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Biomedical subjects

G J Cooper

Publications and source records attributed to G J Cooper.

At least 163 records · Page 9Linked to original sources
PubMed1988

Biochemical evidence that high concentrations of the antidepressant amoxapine may cause inhibition of mitochondrial electron transport.

Overdosage with the antidepressant amoxapine causes metabolic acidosis and may lead to brain damage and death. To better understand the metabolic disturbances caused by amoxapine overdose, its effects on three simple systems were studied: growth of Saccharomyces cerevisiae, mitochondrial energy metabolism, and an electron transport system in microsomal membranes. Growth of yeast on all substrates except lactate was inhibited by amoxapine at 50-100 micrograms ml-1. Growth on lactate was observed at 200 micrograms ml-1 of amoxapine. In beef heart mitochondria, amoxapine at 100 micrograms ml-1 inhibited reactions involving large sections of the electron transport chain. Energy-linked reactions in submitochondrial particles were also inhibited. Electron microscopy showed some disruption of the mitochondrial internal structure by amoxapine and a change from orthodox to condensed conformation. Microsomal NADH-cytochrome b5 reductase was inhibited by amoxapine, but at higher amoxapine concentrations than mitochondrial reactions. The results suggest amoxapine disrupts reactions of membrane-associated enzyme complexes, and mitochondrial energy conservation may be one of the first systems affected. We speculate that lactic acid accumulation in patients with amoxapine overdose may be caused by loss of electron acceptor activity in tissues.

Amoxapine↗
PubMed1988

Calcitonin gene-related peptide and somatostatin inhibit insulin release from individual rat B cells.

Hormone secretion from single, rat pancreatic B cells was visualised by a reverse haemolytic plaque assay for C-peptide. Quantitative analysis of the size and number of haemolytic plaques indicated that exposure to 3, 5, 10 and 20 mM glucose resulted in a dose-dependent increase in both the magnitude of C-peptide, and thus, insulin release by individual B cells and the recruitment of activity secreting B cells. Somatostatin and calcitonin gene-related peptide, fragment 28-37 (CGRP28-37) were shown to inhibit glucose-stimulated insulin release as assessed by the size of individual plaques and the number of recruited B cells, and hence to reduce the total area of plaques formed. In the presence of 15 mM glucose, a dose-dependent effect of CGRP28-37 on the secretion of insulin was observed, with the size of plaques formed by individual B cells reduced at concentrations of CGRP28-37 between 10(-5) and 10(-11) M. Thus, both somatostatin and CGRP28-37 can act directly on individual B cells to inhibit their secretory response to increasing levels of glucose. We suggest that these peptides which can be immunolocalised in islet cells may have a role in the regulation of insulin secretion.

Animals↗
PubMed1988

Amylin found in amyloid deposits in human type 2 diabetes mellitus may be a hormone that regulates glycogen metabolism in skeletal muscle.

Diabetes-associated peptide has recently been isolated and characterized from the amyloid of the islets of Langerhans in type 2 (non-insulin-dependent) diabetics, and immunoreactivity with antibodies to the peptide has been demonstrated in islet B cells of both normal and type 2 diabetic subjects. In view of the evidence presented in this paper that this 37-amino acid peptide may be a hormone present in normal individuals, we now propose the name "amylin" to replace "diabetes-associated peptide." Because increased amylin, deposited as amyloid within the islets of Langerhans, is characteristic of type 2 diabetes, the study below was performed to examine the possible effects of amylin on peripheral glucose metabolism. Whole amylin was synthesized by using solid-phase techniques, with formation of the disulfide linkage by oxidation in dilute aqueous solution and recovery of the peptide by lyophilization. The effects of amylin on glucose metabolism were studied in two preparations in vitro, isolated rat soleus muscle strips and isolated rat adipocytes. In skeletal muscle exposed to 120 nM amylin for 1 hr, there was a marked decrease in both basal and submaximally insulin-stimulated rates of glycogen synthesis, which resulted in significant reduction in the rates of insulin-stimulated glucose uptake. In muscles treated with amylin there was no response at the concentration of insulin required to stimulate glucose uptake half-maximally in untreated (control) muscles. In marked contrast, amylin had no effect on either basal or insulin-stimulated rates of glucose incorporation into either CO2 or triacylglycerol in isolated adipocytes. Therefore, amylin may be a factor in the etiology of the insulin resistance in type 2 diabetes mellitus, as both deposition of the peptide in islet amyloid and decreased rates of glucose uptake and glycogen synthesis in skeletal muscle are characteristic of this condition.

Amyloid↗
PubMed1988

Wound ballistics: contemporary and future research.

Wound ballistics research has contributed much to the understanding of the pathophysiology of missile injury that now exists. From this store of knowledge treatment regimes have evolved which have greatly improved the lot of the soldier wounded in war. However, research must keep pace with changes that are taking place in weapons research and development so that the particular needs of the Army Medical Services on a future battlefield can be met. The differing needs of civilian and military medical services are highlighted. The marked differences that exist between the missile wound seen and treated in a late twentieth century hospital and the wounds likely to be encountered on the modern battlefield are enumerated and discussed.

Humans↗
PubMed1988

Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes.

Morphometric analysis of the endocrine and exocrine pancreas was done on immunoperoxidase stained post-mortem tissue from 15 Type 2 diabetic and 10 age-matched control subjects. Thirteen of the 15 Type 2 diabetic patients had islet amyloid deposits (mean, 6.5% islet area) in the corpus (body, tail and anterior part of the head) but not in the caput (the "pancreatic polypeptide rich" part of the head) whereas none was seen in control subjects. In the corpus in diabetic subjects, the pancreatic area density of B-cells was decreased by 24% (p = 0.005) and A-cells increased by 58% (p less than 0.001) compared with control subjects. The mean A/B-cell ratio increased in the corpus from 0.27 in control subjects to 0.57 in Type 2 diabetic patients. Positive immunoreactivity for the amyloid constituent peptide, Diabetes Associated Peptide, was demonstrated in islet amyloid of diabetic subjects and in B-cells of control and diabetic subjects. The increase in A-cells may contribute to the hyperglucagonaemia and hyperglycaemia of Type 2 diabetes. The impaired insulin secretion in Type 2 diabetes may be due to a decrease in B-cells and to disruption of the islet structure by amyloid. Exocrine fat was similar in the control and diabetic subjects with both groups having more in the corpus than the caput. Diabetic subjects had increased exocrine fibrosis in the corpus region (p less than 0.001), but not in the caput. Exocrine fibrosis may be secondary to disordered islet cell function.

Aged↗
PubMed1987

Islet amyloid formed from diabetes-associated peptide may be pathogenic in type-2 diabetes.

Pancreatic islet amyloid deposits were found in 22 of 24 type-2 diabetic subjects (aged 48-68 years) and were not present in 10 age-matched controls. A novel peptide, 37 aminoacids long, termed diabetes-associated peptide (DAP), has been identified in amyloid-containing pancreatic extracts from 3 type-2 diabetic patients but not in extracts from 6 non-diabetic subjects. DAP has major homology with calcitonin-gene related peptide (CGRP) and the islet amyloid of all 22 diabetics showed CGRP immunoreactivity. The immunoreactivity was inhibited by preabsorption of three different CGRP antisera either with CGRP carboxyterminal peptide 28-37 or with extracted DAP. Both diabetic and non-diabetic subjects had CGRP/DAP immunoreactivity in islet B-cells. Electron microscopy of islets containing amyloid indicated fibrillar amyloid between the endocrine cells and capillaries, usually penetrating into deep invaginations of the plasma membrane of the B-cells. These results suggest that islet amyloid contains DAP, which may originate from B-cells. Accumulation of amyloid in islets is likely to impair islet function and may be a causal factor in the development of type-2 diabetes.

Aged↗
PubMed1987

Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients.

Deposition of amyloid in pancreatic islets is a common feature in human type 2 diabetic subjects but because of its insolubility and low tissue concentrations, the structure of its monomer has not been determined. We describe a peptide, of calculated molecular mass 3905 Da, that was a major protein component of amyloid-rich pancreatic extracts of three type 2 diabetic patients. After collagenase treatment, an extract containing 20-50% amyloid was solubilized by sonication into 70% formic acid and the peptide was purified by gel filtration followed by reverse-phase high-performance liquid chromatography. We term this peptide diabetes-associated peptide, as it was not detected in extracts of pancreas from any of six normal subjects. Diabetes-associated peptide contains 37 amino acids and is 46% identical to the sequences of rat and human calcitonin gene-related peptide, indicating that these peptides are related in evolution. Sequence identities with conserved residues of the insulin A chain were also seen in a 16-residue segment. On extraction, the islet amyloid is particulate and insoluble like the core particles of Alzheimer disease. Their monomers have similar molecular masses, each having a hydropathic region that can probably form beta-pleated sheets. The accumulation of amyloid, including diabetes-associated peptide, in islets may impair islet function in type 2 diabetes mellitus.

Aged↗
PubMed1985

Pregnancy complicated by non-insulin dependent diabetes mellitus and type V hyperlipoproteinaemia: case report.

Type V hyperlipoproteinaemia complicated a pregnancy in a 38 year old Samoan multigravida with previous noninsulin dependent diabetes. The hypertriglyceridaemia was associated with severe insulin resistance, nonacidotic ketosis and poor control of the diabetes. Continuous subcutaneous insulin infusion resulted in excellent diabetic control and plasma triglyceride levels fell to normal without specific dietary fat restriction. The pregnancy resulted in the live birth of a normal healthy infant at 38 weeks' gestation.

Adult↗
PubMed1984

Iodide excretion in a salt-restriction trial.

Twenty-four hour urinary iodide excretion was measured twice, with a four month interval, in 133 individuals who were in a 12-month salt-restriction study in an area where iodine-deficiency goitre was once common and where most household salt is iodised. Half the subjects were salt restricted; their mean 24 h sodium excretion after eight months was 89 mmol for men and 73 mmol for women. Iodide excretion correlated with sodium excretion in the whole group on each occasion. After eight months mean 24 h iodide excretion in the salt-restricted group (men 1.3 SD 0.6 mumol, women 1.1 SD 0.4 mumol) was lower (p less than 0.01) than that in the control group (men 1.8 SD 0.8 mumol, women 1.7 SD 0.8 mumol), but was reasonable in terms of recommended dietary allowances (1.2 mumol, 150 mg). Mean iodide content of local milk was 1.3 mumol/l. Any salt that is used in the home should continue to be iodised. However, it has become unnecessary in this population to use salt (ie, iodised salt) simply in order to avoid iodine deficiency, so long as other foodstuffs continue to contain iodine as at present. As the other sources of iodine may be subject to change, the adequacy of intake of iodine from these sources should be monitored from time to time in samples of the population.

Adolescent↗
PubMed1984

Goitre and thyroid dysfunction during chronic amiodarone treatment.

We measured thyroid function in a cross-sectional survey of 37 unselected patients receiving chronic amiodarone treatment. Palpable goitre was presented in 17 patients and was a new finding in ten. Despite frequent elevations of serum free T4 (67%) or free T4 index (43%), all 37 patients were clinically euthyroid with a normal or decreased serum free T3 or free T3 index. Mean urine iodide/creatinine excretion was increased 13-fold. Three patterns of thyroid function were seen; in 21 patients with normal TRH responses, the mean basal serum TSH was significantly elevated. Five patients had biochemical hypothyroidism which did not require treatment. Eleven patients had evidence of thyroid autonomy and the three patients with absent TRH responses each gave a past history of goitre or thyrotoxicosis; a trial of carbimazole treatment in these three was without clinical benefit. The observed spectrum of subclinical goitre and thyroid dysfunction may result from an unpredictable thyroid response to excessive free iodide combined with a weak goitrogenic effect of amiodarone mediated by increased TSH secretion.

Adult↗