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Biomedical subjects

A J Bellingham

Publications and source records attributed to A J Bellingham.

At least 37 records · Page 2Linked to original sources
PubMed1990

Differential expression of transferrin receptor in duodenal mucosa in iron overload. Evidence for a site-specific defect in genetic hemochromatosis.

In genetic hemochromatosis, metabolic studies have demonstrated inappropriately increased iron absorption by cells of the duodenal mucosa. It is not clear whether this reflects an intrinsic abnormality of iron homeostasis at this site or is a consequence of a more generalized defect in cellular iron metabolism particularly involving the liver. We have previously used the expression of iron-related proteins as markers of iron homeostasis and have demonstrated normal regulation of the transferrin receptor and ferritin in the liver in this condition. In the present study we used immunohistochemical techniques to study transferrin-receptor expression in the gastrointestinal epithelium in normal subjects and patients with iron overload. In untreated genetic hemochromatosis and normal subjects, villus epithelial cells expressed receptor in the basolateral, subnuclear region. In contrast, in patients with secondary iron overload, receptor staining was absent in villus epithelial cells. The cells in the duodenal crypts showed intense staining for the transferrin receptor in all subjects investigated, a finding consistent with the known behavior of this receptor in proliferating cells. Given that body iron stores in both types of iron overload were comparable, these findings indicating a failure of down-regulation of the villus enterocyte transferrin receptor in genetic hemochromatosis may reflect the presence of a regulatory defect associated with the inability to control iron absorption in this condition.

Adult↗
PubMed1990

A logical approach to the investigation of red cell enzymopathies.

This relatively rare group of disorders may cause quite marked morbidity and occasionally be life-threatening. As their inheritance is largely known accurate information in one family member has obvious benefits to other family members as well as the patient. The identification of the defect is dependent on an accurate clinical story which can be used to guide both the use and the interpretation of the various laboratory tests available. From the clinical aspect the enzymopathies can be divided into various broad groups. First, those involving the main glycolysis which produces the red cell's energy requirements in the form of ATP. Defects of this pathway generally cause a non-spherocytic haemolytic anaemia. Second, those involving the pentose phosphate shunt which maintains the redox potential of the cell necessary for its protection against oxidant stress. The commonest enzyme deficiency world wide, G6PD, is in this pathway and is characterized by stress-induced haemolytic crises. Third, defects of the various linked reactions. The most important of these are the methaemoglobin reductases which catalyse the reduction of methaemoglobin to functional haemoglobin and the enzymes in the Rapoport-Luebering shunt which can modulate the 2,3-DPG level. Whilst defects of these metabolic pathways make up the majority of cases associated with haemolysis, defects of other enzymes, on the whole less critical to the red cell's survival, must occasionally be considered. The red cell, because of its relatively easy availability, can be used as a 'biopsy tool' in the diagnosis of some systemic disorders in which the red cell enzymopathy is not the main feature of the disease. Such considerations are particularly important owing to the technological advances that have occurred in the last 10-15 years which have enabled correct assignment of an increased number of difficult cases. Not only is it possible to characterise the variant enzymes more accurately but it is now possible to have a 'metabolic window' on the red cell and examine it for the derangements of metabolism that characterise the various enzyme deficiencies.

Erythrocytes↗
PubMed1990

Clinicopathological features of acute undifferentiated leukaemia with a stem cell phenotype.

Over a 4 1/2-year period, 141 patients with acute leukaemia had morphologic, immunophenotypic and cytochemical studies performed at King's College Hospital. Seven cases were noted to have blast cells which did not express myeloid or lymphoid antigens or cytochemical staining indicative of differentiation but were HLA DR and CD 34 positive. Based on these criteria we have used the term stem cell acute leukaemia to denote these patients. There were five women and two men with a median age of 61 years (16-86). Presentation marrows were heavily infiltrated with blasts (greater than 95% in 6/7) which were usually pleomorphic. Type 2 blasts. Auer rods and dysplastic features were absent. Two of six cases studied showed clonal karyotypic abnormalities. Four patients were treated with high dose chemotherapy. Three of these achieved a complete remission but relapsed at 3, 6 and 7 months respectively. The median survival of the group was 7 months (2-12). We conclude that the stem cell acute leukaemias are a distinct clinicomorphological group which appear to have a poor prognosis with conventional chemotherapy.

Acute Disease↗
PubMed1990

Lead poisoning: clinical, biochemical, and haematological aspects of a recent outbreak.

The clinical, biochemical, and haematological aspects of a recent outbreak of lead poisoning, in which exposure was related to the oxyacetylene cutting of red lead painted ironwork, were investigated. Initial suspicion was raised when a blood film showed punctate basophilia which remains a simple and useful method of picking up lead toxicity. Estimations of blood lead concentration and conventional laboratory data confirmed the diagnosis. Although there was prominent punctate basophilia, spectrophotometric analysis showed only negligible accumulation of pyrimidine-5'-nucleotides despite severe suppression of pyrimidine-5'-nucleotidase activity. The pattern of the red cell glycolytic intermediates, investigated for the first time, suggested that lead may also affect glycolysis at the hexokinase step. Once the diagnosis was made intravenous chelation treatment was begun with a rapid improvement in symptoms. Long term follow up is required to assess any sequelae of intoxication. These cases emphasise the classic features of lead poisoning, and despite the currently available diagnostic tests, lead intoxication may still go unrecognised unless a thorough occupational history is taken.

5'-Nucleotidase↗
PubMed1989

Prenatal diagnosis of a red-cell enzymopathy: triose phosphate isomerase deficiency.

A child with triose phosphate isomerase deficiency was born to nonconsanguineous parents, and died at 13 months of age. The parents were both found to be heterozygous for this enzyme deficiency. At a subsequent pregnancy, analysis of fetal red blood cells obtained by cordocentesis at 19 weeks' gestation enabled prenatal diagnosis of the heterozygous state. This technique may allow diagnosis of other red-cell enzymopathies during the second trimester.

Carbohydrate Epimerases↗
PubMed1989

Red cell glycolytic intermediates in normal, anaemic and transfused human fetuses.

Normal fetal ranges for red cell glycolytic intermediates at 18-24 weeks gestation, which are useful as reference values for the prenatal diagnosis of erythroenzymopathies, were established for the first time. Characteristic increases in glucose-6-phosphate (G6P), fructose-6-phosphate (F6P) and particularly fructose-1,6-diphosphate (FDP) suggest that there is no metabolic block at the phosphofructokinase (PFK) step of glycolysis as previously suggested by others for premature infants on the first day of life. Neither reticulocytosis nor anaemia consistently led to further increases in the early metabolites as occurs in adults. However, very large increases in G6P, F6P and particularly FDP may occur independently of anaemia and reticulocytosis. This suggests that activation of hexokinase (HK) and/or PFK can take place as in adults but the stimulus is probably different to adults. The 2,3-DPG in normal fetuses is higher than in adults and increases still further in anaemic fetuses with or without transfusion of adult blood. The pattern of intermediates found in the fetus suggests that the controlling mechanism for the increased 2,3-DPG may be an in vivo relative preponderance of PFK activity over that of pyruvate kinase (PK) rather than regulation of HK as proposed for adult subjects with anaemia or high altitude hypoxia.

Adult↗
PubMed1989

Mean red cell volume in normal, anemic, small, trisomic and triploid fetuses.

A reference range for fetal mean red cell volume (MCV) with gestation was established from the study of samples obtained by cordocentesis from 466 pregnancies undergoing prenatal diagnosis for non-erythrocyte abnormalities. The mean MCV decreased from 145 fl at 16 weeks to 113 fl at 36 weeks of gestation. Alterations in MCV were investigated in 154 red cell isoimmunized and 231 small for gestational age (SGA) fetuses. In red cell isoimmunization, significant macrocytosis was observed when the fetal hemoglobin concentration deficit was greater than or equal to 6 g/dl. In the chromosomally normal SGA fetuses (n = 178), the MCV was increased and the magnitude of macrocytosis was significantly associated with gestation and the degrees of fetal 'smallness' and fetal hypoxemia. However, the most severely macrocytotic SGA fetuses were those with triploidy (n = 22). In the SGA fetuses with other chromosomal defects (n = 31), the MCV was higher than the controls but lower than that of the chromosomally normal hypoxemic fetuses. It is suggested that in severe growth retardation there is developmental delay in the normal evolution from hepatic to medullary hemopoiesis and this is most marked in triploid fetuses. In contrast, in red cell isoimmunization the switch to medullary erythropoiesis is normal, but in severe anemia there is secondary recruitment of hepatic erythropoiesis.

Anemia, Hemolytic, Autoimmune↗
PubMed1989

Glycated fibrinogen: a new index of short-term diabetic control.

Fibrinogen is a plasma protein with a short half-life of four days and, therefore, glycated fibrinogen may be valuable as an index of short-term diabetic control. We have developed a simple, rapid method for determining glycated fibrinogen using affinity chromatography. The differences in the percentage of glycated fibrinogen between normal subjects, well-controlled diabetics and poorly-controlled diabetics were highly significant. There was a significant correlation between glycated fibrinogen and glycated haemoglobin for all these subjects. However, in selected subjects with rapidly improving diabetic control the difference between the fall over three days in glycated fibrinogen and glycated haemoglobin was highly significant. In subjects with deteriorating control over an average of four weeks there was a significant difference between the increase in glycated fibrinogen and glycated haemoglobin. We suggest that glycated fibrinogen may be a valuable adjunct to glucose measurements in the assessment of short-term diabetic control due to its rapid change following alterations in control.

Adult↗
PubMed1988

The effect of replacing fetal hemoglobin with adult hemoglobin on blood gas and acid-base parameters in human fetuses.

In order to determine whether the differences between fetal and adult hemoglobins are important to fetal oxygenation, pH, PO2, PCO2, bicarbonate, and base excess were measured in umbilical venous and arterial blood samples obtained from fetuses with erythroblastosis fetalis. The values from fetuses that had previously been transfused and had predominantly adult hemoglobins were compared with those that had not been transfused and had predominantly fetal hemoglobin. Umbilical arterial blood was more acidotic and had a greater base deficit, while the umbilical venous PO2 was 4.8 mm Hg higher in the samples with adult hemoglobins than in those with fetal hemoglobin. The results suggest that oxygenation of fetal tissue is better with fetal hemoglobin but that adult hemoglobin can be compensated by an increase in oxygen transfer.

Acid-Base Equilibrium↗
PubMed1988

2,3-Diphosphoglycerate in normal, anaemic and transfused human fetuses.

1. The effect of anaemia and transfusion with adult blood on fetal 2,3-diphosphoglycerate levels was investigated by studying fetal blood from 45 normal pregnancies at 17-42 weeks of gestation and in 34 pregnancies complicated by erythroblastosis fetalis. 2. In normal fetuses, 2,3-diphosphoglycerate concentration was higher than in adults and did not change significantly with gestational age. 3. In erythroblastotic fetuses, there was a significant negative correlation between 2,3-diphosphoglycerate concentration and haemoglobin concentration. 4. When adult blood was transfused into the fetal circulation, 2,3-diphosphoglycerate concentration reached similar levels to that found in untransfused fetuses after allowing for the severity of anaemia.

2,3-Diphosphoglycerate↗
PubMed1987

Gall stones in sickle cell disease in the United Kingdom.

The prevalence of gall stones was studied prospectively by abdominal ultrasound examination in 131 patients with sickle cell disease aged 10-65 years. Of 95 patients with homozygous sickle cell disease, 55 (58%) had gall stones or had had a cholecystectomy. Gall stones were present in four out of 24 (17%) patients with haemoglobin S + C disease and two out of 12 (17%) with haemoglobin S beta thalassaemia. The presence of gall stones was not related to sex, geographical origin, or haematological variables and was not associated with abnormal results of liver function tests. Symptoms typical of biliary colic were reported by 32 out of 47 adult patients with gall stones, and cholecystitis or cholestasis was diagnosed in 18. Cholecystectomy was performed in 29 patients with good relief of symptoms in most cases. Postoperative complications were common, occurring in 10 of the 28 patients who could be evaluated, but not generally serious; they were considerably lessened by a preoperative exchange transfusion that reduced the haemoglobin S concentration to below 40%. It is suggested that all patients with sickle cell disease should be screened for gall stones and that elective cholecystectomy should be performed in those with symptoms or complications.

Adolescent↗
PubMed1987

Life threatening sickle chest syndrome treated with extracorporeal membrane oxygenation.

A young West Indian woman with established sickle cell disease developed a severe episode of sickle chest syndrome. Conventional treatment including exchange transfusions and mechanical ventilation was to no avail, and an infusion of epoprostenol also failed to halt her worsening condition. When her arterial oxygen tension (PaO2) had fallen to 6.5 kPa (49 mm Hg) extracorporeal membrane oxygenation was instituted. Within two days her PaO2 was greatly improved (maximum 11.6 kPa; 87 mmHg), and by the sixth day pulmonary vascular resistance was reduced and angiography showed reperfusion of many vessels. The patient recovered and six months later showed a transfer factor close to the predicted range and normal spirometric values. Extracorporeal membrane oxygenation should be considered for severe sickle chest syndrome when conventional methods of artificial ventilation fail.

Adult↗
PubMed1987

Red cell 3-phosphoglycerate level as a diagnostic aid in pyruvate kinase deficiency.

A case of pyruvate kinase (PK) deficiency is described in which the diagnosis was aided by measurement of the 3-phosphoglycerate (3PG) concentration. Review of the literature on the levels of red cell metabolites in 52 families with PK deficiency confirmed that a rise in 3PG is a valuable indicator of a functional deficiency of PK. Estimation of 3PG is relatively easy (and accurate). Furthermore, reticulocytosis, which sometimes makes the diagnosis of PK deficiency more difficult, has minimal effect on the level of 3PG in comparison with all other glycolytic intermediates or PK activity.

Blood Cell Count↗
PubMed1987

Neonatal haemoglobinopathy screening.

The current practice of cord blood screening was found to be missing 14.3% of 'at risk' infants identified for screening in the antenatal period, largely due to failure of sample collection. The possibility of including haemoglobinopathy screening into the already established Guthrie card screening system for phenylketonuria and hypothyroidism was investigated, using haemoglobin electrophoresis on cellulose acetate membranes, citrate agar gel and isoelectric focussing in polyacrylamide gel. Denaturation of blood once dried onto filter paper made the standard electrophoresis techniques unsuitable, whilst isoelectric focussing gave clear separation of all bands and was therefore accepted as the method of choice.

Electrophoresis, Polyacrylamide Gel↗
PubMed1986

Neonatal screening for sickle cell diseases in Camberwell: results and recommendations of a two year pilot study.

The sickle cell diseases are a major health problem for Afro-Caribbean peoples. Neonatal detection and prophylactic management can reduce mortality and morbidity in childhood. A study was therefore conducted analysing the results of the first two years of cord blood screening in the Camberwell health area. Thirteen cases of sickle cell disease and two of haemoglobin (Hb)C disease were identified among 2202 non-white infants screened. The carrier state, sickle cell trait (HbAS), was present in 11.9% and HbC trait (HbAC) in 4.1% of Afro-Caribbean infants. The incidence of disease and of carrier states was much higher in West Africans than in Caribbeans. The wider implications of screening and the need for a comprehensive plan of care are emphasised.

Anemia, Sickle Cell↗
PubMed1986

Potential use of purine nucleosides and enzyme inhibitors for selective depletion of Thy-lymphoblasts from human bone marrow.

The toxicity of the purine nucleoside, deoxyadenosine in the presence of the adenosine deaminase inhibitor, deoxycoformycin and of deoxyguanosine in the presence of the purine nucleoside phosphorylase inhibitor, 8-aminoguanosine was measured against two Thy-leukemic cell lines. Toxicity was assessed by the survival of clonogenic cells in a colony assay. The kill of clonogenic Thy-leukemic cells was 99.99% with both nucleoside enzyme inhibitor combinations following 4-h incubations when 50 microM concentration of nucleoside were used. With these nucleoside concentrations some reduction in toxicity was apparent when drug treated cells were cultured in the presence of deoxycytidine (50 microM), however, this reduction in toxicity was not apparent when higher nucleoside concentrations were used (100 microM). Survival of bone marrow myeloid progenitor cells (CFU.GM) was only slightly reduced by these nucleoside concentrations following 4 hour incubations. The presence of a twenty-fold excess of normal bone marrow cells reduced the cytotoxic effect but clonogenic cell incubation still ranged from 99.98 to 99.99% for deoxyguanosine and deoxyadenosine respectively. These combinations of nucleosides and enzyme inhibitors may have a therapeutic role in the elimination of malignant Thy cells from human bone marrow.

Adenosine Deaminase Inhibitors↗