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Biomedical subjects

R A Iles

Publications and source records attributed to R A Iles.

At least 37 records · Page 2Linked to original sources
PubMed1996

A method for determination in situ of variations within the hepatic lobule of hepatocyte function and metabolite concentrations.

A method is described for the production of detailed maps of intralobular variations of hepatocyte function and metabolite concentrations, based on variable destruction by digitonin of the lobule from the centrilobular direction. Instead of the conventional approach, in which isolated hepatocytes are then prepared and studied in suspension, perfusion is continued after digitonin treatment and the function of the unaffected lobular remnants is determined, or mean metabolite concentrations are measured by 31P-NMR. These measurements are plotted against the degree of destruction, determined precisely after each study by automated quantitative histomorphometry. These plots are transformed into curves of the function or metabolite concentration of nominal single cells at any point along the radius of the lobule. Gluconeogenesis from lactate remained stable, although reduced, even after 85-90% lobular destruction, predominated periportally and disappeared by 50% along the radius of the lobule. In 31P-NMR studies, employing 1.5 mM lactate as substrate, narrowing of the intracellular P1 resonance was observed as digitonin destruction increased; this was attributed to a decrease in the intralobular heterogeneity of the intracellular pH, which fell from approx. 7.9 to < 7.4 along the first 16% of the lobular radius (from the periportal end) and to < 7.3 in the remainder of the lobule. The ATP concentration rose, and then fell, along the radius of the lobule in a centripetal direction. The method is potentially generally applicable to a wide range of hepatocellular functions and to the measurement of metabolite concentrations, most conveniently those susceptible to estimation by NMR.

Animals↗
PubMed1996

Propionylcarnitine excretion is not affected by metronidazole administration to patients with disorders of propionate metabolism.

UNLABELLED: Propionylcarnitine (PC) excretion has been measured during a clinical trial of metronidazole therapy in two patients with propionic acidaemia and two patients with methylmalonic aciduria. All patients were in good metabolic control and were receiving L-carnitine. While total propionate excretion was reduced by up to 40% in all four patients during metronidazole therapy, the excretion of propionylcarnitine remained largely unchanged. PC comprised up to 80% of total propionate excretion in patients with propionic acidaemia. CONCLUSION: These results suggest an extra-hepatic source and/or differing compartmentation for PC formation from those for the production of other metabolites of propionyl-CoA.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

Cerebral energy metabolism in isovaleric acidaemia.

A newborn infant with an acute metabolic encephalopathy caused by isovaleric acidaemia had severe impairment of cerebral energy metabolism. This was detected by phosphorus and proton magnetic resonance spectroscopy. After treatment she made excellent clinical recovery, her spectroscopic abnormalities resolved, and she was neurologically normal at the age of 1 year.

Brain↗
PubMed1995

Haemodynamic and metabolic effects in diabetic ketoacidosis in rats of treatment with sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate.

To examine factors determining the haemodynamic and metabolic responses to treatment of diabetic ketoacidosis with alkali, groups of anaesthetised and ventilated rats with either diabetic ketoacidosis (mean arterial pH 6.86-6.96, mean arterial blood pressure 63-67 mm Hg) or hypovolaemic shock due to blood withdrawal (mean pHa 7.25-7.27, mean arterial blood pressure 36-41 mm Hg) were treated with sodium chloride ('saline'), sodium bicarbonate or 'Carbicarb' (equimolar bicarbonate plus carbonate). In the diabetic ketoacidosis series, treatment with either alkali resulted in deterioration of mean arterial blood pressure and substantial elevation of blood lactate, despite a significant rise in myocardial intracellular pH determined by 31P-magnetic resonance spectroscopy. These effects were accompanied by falling trends in the ratios of myocardial phosphocreatine and ATP to inorganic phosphate. Erythrocyte 2,3-bisphosphoglycerate was virtually absent in animals with diabetic ketoacidosis of this severity and duration. In contrast, in shock due to blood withdrawal, infusion of saline or either alkali was accompanied by a transient elevation of mean arterial blood pressure and no significant change in the already elevated blood lactate; erythrocyte 2,3-bisphosphoglycerate was normal in these animals. The effect of alkalinization in rats with severe diabetic ketoacidosis was consistent with myocardial hypoxia, due to the combination of very low initial erythrocyte 2,3-bisphosphoglycerate, alkali-exacerbated left shift of the haemoglobin-oxygen dissociation curve and artificial ventilation. No evidence was found for any beneficial effect of 'Carbicarb' in either series of animals; 'Carbicarb' and sodium bicarbonate could be deleterious in metabolic acidosis of more than short duration.

3-Hydroxybutyric Acid↗
PubMed1994

Detection of propan-1,2-diol in neonatal brain by in vivo proton magnetic resonance spectroscopy.

Cerebral in vivo proton magnetic resonance spectroscopy of 13 newborn infants displaying seizures and receiving phenobarbitone, in one case supplemented by phenytoin, showed signals from propan-1,2-diol (the injection vehicle for both these anticonvulsants). Subsequent in vitro spectroscopy of cerebro spinal fluid (CSF) from one of these infants also showed signals from this substance. The estimated in vivo propan-1,2-diol concentration (approximately 3 mM) was less than that measured in the CSF sample (14.4 mM). These observations suggest that propan-1,2-diol may accumulate in cerebral tissue and misidentification of its signals in both in vivo and in vitro proton spectra may confuse diagnoses of metabolic or other disorders.

Brain Chemistry↗
PubMed1994

The effects of sodium bicarbonate and a mixture of sodium bicarbonate and carbonate ("Carbicarb") on skeletal muscle pH and hemodynamic status in rats with hypovolemic shock.

Rats rendered hypotensive and acidotic by withdrawal of blood were treated by infusion of either an equimolar mixture of sodium bicarbonate and sodium carbonate ("Carbicarb"), sodium bicarbonate alone, or sodium chloride. Skeletal muscle intracellular pH (pHi) was measured using magnetic resonance spectroscopy from the chemical shift of the carbon-2 (C2) proton resonance of the imidazole ring of anserine. In the groups treated with alkali, arterial blood pH (pHa) was restored to normal, but no change was observed in the sodium chloride-treated animals. Despite an elevation of arterial blood partial pressure of CO2 (PaCO2) in the group treated with sodium bicarbonate, no significant change in pHi was observed in any group. Blood lactate levels, initially elevated in all groups, underwent only minor changes. In all three groups a transient and similar elevation of arterial blood pressure was observed after infusion. Differential effects of Carbicarb and sodium bicarbonate in metabolic acidosis may be dependent on the model of metabolic acidosis used, and an alteration in PaCO2 induced by alkali therapy may not be a major determinant of changes in pHi.

Acidosis↗
PubMed1994

Utilization of uniformly labeled 13C-polyunsaturated fatty acids in the synthesis of long-chain fatty acids and cholesterol accumulating in the neonatal rat brain.

Polyunsaturated fatty acids are needed for normal neonatal brain development, but the degree of conversion of the 18-carbon polyunsaturated fatty acid precursors consumed in the diet to their respective 20- and 22-carbon polyunsaturates accumulating in the brain is not well known. In the present study, in vivo 13C nuclear magnetic resonance spectroscopy was used to monitor noninvasively the brain uptake and metabolism of a mixture of uniformly 13C-enriched 16- and 18-carbon polyunsaturated fatty acid methyl esters injected intragastrically into neonatal rats. In vivo NMR spectra of the rat brain at postnatal days 10 and 17 had larger fatty acid signals than in uninjected controls, but changes in levels of individual fatty acids could not be distinguished. One day after injection of the U-13C-polyunsaturated fatty acid mixture, 13C enrichment (measured by isotope ratio mass spectrometry) was similar in brain phospholipids, free fatty acids, free cholesterol, and brain aqueous extract; 13C enrichment remained high in the phospholipids and cholesterol for 15 days. 13C enrichment was similar in the main fatty acids of the brain within 1 day of injection but 15 days later had declined in all except arachidonic acid while continuing to increase in docosahexaenoic acid. These changes in 13C enrichment in brain fatty acids paralleled the developmental changes in brain fatty acid composition. We conclude that, in the neonatal rat brain, dietary 16- and 18-carbon polyunsaturates are not only elongated and desaturated but are also utilized for de novo synthesis of long-chain saturated and monounsaturated fatty acids and cholesterol.

Aging↗
PubMed1993

An investigation of argininosuccinic acid anhydrides in argininosuccinic acid lyase deficiency by 1H-NMR spectroscopy.

Argininosuccinate (ASA) is excreted in large amounts in the urine of patients with argininosuccinate lyase (EC 4.3.2.1) deficiency (ASLD). Previous workers have reported the presence of anhydrides of ASA in the urine of patients with this disorder. We have used 1H-NMR spectroscopy to investigate the presence of these compounds in untreated urine. Our results indicate that the anhydrides were absent from urine and are artifacts produced by the conditions prevailing in the methods of analysis previously used to investigate the urine from patients with ASLD. We have also attempted to reproduce the conditions that might promote the transition to the anhydrides in the urine from a patient with ASLD and in solutions of argininosuccinate. Resolution of ASA and the two anhydrides is possible and a spectrum of the urine from a patient with ASLD shows that the anhydrides are present at below 1% of the total ASA under normal physiological conditions.

Amino Acid Metabolism, Inborn Errors↗
PubMed1993

A 31P and 1H-NMR investigation in vitro of normal and abnormal human liver.

Spectral changes in human hepatic tumours and possible systemic effects of tumour on host liver were assessed by 31P and 1H in vitro NMR spectroscopy. The 1H and 31P spectra from liver tumour biopsies showed significant elevation in phosphoethanolamine, phosphocholine, taurine, citrate, alanine, lactate and glycine, and significant reduction in GPE (glycerophosphoethanolamine), GPC (glycerophosphocholine), creatine and threonine compared to histologically normal tissue. 31P-NMR spectra obtained from histologically normal tissue within tumour-bearing livers showed significant elevation in phosphoethanolamine and phosphocholine compared to data from liver biopsies from nontumour-bearing patients (pancreatitis). These results suggest that alterations in membrane metabolism in host liver can be detected by 31P-NMR.

Biopsy↗
PubMed1993

Bicarbonate in the treatment of metabolic acidosis: effects on hepatic intracellular pH, gluconeogenesis, and lactate disposal in rats.

The effects of agents used in the treatment of metabolic acidosis could depend on the induced changes in intracellular pH (pHi). To determine the effect of sodium bicarbonate on hepatic pHi and function, this agent was infused into anesthetized rats with acute metabolic acidosis due to either diabetic ketoacidosis (DKA) or HCl infusion. Hepatic pHi was measured by 31P-magnetic resonance spectroscopy (MRS). A substantial increase in pHi occurred (from 7.13 +/- 0.08 to 7.32 +/- 0.08, P < .05) despite an increase in mixed venous PCO2. Isolated livers from normal rats or those with DKA were perfused at pH 6.8 and normal PCO2. With infusion of sodium bicarbonate, there was again an increase in pHi (delta pHi, + 0.27 +/- 0.06, P < .02) despite increases in both portal and hepatic venous PCO2. Lactate uptake was increased twofold to threefold (P < .001) by bicarbonate infusion in perfusions from both types of animals. Glucose output was increased twofold (P < .001) only in livers from normal animals.

Acidosis↗