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Biomedical subjects

J M Bridges

Publications and source records attributed to J M Bridges.

At least 55 records · Page 3Linked to original sources
PubMed1984

Human umbilical cord conditioned medium: a stimulus for human CFU-G.

Segments of human umbilical cord have been used to prepare a highly active conditioned medium (HUCCM) for in vitro human granulopoiesis and have been compared with human placenta conditioned medium (HPCM) and feeder layers. The HUCCM produced more colonies on day 7 than HPCM (P less than 0.001), and colonies consisted almost exclusively (over 98%) of granulocytic cells by both morphological and cytochemical analysis. The HUCCM-stimulated colonies have a short culture life, the number of colonies being maximal on day 7 of culture with few colonies remaining on day 10. The main source of the colony-stimulating activity in the umbilical cord was found in the Wharton's Jelly component.

Colony-Forming Units Assay↗
PubMed1984

An evaluation of three statistics of structured exploratory data analysis.

The power of structured exploratory data analysis (SEDA) to discriminate among major genic, polygenic, and nongenetic determination of phenotypes was investigated using computer simulation. Three classes of SEDA indices (the major gene index, the offspring between parents function, and the midparent-child correlation coefficient) were evaluated. These three statistics, in combination, were reasonably sensitive in detecting the presence of a major locus and in discriminating between phenotypes with genetic effects and those with no genetic component. However, they were unable to discriminate between major genic and polygenically determined phenotypic models.

Chromosome Mapping↗
PubMed1983

Metabolism of exogenous adenine in a pyruvate kinase-deficient patient.

The metabolism of adenine, administered intravenously and orally, was studied in a patient with red cell pyruvate kinase (PK)-deficiency. Intravenous infusion of 58.5 mumol of adenine per kg containing 6475 Bq of 8-14C adenine caused an initial decrease in red cell ATP level and the gradual return to the pre-infusion level coincided with an increase in radiolabelled ATP. Of the infused adenine, 1.3% had entered the red cell pool after 2 h. The route of administration affected the urinary excretion of adenine and its oxymetabolites; after 6 h, 10.7% of the infused adenine had been excreted, compared with 7.4% after ingestion of a similar dose. In 10 control subjects given 45.1-55.5 mumol/kg, excretion of adenine plus oxymetabolites accounted for 13.5 +/- 2.9% of the ingested dose. Differences were also observed in the urinary purine excretion patterns for the two routes of administration. This study has shown that adenine can be incorporated into ATP in the red cells of a PK-deficient patient.

Adenine↗
PubMed1982

Adult T-cell lymphoma-leukaemia in Blacks from the West Indies.

Six Black patients (five born in the West Indies and one in Guyana), aged 21-55 years, had adult T-cell lymphoma-leukaemia diagnosed in the U.K. This disorder is rare in Europe and the U.S.A., but is more common in Japan. Five patients had severe hypercalcaemia which correlated with disease activity, although osteolytic lesions were found in only one. Other clinical features were lymphadenopathy and a high white blood-cell count (range 27-67 X 10(9)/l) with a predominance of pleomorphic lymphoid cells with pronounced nuclear irregularities prominent at ultrastructural level. The cells in all cases formed rosettes with sheep red blood-cells and lacked terminal transferase. Analysis with OKT monoclonal antibodies in four cases confirmed a mature T-cell phenotype defined as helper/inducer (T4+, T6-, T8-) in three. Combination chemotherapy resulted in short-lived remissions; four patients died and two have survived 3-6 months. The disease in these patients is indistinguishable on clinical and pathological grounds from adult T-cell leukaemia/lymphoma in Japan. Geographical clustering among certain racial groups suggests common aetiological factors in the pathogenesis of this disease. The finding of high titre antibody against the structural core protein (p24) of a new human C-type leukaemia virus (human T-cell leukaemia/lymphoma virus) in all tested cases from this series and data from all but one case from Japan suggest that one such factor may be viral.

Adult↗
PubMed1982

Can severe vincristine neurotoxicity be prevented?

Neurotoxicity in vincristine treatment has generally been considered a consequence of the cumulative dose of the drug, and liver dysfunction had been recognised as an indication to reduce the dosage. We demonstrate that neurotoxicity is also related to individual doses and that even when there is no other evidence of liver dysfunction, a raised level of serum alkaline phosphatase may predict severe neurotoxicity. Exposure to vincristine following IV injection of the drug was studied in 27 subjects by measuring the area under the vincristine plasma concentration time curve (AUC 0-infinity). A statistically significant relationship was found between the AUC0-infinity and the degree of neurotoxicity. The AUC0-infinity was related both to dose and to elevation of serum alkaline phosphatase, suggesting that elimination of the drug is impaired when serum alkaline phosphatase is raised. Among patients with elevated serum alkaline phosphatase, a small reduction in the dose of the drug resulted in lower vincristine plasma AUC0-infinity and less neurotoxicity.

Adolescent↗
PubMed1982

The pharmacokinetics of vincristine in man: reduced drug clearance associated with raised serum alkaline phosphatase and dose-limited elimination.

A radioimmunoassay has been used to investigate the pharmacokinetics of vincristine in 39 cancer patients who received between 0.4 and 1.54 mg vincristine/m2 as part of standard treatment protocols. There was wide interindividual variation in both the terminal elimination half-life of vincristine (t1/2beta) and the associated volume of distribution (Vd), resulting in an 11-fold range of dose-corrected area under the plasma concentration versus time curve values (AUC0-infinity). Elevated vincristine AUC0-infinity values were observed in those patients with raised serum alkaline phosphatase at the time of vincristine estimation. The t1/2beta was significantly longer in these patients than in those with serum alkaline phosphatase within normal limits, suggesting that biochemical evidence of cholestasis is associated with reduced clearance of vincristine. Evidence is also presented to suggest that the clearance of vincristine is dose-dependent within the therapeutic dose range. We observed a disproportionate rise in vincristine plasma concentration at doses exceeding t1/2beta compared with that observed for patients receiving 1 mg vincristine/m2 or less.

Adult↗
PubMed1982

Pharmacokinetics of low-dose methotrexate in children receiving maintenance therapy for acute lymphoblastic leukaemia.

Serum methotrexate (MTX) concentrations were measured by immunoassay in 28 children receiving maintenance therapy for acute lymphoblastic leukaemia. Patients were studied either after a single weekly dose or on the first day of a 5-day course of treatment. A standard dose (15 mg/m2) was given PO and/or IV. After PO dose the peak serum MTX concentration and its timing varied widely between cases and there was a significant positive correlation between the rate of serum concentration rise and the area under the concentration curve up to 4 h. The absorption rate constant showed a biphasic distribution and correlated less closely with early serum concentrations. After IV and PO administration drug disposition was triphasic with an initial rapid distribution phase, an intermediate phase, and a prolonged terminal elimination phase. The intermediate phase half-life was significantly longer after PO than after an IV dose. The MTX clearance rate was consistently lower than the glomerular filtration rate and there was no significant correlation between the two. The mean bioavailability (PO/IV) was 42%, but bioavailability was as low as 6% in some cases due to prolonged high serum concentrations after an IV dose, which was not seen with the equivalent PO dose.

Administration, Oral↗
PubMed1982

Letterer-Siwe disease: a study of thirteen cases over a 21 - year period.

In Northern Ireland, with a population of 1.5 million, thirteen cases of Letterer-Siwe disease have been diagnosed over the past 21 years. The average age of onset was 10.5 months. There was a 69% mortality with an average survival time from diagnosis to death of 3.3 months. Four children survived with no morbidity. All deaths were from pulmonary complications, but two cases with pulmonary infiltration responded to treatment with quadruple chemotherapy. There were no familial cases in this study.

Child, Preschool↗
PubMed1982

The in vitro effect of adenine on pyruvate kinase-deficient red cells.

In pyruvate kinase (PK)-deficient blood with high levels of reticulocytes, the degree of haemolysis after incubation at 37 degrees C for 48 h was halved by the inclusion of adenine in the medium. the decrease in haemolysis was associated with a higher ATP level but was not related to the pH of the incubation mixture. The incorporation of adenine into nucleotides studied over a 3 h period was similar in normal and PK-deficient blood. The observed increase in cellular ATP was equivalent to that shown by radioactive measurements to have been synthesized from added adenine. Inhibition of mitochondrial oxidative phosphorylation in the reticulocytes of the PK-deficient blood by KCN reduced the amount of adenine taken up by the cells by a factor of 3 and altered the pattern of incorporation into the nucleotides. Only 25% of the adenine which entered the blood cells was converted into ATP compared with 85% in the absence of cyanide. Despite the synthesis of small amounts of ATP from labelled adenine, the overall ATP content fell to less than 50% of its original level. It is suggested that incubation with adenine increased the ATP level in the reticulocytes by virtue of mitochondrial oxidative phosphorylation thereby reducing the haemolysis of these cells.

Adenine↗
PubMed1981

Three pyruvate kinase variants with increased affinity for PEP.

Three variants of pyruvate kinase are described which have marked reduction of activity associated with severe non-spherocytic haemolytic anaemia. Each variant shows a reduced K0.5 PEP (the value of the intercept of the abscissa on the Hill plot) and reduced Hill coefficient; FDP activation and ATP inhibition are less than normal and utilization of GDP is increased. The variants are slightly less inhibited by 2,3DPG than controls but require more FDP to relieve this inhibition. Cases 1 and 2 have decreased thermostability but case 3 is normal. The mutant enzymes are further distinguished by their affinity for FDP. Their kinetic and physicochemical properties are compared with other known cases with high affinity for PEP and discussed in terms of a R in equilibrium to T model model for allosteric enzymes.

Adenosine Triphosphate↗
PubMed1981

Small bowel enterocyte abnormalities caused by methotrexate treatment in acute lymphoblastic leukaemia of childhood.

Jejunal biopsy specimens from 10 children with acute lymphoblastic leukaemia on methotrexate treatment were compared with 10 from children being investigated for diarrhoea or failure to thrive. In association with methotrexate treatment on both light and electron microscopy, there were marked morphological abnormalities in the villus enterocytes. These consisted of a striking distention of the lateral basal intercellular spaces, cell vacuolation and patchy necrosis and was most marked when methotrexate treatment was given between 24 and 72 h before biopsy. Two mechanisms may be involved: an early direct toxic effect on the mature enterocyte coupled with interference with crypt cell generation, possibly causing ageing and loss of cells proximal to the normal extrusion zone. These pathological changes may account for the malabsorption in association with methotrexate treatment.

Acute Disease↗
PubMed1980

Can food influence the absorption of methotrexate in children with acute lymphoblastic leukaemia?

Serum levels of methotrexate (MTX) were measured in 10 children with acute lymphoblastic leukaemia over a 4 hour period after oral administration. The drug was given to each child on three occasions: first, with no food, then with a milky meal, and finally with a citrus meal. Peak serum MTX levels were significantly reduced by the milky meal and both meals delayed drug absorption in most children. The area under the absorption curve was also significantly reduced by the milky meal. Thus, for maximum serum levels, MTX should not be given with food, and if patients are to be grouped on the basis of their MTX absorption profile this should be determined under standard conditions in relation to meals.

Administration, Oral↗