Biomedical subjects
Publications and source records attributed to H Kronenberg.
Using gene mapping, 16.3% of Polynesians were shown to have alpha thalassemia. These results are surprising since malaria is not found in Polynesia. Moreover, triplicated alpha gene rearrangements were identified in a further 7.7%, a frequency not seen in other populations.
Despite markedly prolonged activated partial thromboplastin times (APTT) patients with Fletcher factor (prekallikrein) deficiency do not clinically bleed. However, there is one reported case of myocardial infarction associated with prekallikrein deficiency. These clinical observations suggest that the contact mechanism has a minor role in normal in vivo hemostatic function. We report a further two cases of prekallikrein deficiency in Caucasian siblings. The propositus presented with multiple cerebral thrombosis. Cautious anticoagulation resulted in massive cerebral hemorrhage and death of this patient. The sibling was investigated in an attempt to establish a possible defective fibrinolytic pathway in vivo. New sensitive tests for fibrinolysis were used. These included radioimmunoassay of fibrin degradation product "D," B beta 15-42, and in vitro 125I-labelled fibrin lysis assays. The plasma half-life of prekallikrein in this patient was calculated to be 58 hr. Family studies of heterozygotes were also performed. Prekallikrein deficiency is found not to be important in normal in vivo fibrinolysis, which possibly operates via tissue or vessel wall fibrinolytic activator release.
Evidence of a defect in the negative feedback control of granulopoiesis in the myeloproliferative disorders is presented. Neutrophil release of lactoferrin, plasma lactoferrin concentration, the number of lactoferrin receptor sites on mononuclear cells and granulocyte-monocyte colony stimulating factor (GM-CSF) release from peripheral blood cells were determined in patients with myeloproliferative disorders and compared with normal individuals. There was a significantly (P less than 0.001) decreased release of lactoferrin from the neutrophils of patients with myeloproliferative disorders which could be responsible for a reduced suppression of GM-CSF release from mononuclear cells which in turn may be responsible for the increased myeloid proliferative activity in patients with myeloproliferative disorders.
Two patients with diffuse lymphoma, one diffuse large cell and the other diffuse mixed, large and small cell, developed an illness characterised by a high swingeing fever and a pulmonary infiltrate. In both patients there was clinical evidence of chemotherapy-induced tumour response elsewhere at the time lung infiltrates progressed. Blood and sputum cultures, bronchial washings, and, in one case, trans-bronchial lung biopsy did not establish a diagnosis and there was progressive clinical deterioration. Post mortem examination showed widespread involvement of both lungs with lymphoma. The differential diagnosis of fever and pulmonary infiltrates in patients with diffuse lymphoma is discussed, in particular the possibility of this being due to rapidly progressive lymphoma.
2 cases of diffuse large-cell non-Hodgkin's lymphoma developing in conjunction with idiopathic myelofibrosis are described. In neither case could any predisposition to neoplastic transformation be discerned. The possible pathogenetic implications of this association are discussed, and a brief literature review of the relationship between myeloproliferative and lymphoproliferative disease is presented.
Manual methods of counting reticulocytes using supravital stains, such as new methylene blue, have long been recognized to be subject to technical errors. Automated reticulocyte enumeration has recently become available with the development of an automated cell flow-cytometer, the Ortho Spectrum III. In this method a fluorescent dye, acridine orange, which stains RNA in a manner similar to supravital stains, is used to distinguish reticulocytes from mature erythrocytes. We have evaluated this technique and found that it compares favourably with manual counting methods.
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Prenatal diagnosis of hemoglobinopathies may be obtained during the first trimester of pregnancy by a combination of chorion biopsy and DNA mapping. This study illustrates 2 DNA approaches which are available for identification of abnormal globin genes. These include restriction fragment length polymorphisms (RFLPs) and direct gene mapping.
A series of monoclonal antibodies have been produced which recognize different epitopes of the factor VIII molecule. The antibodies were raised in mice against high purity factor VIII (FVIII) and the mouse spleens used in cell fusion experiments. Following cell fusion the hybridoma supernatants were used for screening with a solid phase radioimmunoassay (RIA) technique. The antibodies detected were differentiated by their degree of attachment to 2 components of the FVIII molecule, FVIII related antigen (FVIIIR:Ag) (also called von Willebrand's Factor) and FVIII coagulant (FVIIIC). Immunofluorescence and immunoperoxidase studies both showed the FVIIIR:Ag antibodies to be localized to the endothelial cells of the blood vessel walls. They can, therefore, be used for histological identification of these cells on cryostat and paraffin sections. The anti-FVIIIR:Ag antibodies have no anticoagulant properties, whereas the anti-FVIIIC antibody reacts as an instant inhibitor with a strength of 35,000 new Oxford U/ml. These antibodies are stable reagents and suitable for radioimmunoassay for both FVIIIR:Ag and FVIIIC.
Of hemophilia B carriers, 67% were shown to have informative restriction fragment length polymorphisms (Taq I or Xmn I) associated with the factor IX gene. Analysis of DNA for these polymorphisms can enable the detection of the hemophilia B carrier state in females and of hemophilia B in the male fetus in the first trimester. Extensive mapping of the factor IX gene in one hemophiliac who developed antibodies to factor IX failed to detect structural abnormalities in his gene. A non-deletional basis for hemophilia B is proposed in this instance.
Optimal therapy in patients with multiple myeloma relies on methods which indicate stability or progression of disease. At present, patients are assessed by monitoring the myeloma M-component in the serum and the urinary light chain excretion levels, or by calculating the myeloma cell mass. However, clinical disease activity does not always correlate with changes in these indices. Recent studies suggest that monitoring the expression of light chain isotypes on peripheral blood lymphocytes may provide evidence of progressive disease before clinical deterioration. Stable plateau phase disease has been shown to be associated with suppression of the expression, on peripheral blood lymphocytes, of the light chain isotype concordant with the malignant paraprotein. Loss of this suppression has been associated with active disease.
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A familial hypodysfibrinogenaemia occurring in four females with occasional haemorrhagic problems in an Adelaide family was investigated. Affected family members had slightly prolonged thrombin time, prothrombin time and Reptilase time tests, and apparently elevated levels of fibrin degradation products (FDPs). Fibrinogen assessed by reactivity with thrombin (Clauss method) was significantly less than fibrinogen determined by various other methods, though even by immunoquantitation fibrinogen levels were only slightly above half normal in affected family members. Isoelectric focussing (IEF) of the reduced patient's fibrinogen in urea/polyacrylamide gel revealed minor components with higher isoelectric points (pI) than present in normal fibrinogen or fibrin. These were shown to have a molecular weight similar to the alpha chain of fibrin by subsequent sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). The abnormal species tended to remain in plasma after clotting with Reptilase or thrombin although polymerization of the clotted fibrin was normal. The magnitude of the pI shift relative to normal fibrin alpha chain indicated an increased positive charge on the abnormal species.
Light chain isotype suppression in multiple myeloma has been reported in the plasma cells of the lamina propria of the gut (Leonard et al, 1979). In this paper we present further evidence of systemic suppression of the light chain isotype of the paraprotein expressed on normal peripheral blood lymphocytes in myeloma. Twenty patients with myeloma in plateau phase were monitored over 6 months for the expression of either kappa or lambda light chains on the surface of peripheral blood lymphocytes using monoclonal antibodies. The surface markers were analysed on an Ortho Spectrum III flow cytometer. Results of these studies indicate a selective suppression of the cells expressing the light chain isotype of the paraprotein in stable myeloma. Thus, in kappa myeloma there is a low kappa/lambda ratio and in lambda myeloma there is a high kappa/lambda ratio, and this suppression is lost with progressive disease.
Recently, Acquired Immune Deficiency Syndrome (AIDS) has been reported in hemophiliacs in the USA, Canada and Spain, and this has caused considerable concern amongst hemophiliacs regarding the use of factor VIII concentrates. The aim of this study was to determine whether hemophiliacs in Australia have T-lymphocyte subpopulation changes similar to those observed in patients with AIDS. Factor VIII produced in Australia is derived from a totally volunteer blood donor system and none of the hemophiliacs in this study had received commercial blood products. For the hemophiliacs, the T-helper cell to T-suppressor cell ratio was 1.1 +/- 0.6 (mean +/- SD) which was significantly less (p less than 0.001) than that of the normal age and sex-matched controls. There was a significant relative (p less than 0.001) and absolute (p less than 0.05) reduction of the helper cell subsets and a significant relative (p less than 0.001) and absolute (p less than 0.05) increase of the suppressor cell subsets, in the hemophiliacs compared to the normal controls. There appears to be no correlation between the amount of factor VIII therapy received during the last three years and the T-cell subset changes. All patients with Christmas disease had T-cell subsets within the normal range. All patients were negative for the hepatitis B virus antigen, but all were positive for the antibody, indicating that there had been exposure to the hepatitis virus in all cases. Cytomegalovirus titres were uniformly low and immunoglobulin levels were normal.(ABSTRACT TRUNCATED AT 250 WORDS)
A study of genotypes in alpha thalassemia and their corresponding hematological phenotypes has shown that alpha(+) thalassemia is the most frequent type encountered in a Sydney population. Phenotypes of heterozygous alpha(+) thalassemia (alpha alpha/-alpha) in adults or children differ little from normal and so the disorder is difficult to identify. In contrast, Hb Bart's (gamma 4) is a useful marker for alpha alpha/-alpha in cord blood samples. Abnormal phenotypes are present in homozygous alpha(+) thalassemia (-alpha/-alpha), heterozygous alpha(0) thalassemia (alpha alpha/--) and non-deletional alpha thalassemia. Therefore, detection by routine hematological studies should be possible. A less severe phenotype in -alpha/-alpha compared to alpha alpha/-- was found which is interesting since 2 alpha globin genes are lost in both instances.
Alpha thalassaemia as a cause of hypochromic, microcytic anaemia in pregnancy is described. The problems associated with accurate diagnosis of this condition and prediction of fetal outcome is now made much easier by use of recombinant DNA techniques such as gene mapping. Two Greek Cypriot families with alpha thalassaemia have been studied by DNA mapping. Definitive assessment of alpha thalassaemia genotype in these cases enabled confident genetic counselling.