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Biomedical subjects

G S Morris

Publications and source records attributed to G S Morris.

At least 37 records · Page 2Linked to original sources
PubMed1989

ATP formation from deoxyadenosine in human erythrocytes: evidence for a hitherto unidentified route involving adenine and S-adenosylhomocysteine hydrolase.

A novel route of ATP formation has been identified using erythrocytes from patients deficient in four different enzymes associated with ATP formation. It entails prior adenine production from deoxyadenosine (or adenosine) in a reaction involving S-adenosylhomocysteine hydrolase. The postulated route has been demonstrated in human erythrocytes which, unlike other human cells, cannot form ATP from IMP. It is based on studies by others using purified S-adenosylhomocysteine hydrolase preparations in vitro. The results provide the first confirmation that this reaction occurs in intact human cells in vitro and thus most probably in vivo. This adenine production is normally masked in intact cells by further metabolism to ATP. Clinical significance for such a route is suggested by the fact that some adenosine analogues with potent oncostatic and antiviral properties also release adenine (or analogues) in vitro.

Adenine↗
PubMed1989

Dietary carbohydrates modify cardiac myosin isoenzyme profiles of semistarved rats.

Although food restriction reduces the relative expression of the rodent cardiac myosin isoenzyme V1, the contribution of accompanying metabolic changes to the induction and maintenance of this isoenzyme shift remains unknown. Hence, this study was undertaken to determine the role of carbohydrate (CHO) utilization in the regulation of cardiac myosin isoenzyme distribution in food-restricted rats. Female Sprague-Dawley rats received either a mixed diet (55% of calories as CHO, M) or a high-carbohydrate diet (75% of calories as CHO, HC). Additional animals in each dietary group received daily injections of triiodothyronine (T3; 0.075 microgram/100 microM + T3, HC + T3). Three weeks of food restriction reduced left ventricular Ca2+-activated myofibrillar adenosinetriphosphatase activity by 24% and the relative amount of the myosin V1 isoenzyme by 57% in the M group relative to free-eating controls (P less than 0.05). In contrast, these measures were reduced by only 9 and 21%, respectively, in the HC group. Administration of T3 exerted no apparent effect on V1 expression, regardless of diet. Furthermore, the increased expression of V1 in both HC and HC + T3 groups occurred independently of changes in several measures of thyroid status including serum T3 levels, O2 consumption, heart rate, and systemic blood pressure. These results further suggest that metabolic factors, specifically those associated with CHO utilization, can influence cardiac myosin isoenzyme expression.

Animals↗
PubMed1989

Both acute and chronic exercise enhance in vivo ethanol clearance in rats.

Rates of ethanol clearance were measured at rest and with acute exercise in four groups of female Sprague-Dawley rats. Two groups were trained to run on a motor-driven rodent treadmill at 27 m/min, 1 h/day, 5 days/wk and were given a nutritionally balanced liquid diet; one of these groups received 35% calories as ethanol whereas in the other, sucrose was isocalorically substituted for the ethanol. Appropriate sedentary and nonethanol controls were also used. Clearance of a 1.75-g/kg ethanol dose injected intraperitoneally was determined by measuring ethanol levels in the blood each hour and utilizing these values in the Widmark equation (R. Teschke, F. Moreno, and A. Petrides, Biochem. Pharmacol. 30: 1745-1751, 1981) for calculating whole-body ethanol clearance. Rates of ethanol clearance were determined for each rat at 4 and 7 wk of training. The clearance tests at 4 wk included a 60-min period of running exercise, whereas the tests 3 wk later were conducted at rest. The results indicate that both acute exercise and exercise training can increase rates of in vivo ethanol clearance. In addition, the chronic exercise appeared to increase in vitro ethanol metabolism by hepatic microsomes without altering in vitro hepatic alcohol dehydrogenase activity.

Alcohol Dehydrogenase↗
PubMed1988

Altered erythrocyte nucleotide patterns are characteristic of inherited disorders of purine or pyrimidine metabolism.

This paper compares erythrocyte nucleotide levels in patients with eight different inherited purine or pyrimidine enzyme defects identified amongst a variety of patients referred predominantly for investigation of severe neurological abnormalities, or immunodeficiency syndromes. Characteristic nucleotide patterns were identified only in the six disorders (four involving purine and two pyrimidine metabolism) where there was clinical evidence of cellular toxicity. They were frequently related to the accumulation of abnormal metabolites in body fluids. These erythrocyte studies have demonstrated the following. 1. ATP depletion is not an invariable feature of adenosine deaminase (ADA) deficiency, but the accumulation of the deoxyribonucleotides dATP, or dGTP, is diagnostic of ADA, or purine nucleoside phosphorylase (PNP) deficiency, respectively. The early accumulation of dATP in foetal blood is a valuable aid to prenatal diagnosis of ADA deficiency. 2. GTP depletion appears to reflect the degree of CNS involvement in hypoxanthine-guanine phosphoribosyltransferase and PNP deficiency, as well as PP-ribose-P synthetase superactivity. Other diagnostic changes involving increased pyrimidine sugars and increased or decreased NAD levels, or ZTP in Lesch Nyhan erythrocytes, show no consistent correlation with the clinical manifestations. 3. These altered nucleotide levels afford a novel means for carrier detection of the X-linked defect associated with aberrant PP-ribose-P synthetase activity, where no other test is yet available. Measurement of erythrocyte nucleotide levels thus provides a simple and rapid aid to diagnosis and may sometimes be essential for determining prognosis, carrier detection, or monitoring therapy. These characteristic 'fingerprints' may give some insight into the mechanism by which the abnormal gene product produces disease. Such grossly altered nucleotide levels could also result in loss of erythrocyte flexibility, increased destruction and hence the anaemia, or other clinical manifestations, observed in some disorders.

Adenosine Diphosphate↗
PubMed1988

Effect of educational kinesiology on static balance of learning disabled students.

Educational Kinesiology is a movement-based program designed to enhance academic performance and may also influence performance of motor skills. The purpose of this study was to determine whether the Educational Kinesiology techniques of repatterning and/or integration movements affected static balance of 60 learning disabled students, ranging in age from 7 to 11 yr. Subjects were matched on age and sex and assigned to one of three groups: control, movement, or repatterned. Children in the repatterned group received a 10-min. individual session of combined arm and leg movements coordinated with eye-placements prior to the start of the 6-wk. program. Both treatment groups then participated in a movement program for 5 min. twice a day, 5 days a week for 6 wk. The control group received no exposure to these special techniques. Static balance was pretested and posttested in each group using the Modified Stork Stand test. A one-way analysis of variance indicated a significant difference between groups. A Scheffé post hoc test showed that the repatterned group improved more than the movement group, who in turn improved more than the control group.

Child↗
PubMed1987

Solubilization and properties of the liver plasma membrane transglutaminase.

We recently reported that rat liver contains a transglutaminase activity which is specifically associated with the lateral plasma membrane domain [D. J. Tyrrell, W. S. Sale, and C. W. Slife (1986) J. Biol. Chem. 261, 14833-14836]. In this manuscript, conditions for maintaining the activity of this plasma membrane-associated enzyme are described and an unusual method for solubilizing the enzyme is detailed. When rat liver plasma membranes were stored at 4 degrees C, the transglutaminase activity was rapidly lost unless dithiothreitol was present. If calcium or EDTA were included with the reducing agent, a time-dependent enhancement of enzyme activity occurred. These reagents probably prevented and perhaps reversed the oxidation of critical thiol residues in the transglutaminase. When the membranes were incubated at 37 degrees C, increased enzyme activity was found only if 50% glycerol was added to the dithiothreitol and calcium-containing buffer. Under these latter conditions, a selective release of the enzyme from the membrane also occurred, with the enzyme remaining soluble after the glycerol was removed. These data, and our inability to solubilize the enzyme with detergents, indicate that the plasma membrane transglutaminase is a peripheral membrane protein which associates only with a specific plasma membrane domain.

Animals↗
PubMed1987

Effects of exercise and ethanol on liver mitochondrial function.

Rates of ADP stimulated respiration for various substrates were determined in mitochondria isolated from the livers of female Sprague-Dawley rats following 8 weeks of treatment with daily swimming, ethanol consumption, or both. All rats were fed an American Institute of Nutrition (AIN) type liquid diet with the ethanol treated rats receiving 35% of the calories as ethanol. Chronic exposure to ethanol depressed both state 3 respiration with glutamate as a substrate and cytochrome oxidase activity. Respiratory control ratios and P:O ratios, however, were unaffected by the ethanol exposure. Exercise alone had no effect on hepatic mitochondrial function. There were also no significant alterations in oxidative function of hepatic mitochondria from rats which were endurance-trained by swimming while receiving the ethanol diet. This lack of alteration in mitochondrial function was in spite of the fact that these rats consumed an identical amount of ethanol as those which incurred mitochondrial dysfunction. These results indicate that regular exercise has the potential to attenuate the ethanol induced decline in hepatic mitochondria.

Animals↗
PubMed1987

Differential effects of carbohydrate intake on cardiac myosin isoform expression in normal weanling and adult rats.

Dietary manipulations involving high carbohydrate feeding increase V1 cardiac myosin isoform expression in hormonally deficient rats. The purpose of this study was to determine if extremes in dietary carbohydrate availability could alter cardiac myosin isoform patterns in normal weanling and adult rats. Three and six weeks of dietary manipulations (either high or low carbohydrate diets) failed to change calcium-activated myofibril ATPase activity, calcium regulated myofibril ATPase activity, or the myosin isoform distribution in the adult. In contrast, a four week, high carbohydrate diet reduced calcium activated myosin ATPase activity by 33%, calcium regulated myofibril ATPase activity by 10%, and V1 isoform expression by 66% in weanling rats. Although the low carbohydrate diet caused no change in the myosin ATPase properties, it decreased V1 isoform expression by 17%. These results show that carbohydrate availability can alter cardiac myosin isoform expression in normal rats, but only at weanling age. The reason for this age-related contrast in response to dietary manipulations is unknown at this stage. The dietary manipulations may have acted directly on the heart by creating a state of malnutrition, or indirectly, by altering some developmental process which links maturation of the sympathetic nervous system with myosin isoform expression.

Adenosine Triphosphatases↗
PubMed1987

Urinary oxalate levels are not affected by dietary purine intake or allopurinol.

We showed previously that ingestion of a non-specific high purine diet by healthy subjects increased not only urinary uric acid levels but urinary oxalate as well. Both increments were reduced significantly during concomitant allopurinol therapy. The present study was undertaken to investigate these findings in more detail under carefully controlled dietary conditions where a single specific purine, guanosine, was used as an additive and several different methods for oxalate determination (GLC, HPLC, isotacophoresis) were compared with the enzymatic method used previously. Results obtained by two direct techniques of oxalate determination showed no significant alteration in oxalate levels during any dietary regime, suggesting that the earlier results derived from problems inherent in the experimental design and methodology employed. The study confirmed that one of the beneficial effects of allopurinol was to reduce dietary purine absorption. The results may thus provide a logical explanation for the reduced incidence of urolithiasis during allopurinol therapy in some idiopathic oxalate stone formers addicted to purine-rich foods and beverages.

Adult↗
PubMed1987

Central nervous system dysfunction and erythrocyte guanosine triphosphate depletion in purine nucleoside phosphorylase deficiency.

Developmental retardation was a prominent clinical feature in six infants from three kindreds deficient in the enzyme purine nucleoside phosphorylase (PNP) and was present before development of T cell immunodeficiency. Guanosine triphosphate (GTP) depletion was noted in the erythrocytes of all surviving homozygotes and was of equivalent magnitude to that found in the Lesch-Nyhan syndrome (complete hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency). The similarity between the neurological complications in both disorders indicates that the two major clinical consequences of complete PNP deficiency have differing aetiologies: neurological effects resulting from deficiency of the PNP enzyme products, which are the substrates for HGPRT, leading to functional deficiency of this enzyme. immunodeficiency caused by accumulation of the PNP enzyme substrates, one of which, deoxyguanosine, is toxic to T cells. These studies show the need to consider PNP deficiency (suggested by the finding of hypouricaemia) in patients with neurological dysfunction, as well as in T cell immunodeficiency. They suggest an important role for GTP in normal central nervous system function.

Central Nervous System↗
PubMed1987

Heterogeneity of biochemical, clinical and immunological parameters in severe combined immunodeficiency due to adenosine deaminase deficiency.

There was considerable heterogeneity of the biochemical, clinical and immunological findings in 12 patients and two fetuses from 16 kindreds affected by severe combined immunodeficiency (SCID) due to a complete deficiency of the enzyme adenosine deaminase (ADA). Despite this heterogeneity a consistent pattern was observed, in which levels of abnormal purine metabolites paralleled the severity of the immunodeficiency. A high level of urinary deoxyadenosine was a universal finding for homozygous ADA deficiency. ATP depletion, in association with raised deoxy-ATP (dATP) levels, was found in the erythrocytes of nine infants with profound cellular and humoral immunodeficiency. There was no erythrocyte ATP depletion in two patients with some residual immunity, who presented later, but adenosine accumulated in their plasma and urine. This finding, together with the presence of some T and normal B-lymphocytes in less severely affected patients, suggests that adenosine is relatively non-toxic. The other results are consistent with the hypothesis that the sequence of deoxyadenosine accumulation, dATP formation and ATP depletion represents the major mechanism of toxicity to the immune system. Low numbers of T lymphocytes and dATP accumulation were also found in the blood of affected fetuses at 18 weeks gestation. Since extreme instability of erythrocyte ADA was demonstrated in some heterozygotes, and heterozygote ADA levels were detected in one infant with SCID, simultaneous immunological and biochemical analysis of fetal blood are important for precise antenatal diagnosis.

Adenosine Deaminase↗
PubMed1986

Allopurinol in renal failure and the tumour lysis syndrome.

This paper illustrates several important points relating to the use of allopurinol in renal failure, or situations of purine overproduction: It is very easy to give too much allopurinol. Most of the side effects (bone marrow depression, exfoliative dermatitis, etc) are the result of overdosage due to the retention of oxipurinol, an effect exaggerated by thiazide diuretics. Monitoring of plasma oxipurinol levels (ideally less than 100 mumol/l) by high-pressure liquid chromatography is helpful for adjusting dosage in renal failure. Some estimate of the anticipated purine excess is equally vital in deciding dosage during tumour lysis if the risk of urate nephropathy is not to be substituted for the certainty of xanthine nephropathy. In this situation the use of allopurinol may even be questioned. Patients with HGPRT deficiency are exquisitely sensitive to allopurinol, and careful monitoring of the effect on urinary purine levels is essential if xanthine colic is to be avoided.

Adult↗
PubMed1986

Use of biological fluids for the rapid diagnosis of potentially lethal inherited disorders of human purine and pyrimidine metabolism.

Inherited purine and pyrimidine disorders may be associated with serious, sometimes life-threatening consequences. Early and accurate diagnosis is essential. Difficulties encountered when using existing high pressure liquid chromatographic (HPLC) methods led to the development of an improved method based on prior fractionation of urine. The advantages are as follows. 1. Production of fingerprints demonstrating altered urinary excretion patterns characteristic of any one of ten different disorders, in 30 minutes. 2. Positive identification and quantification by comparison with established methods (using conventional chromatography, electrophoresis and UV spectrophotometry) in addition to specific retention times and characteristic UV absorbance ratios at two separate wavelengths (245 and 280 nm) by HPLC. 3. Direct analysis of all the purines and pyrimidines normally found in human body fluids as well as identification of abnormal compounds. 4. Short time between successive analyses while maintaining excellent resolution between compounds of interest and column longevity. 5. Improved separation of the different adenine-based compounds encountered in some disorders, plus demonstration of potential interference by dietary or drug metabolites. 6. Applicability to the monitoring of therapy involving a variety of different purine and pyrimidine analogues. Particular attention should be paid to sample preparation. Plasma profiles will confirm the diagnosis in some, but not all, of these disorders.

Chromatography, High Pressure Liquid↗