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Biomedical subjects

H A Simmonds

Publications and source records attributed to H A Simmonds.

At least 181 records · Page 10Linked to original sources
PubMed1984

dATP accumulation and ATP depletion in platelets in adenosine deaminase deficiency: significance for the immune response?

High levels of dATP and dADP, accompanied by ATP depletion, were found in the platelets of two ADA-deficient children with severe combined immunodeficiency (SCID). In vitro studies demonstrated that even normal platelets had the ability to make dATP from deoxyadenosine (dAR) under physiological conditions. This capability was greatly enhanced by conditions simulating ADA deficiency. These results question whether the platelet has a specific role in the normal immune response.

Adenosine Deaminase↗
PubMed1984

Failure of protein loading tests to identify heterozygosity for ornithine carbamoyltransferase deficiency.

Protein loading tests for the diagnosis of heterozygous ornithine carbamoyltransferase deficiency were performed on two occasions on an asymptomatic woman whose daughter and two infant sons died of the disease. Neither loading test produced the expected increases in urinary orotic acid excretion and studies of other pyrimidine and purine metabolites in urine and plasma did not suggest that these would provide better discrimination from non-carriers. The results probably reflect an extensive inactivation of the mutant X chromosome in liver cells and reinforce the need for caution in interpreting negative test results.

Adult↗
PubMed1984

Pregnancy in xanthinuria: demonstration of fetal uric acid production?

This paper reports biochemical studies in a pregnant xanthinuric female (McKusick 27830) and compares the results with findings in three other xanthinurics studied by us, including a previously unreported female who had a nephrectomy for xanthine stones. The findings of raised levels of uric acid in plasma and urine at presentation in the third trimester of pregnancy, and the subsequent fall to almost undetectable levels 6 weeks post-partum, is regarded as evidence of the extent of fetal uric acid production and clearance by the maternal circulation.

Adult↗
PubMed1984

Azapropazone--a treatment for hyperuricaemia and gout?

In a metabolic ward study of five patients, azapropazone lowered plasma uric acid but exerted only a modest and variable uricosuric effect without altering urinary xanthine and hypoxanthine levels. An alternative mechanism other than uricosuria or xanthine oxidase inhibition must account for some of the hypouricaemic action of this drug. During the first day of treatment urine volume and pH declined sharply. In a separate investigation, 22 patients were given azapropazone and 18 were given allopurinol combined with colchicine for 3 months. Allopurinol reduced plasma uric acid more quickly but at the end of the study there was little difference in the hypouricaemic results achieved by both drugs. Recurrent gout occurred more frequently with allopurinol but side-effects were confined to those taking azapropazone. A slight rise in blood urea and creatinine and a fall in haemoglobin were also features of long-term azapropazone treatment.

Adult↗
PubMed1984

Beer drinking and its effect on uric acid.

This study attempted to simulate the drinking habits of gout patients. Beer or squash was drunk over a 4-hour period on two successive days by five gouty and five normouricaemic men. Serum lactate increased with beer and squash, but elevation of plasma uric acid was confined to beer drinking. Urate clearance increased with both beverages, but 24-hour uric acid excretion was accentuated only by beer. The purine content of several beers was measured and the principal constituent found to be guanosine, which is probably the most readily absorbed dietary purine. It was concluded that the hyperuricaemic effect of beer was mediated by the digestion of purines contained by the beer and by an effect of ethanol on uric acid synthesis. There was no evidence that beer taken in usual quantities reduced the renal excretion of uric acid.

Alcohol Drinking↗
PubMed1984

B cells as well as T cells form deoxynucleotides from either deoxyadenosine or deoxyguanosine.

Enzyme inhibitors used to simulate the inherited immunodeficiency diseases, adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency, have been assessed in cultured human lymphocytes. Only 2'-deoxycoformycin (dCF) completely inhibited ADA in T and B cells at concentrations in excess of 5 microM. Erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) and 8-amino guanosine (8-NH2GR) did not inhibit ADA or PNP completely at any concentration. Detailed metabolic experiments comparing viability and deoxynucleotide accumulation showed that B cell lines of malignant origin also accumulated high levels of dATP from 2'-deoxyadenosine (dAR), and dGTP from 2'-deoxyguanosine (dGR) as effectively as T cells--even without inhibitors, however, dAR reduced cell viability only when ADA was inhibited by dCF, whilst dGR was equally toxic with or without inhibitor, even to a line which accumulated no dGTP. These experiments indicate that cultured lymphocytes, using either EHNA or 8-NH2GR as enzyme inhibitor, are not valid models of the toxicity to the immune system in inherited ADA or PNP deficiency. They demonstrate that the ability to accumulate high levels of dATP or dGTP is not exclusive to T cells and that the in vitro toxicity of dAR or dGR could relate to the use of excess substrate and/or accumulation in different nucleotide, not deoxynucleotide pools.

Adenine↗
PubMed1984

Prenatal diagnosis of three cases of severe combined immunodeficiency: severe T cell deficiency during the first half of gestation in fetuses with adenosine deaminase deficiency.

The prenatal diagnosis of severe combined immunodeficiency (SCID) was made in three fetuses by staining fetal blood obtained at fetoscopy with a panel of monoclonal antibodies. There were less than 100 T cells/mm3 of fetal blood in these three cases compared to 2,500/mm3 in 14 immunologically normal fetuses. Cells bearing the cortical thymocyte antigen (NA1/34) were not detected in any of the normal or affected fetal blood samples. Two of the affected fetuses were also homozygous for a deficiency of adenosine deaminase (ADA) with undetectable levels of red cell ADA. All three affected fetuses were aborted and postmortem tissue was obtained in two cases. In both of these cases the thymus was markedly hypoplastic and contained no lymphoid cells. One of these fetuses was homozygous for ADA deficiency and the virtual absence of T cells or thymocytes during the second trimester of pregnancy indicates that placental access to the maternal circulation does not prevent damage to the T lineage stem cells in this disease. Prenatal diagnosis of SCID has previously only been possible in patients with a defined metabolic defect such as ADA deficiency, but these studies indicate that prenatal diagnosis now may be offered for most at risk pregnancies.

Adenosine Deaminase↗
PubMed1983

Gout and uric acid nephropathy: some new aspects in diagnosis and treatment.

It has been recognized that primary disorders of uric acid metabolism result from impaired renal excretion or increased endogenous production of uric acid. It has also been found that these two mechanisms do not comprise two distinct syndromes, but may each constitute a group of syndromes. Contrary to earlier as well as currently published reports we conclude from our clinical and experimental experience that the fraction of so-called over-producers is less than 1% of all patients with primary hyperuricaemia and gout. A procedure for the diagnosis of uric acid overproduction is suggested. The manifestation of hyperuricaemia and gout mainly depends on renal uric acid clearance and is greatly influenced by dietary habits in most of the patients. An impaired renal uric acid excretion results in an increased intestinal excretion; this partly compensates for the defect. Normalization of serum uric acid should be achieved by dietary regimens with or without additional drug treatment, but not by drug treatment alone. With drug treatment xanthine oxidase inhibitors are preferable to uricosurics; no other xanthine oxidase inhibitor besides Allopurinol has been in clinical trial, however. Due to the enhancement of uric acid clearance with uricosurics, there are groups of patients who should not be treated with these drugs. Fixed combinations of Allopurinol and uricosurics should not be used. Drugs which have uricosuric as well as other pharmacologic properties are under investigation. So far they have not reached general clinical application.

Adult↗
PubMed1983

On the metabolism of allopurinol. Formation of allopurinol-1-riboside in purine nucleoside phosphorylase deficiency.

Allopurinol-1-riboside, a major metabolite of allopurinol, is commonly thought to be directly synthesized by purine nucleoside phosphorylase (PNP) in vivo. As this enzyme is otherwise believed to function in vivo primarily in the direction of nucleoside breakdown, we have determined by high performance liquid chromatography and a conventional chromatographic method the urinary metabolites of allopurinol in a child deficient of PNP. In this patient approximately 40% of urinary allopurinol metabolites consisted of allopurinol-1-riboside, thus proving the possibility of indirect formation of allopurinol-1-riboside via allopurinol-1-ribotide in vivo, catalysed by hypoxanthine guanine phosphoribosyltransferase (HGPRT) and a phosphatase.

Allopurinol↗
PubMed1983

Methylthioadenosine phosphorylase activity in human erythrocytes.

An enzyme capable of degrading 5'-methylthioadenosine to adenine was found in the human erythrocyte. A rapid assay for this enzyme, 5'-methylthioadenosine phosphorylase, was developed using high pressure liquid chromatography. The specific activity in 24 normal subjects was 8.9 +/- 2.0 nmol . mg-1 Hb . h-1. Levels within this range were also found in erythrocyte lysates from gouty subjects and patients with a variety of inborn errors of purine metabolism, including patients with a complete deficiency of the adenine salvage enzyme--adenine phosphoribosyltransferase. Erythrocyte lysates from the latter however, were unable to convert the adenine produced to AMP in a linked assay system, in contrast to controls and other patients. These results support the suggestion that adenine, which is excreted in quantity by patients with adenine phosphoribosyltransferase deficiency is derived endogenously from 5'-methylthioadenosine as a by-product of polyamine biosynthesis.

Adenine↗
PubMed1983

Importance of platelet-free preparations for evaluating lymphocyte nucleotide levels in inherited or acquired immunodeficiency syndromes.

Low ATP/ADP ratios have been reported consistently for nucleotide levels of mononuclear cells separated from peripheral blood by conventional techniques. We have established that these low values (mean 2.3:1) were not due to cell damage or poor viability, but resulted from heavy platelet contamination, which is unavoidable when heparinized blood is used. The results reflect the low ATP/ADP ratios (mean 1.6:1) characteristic of platelets. Platelet-free extracts from defibrinated blood had very high ATP/ADP ratios (mean 17.4:1). The initial finding of detectable amounts of deoxy-ATP and deoxy-GTP in mononuclear cells from children with two distinct inherited immunodeficiency disorders [adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency respectively] many have been due to contamination by nucleated erythrocytes as well as platelets in non-defibrinated preparations. Defibrination before nucleotide extraction of mononuclear cells from a patient with T-cell leukaemic/lymphoma treated with the ADA inhibitor deoxycoformycin enabled the demonstration of grossly raised deoxy-ATP levels relative to deoxy-ADP levels (ratio 16.1:1), associated with severe ATP depletion. This reciprocal relationship between ATP and dATP was found by us previously in the erythrocytes in inherited ADA deficiency. These findings underline the importance of extracts uncontaminated by platelets, or nucleated erythrocytes, in the evaluation of lymphocyte nucleotide levels in inherited or acquired immunodeficiency syndromes.

Adenosine Deaminase↗
PubMed1983

A controlled study of diet in patients with gout.

To determine whether patients with gout have a diet which is distinctive in quality or quantity a careful dietary questionnaire was posed over 7 days to 61 men with gout and 52 control subjects. The average daily intake of most nutrients, including total purine nitrogen, was similar except that the patients with gout drank significantly more alcohol. Beer was the most popular beverage, and 25 (41%) of those with gout consumed more than 60 g alcohol daily (equivalent to 2 . 5 litres of beer). The heavy drinkers had a significantly higher intake of purine nitrogen, half of which was derived from beer. Though the effect of ingested purine on the blood uric acid is difficult to estimate, it probably was sufficient to have a clinical effect, augmenting the hyperuricaemic effect of alcohol itself.

Alcoholic Beverages↗