients compared with the rest of the patients.
Adult↗
Changes in melatonin levels but not cortisol levels are associated with depression in patients with eating disorders.
Disturbances were studied in the nocturnal circadian pattern of serum melatonin and plasma cortisol levels in 33 female patients with an eating disorder (anorexia nervosa, n = 11; bulimia nervosa, n = 12; or both, n = 10) and in ten female control subjects of comparable age. Blood samples were obtained hourly from 8 PM to 6 AM under controlled darkness. Serum melatonin levels in all patient groups were initially similar to those of control subjects. When patients were divided according to depression status, those with concurrent major depression had significantly lower nocturnal melatonin values than the nondepressed group. Weight did not appear to influence melatonin levels. In contrast, all patient groups had significantly higher nocturnal levels of plasma cortisol than control subjects, and neither weight nor depression separated patient groups on profiles of plasma cortisol.
Adolescent↗
Blockade of the postictal prolactin surge by methysergide.
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Electroconvulsive Therapy↗
Pineal involvement in the diurnal rhythm of nociception in the rat.
Male Wistar rats under cyclic lighting conditions (LD 12:12) were tested for tail flick latencies. A day-night rhythm of pain sensitivity was clearly demonstrated; response latencies were longest 2 hrs. before 'lights on' (-2 hrs.) and shortest 4 hours into the light phase (+4 hrs.). Hot plate data conformed to the tail flick results and supported the notion that the light-dark cycle cues were responsible for the observed diurnal rhythm of analgesia. The possible involvement of the pineal was studied on rats under LD 12:12 schedules, using two paradigms: (1) Functional pinealectomy by light induced suppression and (2) Surgical pinealectomy. The difference between hot plate response latencies measured at '-2 hrs.' and '+4 hrs.', was reduced when the analgesia tests were preceded by either functional pinealectomy or surgical removal of the pineal gland. The data indicates that the pineal gland is involved in modulation of the baseline diurnal rhythm of analgesia in the rat.
Analgesia↗
Bronchoalveolar leukocyte response in experimental silicosis: modulation by a soluble aluminum compound.
The biological properties of quartz have been related to its surface reactivity. We have addressed the role of particle surface reactivity in mediating the biological activity of quartz in mixed dusts, by treating the quartz with aluminum lactate. Intratracheal instillation of untreated quartz in rats caused a rapid, sustained alveolitis and bronchoalveolar leukocytes obtained from these animals had enhanced activity in degrading fibronectin, but reduced ability to mount a respiratory burst. Quartz pretreated with aluminum elicited a markedly reduced inflammatory response; the reduced activity of the treated quartz was also reflected in the attenuated change in the key functional parameters, oxidant production and proteolysis of fibronectin. Late intratracheal dosing with aluminum after the quartz-induced alveolitis was well established reduced the inflammatory response and abrogated the effect of quartz on the respiratory burst, but did not alter fibronectin degradation by the leukocytes. Aluminum did not affect the inflammatory response to Corynebacterium parvum and thus the effect was on the quartz particles and not on the inflammatory leukocytes. These findings have implications for the likely pulmonary responses to mixed dusts containing quartz and aluminum silicate clays.
Animals↗
Increased frontal and reduced parietal glucose metabolism in acute untreated schizophrenia.
Frontal and parietal lobe metabolism was measured by [18F] fluorodeoxyglucose positron emission tomography in 8 never-medicated DSM-III schizophrenic patients and in 10 control subjects. Patients were in a psychotic episode at the time of this scan. Seven of eight had been ill less than 2 years and had only mild neurocognitive impairment. Frontal lobe glucose metabolism was significantly greater in schizophrenic patients than in controls. This finding differs from that of hypofrontality reported in chronic patients previously treated with neuroleptics. Relative glucose metabolism in the interior parietal lobe was significantly lower in schizophrenic patients than in controls. The frontal/parietal ratios were significantly greater in patients than in controls.
Acute Disease↗
Melatonin and cortisol "switches" during mania, depression, and euthymia in a drug-free bipolar patient.
Low melatonin and elevated cortisol levels have typically been reported during depression. The evidence that the converse is true during mania has been less well documented. In a single case design, repeated measures of nocturnal melatonin and cortisol were taken during mania, depression, and euthymia. Elevated levels of melatonin during mania and elevated cortisol levels during depression were the principal findings. There also did not appear to be any marked change in circadian rhythm of hormone output during the three clinical states. The implications of these findings in relation to noradrenergic dysfunction are discussed.
Adult↗
Effect of morphine on cortisol and prolactin secretion in anorexia nervosa and depression.
Endogenous opioid peptides are involved in feeding regulation, and alterations in opioidergic regulation have been implicated in the pathophysiology of eating disorders. To investigate further this hypothesis, we conducted a placebo-controlled study of the effect of the opiate alkaloid morphine on cortisol and prolactin secretion in six patients with anorexia nervosa and six age-matched healthy volunteers, and compared the results with those obtained in nine depressed patients. Basal cortisol but not basal prolactin levels were elevated in patients with anorexia nervosa and patients with depression. Following the administration of morphine plasma concentrations of cortisol levels declined progressively and at a similar rate in all three groups. The prolactin response to morphine was attenuated significantly in patients with depression. Neither the cortisol and prolactin response to morphine in the anorectic patients nor the cortisol response in the depressed patients we observed in this study suggests altered opiate receptor sensitivity. However, the decreased prolactin response to morphine in depressed patients remains compatible with this hypothesis.
Adolescent↗
Phagocyte-derived oxidant and protease in mineral dust-related lung disease.
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Animals↗
Inflammatory responses in lungs of rats inhaling coalmine dust: enhanced proteolysis of fibronectin by bronchoalveolar leukocytes.
Chronic exposure to coalmine dust is associated with the accumulation of inflammatory leukocytes in the bronchoalveolar region of the lung and, in the long term, with fibrosis and emphysema of the lung parenchyma. Degradation of connective tissue by inflammatory leukocytes has been implicated in the parenchymal damage that precedes the development of fibrotic or emphysematous lesions in the lung. The ability of inflammatory leukocytes obtained by bronchoalveolar lavage from rats inhaling coalmine dust to degrade fibronectin in vitro was assessed. The animals were exposed to an airborne mass concentration of dust similar to the maximum permissible level in United Kingdom collieries. The bronchoalveolar lavage cell population showed changes with duration of dust exposure; there were increases in the total number of leukocytes and in the percentage of polymorphonuclear leukocytes, and the macrophage component of the lavage became increasingly activated, as assessed by the ability of these cells to spread on glass. In addition, degradation of a radiolabelled fibronectin matrix by the coalmine dust exposed bronchoalveolar leukocytes increased with duration of dust exposure. Thus exposure to airborne coalmine dust causes an influx of inflammatory leukocytes to the alveolar region. These cells have enhanced ability to degrade fibronectin and this may be important in subsequent disease development.
Animals↗
Inflammation generating potential of long and short fibre amosite asbestos samples.
Previous studies have shown that long thin asbestos fibres are more pathogenic in in vivo and more active in in vitro assays than short fibre samples. In the present study a long fibre amosite asbestos sample and a short fibre sample prepared from it were tested for ability to cause inflammation in the peritoneal cavity of the mouse; a UICC sample intermediate in fibre size and an inert compact dust, TiO2, were also tested. The ability of the dust samples to cause inflammation, as judged by macrophage and neutrophil recruitment, was ranked in the order long fibre greater than UICC greater than short fibre greater than TiO2. Ability of amosite samples to cause inflammation was therefore related to the proportion of long fibres. The enhanced ability of long fibres to cause inflammation and cause macrophage activation is probably a key factor in the ability of long fibres to cause pulmonary fibrosis and may also be important in fibre carcinogenesis.
Animals↗
Neuroendocrine probes as biological markers of affective disorders: new directions.
Numerous endocrine abnormalities are found in depressive illness and, among these, several have been proposed as useful markers in diagnosis, prediction of treatment response, monitoring treatment outcome or in understanding of etiology. This paper reviews five endocrine systems--the hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-thyroid axis, growth hormone regulation, prolactin regulation and pineal function, in which such abnormalities have been reported. The dexamethasone suppression test (DST) results are affected by a variety of other diseases and confounding conditions. Furthermore, variability in dexamethasone availability has recently been shown to be an important factor, influencing post-DST cortisol levels. Refined tests, taking into account all these factors, or alternative tests of hypothalamic-pituitary-adrenal function may lead to improved clinical utility. Pineal function is now the focus of considerable investigation. Low nocturnal output of melatonin is found in unipolar and bipolar affective disorder and is normalized by treatment with antidepressant drugs which block re-uptake of noradrenaline. These findings support the hypothesis of noradrenergic abnormality in depression. In seasonal affective disorder there is evidence for a phase delay in the melatonin rhythm which may be a key factor in the seasonal disorder. Effective light therapy causes a phase advance in the abnormal melatonin rhythm. Whether the normalization of the melatonin rhythm is instrumental in producing the antidepressant effect is yet to be determined. There are wide spread neuroendocrine abnormalities in depressive illness. These abnormalities encompass many different pituitary hormones, as well as the pineal.(ABSTRACT TRUNCATED AT 250 WORDS)
Depressive Disorder↗