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Biomedical subjects

R A Chalmers

Publications and source records attributed to R A Chalmers.

At least 19 recordsLinked to original sources
PubMed1992

Neuropathology of biotinidase deficiency.

A patient with biotinidase deficiency and a progressive neurological disorder died just before the biochemical diagnosis was established. Post-mortem examination of the brain and spinal cord revealed necrotising lesions similar to those in Leigh's disease and Wernicke's encephalopathy. Unlike these two conditions, the regions affected included the hippocampus and parahippocampal cortex. In addition there was severe focal oedema in deep cerebral grey matter, the brain stem, and the spinal cord. These lesions appear to result from a number of severe metabolic disturbances, perhaps linked to an underlying disordered pyruvate metabolism. The nature of the pathology explains why a neurological deficit may persist despite treatment.

Amidohydrolases↗
PubMed1991

Carnitine therapy and metabolism in the disorders of propionyl-CoA metabolism studied using 1H-NMR spectroscopy.

1H-NMR spectroscopy has been used to study metabolic perturbations in patients with disorders of propionyl-CoA metabolism during the administration of oral and intravenous L-carnitine. The administration of L-carnitine either in the form of a challenge or as a therapeutic measure resulted in an increased excretion of propionylcarnitine, consistent with the removal of accumulated intramitochondrial propionyl-CoA esters. Additionally, during the therapeutic administration of L-carnitine excretion of acetylcarnitine occurred, coincident with an improvement in clinical condition and confirming the intracellular propionyl-CoA depletion. An additional benefit from the formation of acylcarnitines may be an accompanying intracellular alkalinisation.

Acyl Coenzyme A↗
PubMed1991

Urinary excretion of nitrogenous and non-nitrogenous compounds in the chronic ethanol-fed rat.

1. The metabolic consequences of chronic ethanol feeding was investigated by assay of urinary metabolites. Male Wistar rats were fed a liquid diet containing 35% of total energy as ethanol or isovolumetric, isocaloric and isonitrogenous amounts of the same diet in which ethanol was substituted by isocaloric glucose (controls). 2. At 6 weeks the entire skeletal muscle mass was reduced by approximately 20%. The urinary excretion of nitrogen, urea and uric acid increased by between 23 and 128%. Urinary creatinine excretion was not significantly altered. 3. Urinary excretion of magnesium was significantly increased by 43%. Urinary excretion of sodium, potassium, calcium and phosphate was increased slightly (i.e. 5-22%), but this change was not statistically significant. 4. Proton n.m.r. spectroscopic analysis showed that ethanol feeding reduced the urinary excretion of citrate and 2-oxoglutarate (by approximately 50%), suggesting decreased citric acid cycle activity. There was an increased excretion of alanine (44%), but excretion of succinate and acetate was not significantly altered. Ethanol in the urine of ethanol-fed rats comprised approximately 2% of total ethanol intake and less than 1% of total energy intake. 5. Lactose was detectable in urine of ethanol-fed rats, but not in control rats, reflecting the reported decreased intestinal lactase activity and increased gut permeability in alcoholics. Urinary galactose excretion decreased by 41%, but relatively large increases in lactate excretion (50%) did not achieve statistical significance. 6. It was concluded that chronic ethanol feeding causes disturbances in whole-body nitrogen homoeostasis and alterations in intermediary metabolism.

Alanine↗
PubMed1991

Enzymologic studies on patients with methylmalonic aciduria: basis for a clinical trial of deoxyadenosylcobalamin in a hydroxocobalamin-unresponsive patient.

Eleven patients with methylmalonic aciduria have been classified on the basis of detailed enzymology on cultured skin fibroblasts. Nine were classified as mutase deficiencies and were unresponsive to hydroxocobalamin in vivo or in vitro. One was classified as a Cbl A variant and was responsive to hydroxocobalamin therapy in vitro and in vivo. Patient 11 was classified as having deoxyadenosyltransferase deficiency (Cbl B). However, a clinical therapeutic trial of deoxyadenosylcobalamin resulted in no clinical or biochemical improvement. Further studies on the patient's cultured fibroblasts suggested that deoxyadenosylcobalamin fails to reach the mitochondria in an intact form. These studies show that detailed enzymologic classification is essential for the reliable evaluation of the response to therapeutic maneuvers; complementation studies alone may be inadequate to completely classify these patients. Therapy with deoxyadenosylcobalamin offers no advantages over the use of hydroxocobalamin in the treatment of patients with methylmalonic aciduria.

Alkyl and Aryl Transferases↗
PubMed1990

Creatine metabolism during metabolic perturbations in patients with organic acidurias.

Creatine excretion was measured in two patients with methylmalonic aciduria and two patients with 3-hydroxy-3-methylglutaric aciduria. During periods of metabolic decompensation the creatine/creatinine ratio increased and fell during recovery. Prolonged periods of metabolic decompensation may result in the loss of a large proportion of the creatine pool. In one study, measurements of total daily urinary output of metabolites demonstrated that the absolute creatine excretion followed a similar qualitative pattern to the creatine/creatinine ratio. However, apparent fluctuations in methylmalonate excretion when expressed as methylmalonate/creatinine ratio were absent when absolute methylmalonate excretion was calculated. The increased creatine excretion during metabolic perturbations may result from loss from creatine containing tissues such as muscle and may represent an underlying defect in energy metabolism. Alternatively creatine transport may be disrupted by accompanying acidosis. The use of metabolite/creatinine ratios as a measure of metabolite excretion rates during metabolic decompensation whilst qualitatively sound may need a re-appraisal.

3-Hydroxybutyric Acid↗
PubMed1990

The contribution of protein catabolism to metabolic decompensation in 3-hydroxy-3-methylglutaric aciduria.

Leucine and protein metabolism were studied using stable isotope techniques in 6-year-old twins with 3-hydroxy-3-methylglutaric aciduria during acute metabolic decompensation. The decompensation was preceded by prolonged fasting in twin 1 and by an upper respiratory infection in twin 2. Twin 2 was also studied when well (control study). During infection, leucine oxidation (36 mumol/kg per hour), protein catabolism (6.0 g/kg per day) and urinary excretion of major leucine metabolites (104 mumol/kg per hour) were all increased compared with the control study (16 mumol/kg per hour, 4.7 g/kg per day and 28 mumol/kg per hour respectively). During fasting, leucine oxidation (18 mumol/kg per hour) was unchanged and protein catabolism (4.1 g/kg per day) was decreased despite substantially increased urinary metabolite excretion (87 mumol/kg per hour) compared with the control study. These results indicate that protein mobilisation and leucine oxidation played important roles in metabolic decompensation during infection but not during fasting. It is likely that the increased metabolite excretion during fasting arose primarily from fatty acid catabolism, indicating the importance of this substrate in metabolic decompensation in 3-hydroxy-3-methylglutaric aciduria.

Amino Acid Metabolism, Inborn Errors↗
PubMed1979

In vitro studies on resealed erythrocyte ghosts as protein carriers.

Resealed erythrocyte ghosts have been proposed as in vivo carriers for enzyme replacement therapy of inherited metabolic diseases. In comparative studies of methods for reversible hypotonic haemolysis of erythrocytes, a five-fold increased entrapment of human serum albumin was obtained by use of a dialysis procedure instead of direct dilution. The percentage incorporation of protein was also affected by varying mixing procedure, haematocrit, lysis, and resealing times but not by varying buffer composition or added protein concentrations over a wide range. Higher protein entrapment was observed with time-expired blood compared to fresh blood and this may be ascribed to increased osmotic fragility of the erythrocyte membrane in stored cells. Haemolysed and resealed ghosts prepared by any method used were smaller than normal erythrocytes as measured with a Coulter Counter and with a fluorescence-activated cell sorter, and protein entrapment reduced the ghost size further.

Blood Preservation↗
PubMed1979

Identification of 5-hydroxyhexanoic acid in the urine of twin siblings with a Reye's-like syndrome associated with dicarboxylic aciduria and hypoglycaemia and with similarities to Jamaican vomiting sickness.

Twin male infant siblings who presented in Harrow, UK, with a Reye's-like syndrome associated with profound hypoglycaemia, vomiting, diarrhoea, coma and death in one child, with dicarboxylic aciduria, and similarities to Jamacian vomiting sickness (hypoglycin toxicity) have been shown to excrete large amounts of a previously unrecorded urinary organic acid. This has been identified as 5-hydroxyhexanoic acid by gas chromatography mass spectrometry using a synthesized standard. Concentrations observed were 340 and 330 mg g-1 creatinine in the two patients. The metabolic precursor of the urinary acid is suggested to be hex-4-enoic acid, a probable chemical toxin closely related to the active organic acid metabolite of hypoglycin. The possibility of omega - 1 oxidation of hexanoic acid to 5-hydroxyhexanoic acid in these and other patients with dicarbocylic aciduris is also discussed.

Caproates↗
PubMed1979

Studies on some possible biochemical treatments of primary hyperoxaluria.

The effects of some putative inhibitors of oxalate production or urinary oxalate excretion have been investigated in the Cynamolgus monkey and in patients with Type I primary hyperoxaluria (hyperoxaluria with glycollic aciduria). Sodium-1-hydroxybutan-sulphonate, D,L-phenyllactate, succinimide and isocarboxazide did not reduce the urinary oxalate excretion in the monkeys. Pyridoxine reduced the excretion of oxalate and glycollate in some patients, and its therapeutic use has been documented over a five-year period. Succinimide, which has been used by other workers for the treatment of non-hyperoxaluric stone formers, did not decrease the excretion of either oxalate or glycollate in three patients in whom it was tried. It did not change the inhibitory activity of the urine with respect to the growth and aggregation of calcium oxalate crystals in any of the three patients, and it did not have any consistent effect on the excretion of calcium oxalate crystals in the one patient who had detectable crystaluria before treatment. We have identified several metabolites of succinimide in the urine of patients taking the drug. These include 2,3-dehydrosuccinamic, 2-hydroxysuccinamic and 3-hydroxysuccinamic acids. Isocarboxazide, cholestyramine and thiamine did not affect the urinary oxalate excretion in the patients. The significance of these observations from the viewpoint of the treatment of primary hyperoxaluria is discussed.

Adolescent↗
PubMed1979

A new variant form of phenylketonuria.

We report a family (parents and two sets of twin girls) in which the propositus presented as a case of phenylketonuria with a somewhat less severe degree of phenylalanine intolerance than occurs in patients with classical phenylketonuria and whose phenylalanine tolerance was further impaired by giving cotrimoxazole. The trimethoprim component of cotrimoxazole reduces the phenylalanine tolerance of normal subjects but does not augment the degree of phenylalanine intolerance in patients with classical phenylketonuria. The results of the present study of the phenylalanine tolerance and the way in which cotrimoxazole modifies it in the members of this family are compatible with the segregation of an abnormal gene which causes a previously unrecognized type of phenylketonuria when it is present in the homozygous state. The possible relationship of this to other inherited biochemical lesions of the phenylalanine hydroxylase system is briefly discussed.

Adult↗
PubMed1979

Measurement of 4-hydroxyphenylacetic aciduria as a screening test for small-bowel disease.

We evaluted measurement of urinary 4-hydroxyphenyl acetic acid as a potential screening method for small-bowel disease and bacterial overgrowth syndromes in 360 unselected acutely ill infants and children. Control data were obtained on 120 healthy children, ages 1.5 to 15 years, from a general medical practice, 48 healthy infants, ages one to five years, from local day nurseries, and 150 healthy babies, ages less than one to eight days. Comparative data were from 300 acutely ill hospitalized babies and children, ranging in age from less than one day to 15 years and without clinical evidence for small-bowel disease and bacterial overgrowth syndrome. No false-negative results and only 2% false-positive results were observed. Among the 10 patients whose urinary excretion of the analyte was considered to be abnormal were patients with Giardia lamblia infestation, ileal resection with blind loop, and other diseases of the small intestine associated with bacterial overgrowth. We conclude that measurement of 4-hydroxyphenylacetic acid excretion is useful in screening for such diseases.

Adolescent↗