Biomedical subjects
M Greaves
Publications and source records attributed to M Greaves.
Urinary thromboxane and 6-keto-prostaglandin F1 alpha are early markers of acute rejection in experimental pancreas transplantation.
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Resistance to activated protein C.
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Interleukin 7-dependent B lymphocyte precursor cells are ultrasensitive to apoptosis.
We have compared the sensitivity of clonogenic interleukin 7 (IL-7)-dependent murine B cell precursors with that of clonogenic mature B cells and myeloid precursors to alpha-particles from plutonium-238 and X radiation. All three populations are relatively sensitive, but B cell precursors are ultrasensitive. This differential sensitivity is also observed with corticosteroid, etoposide, and cisplatin, all apoptosis-inducing drugs used in the treatment of leukemia and other cancers. Further, we show that x-rays and drugs induce the bulk of the B cell precursor population to undergo rapid apoptosis, despite the continued presence of IL-7. B cell precursors were found to express very low levels of BCL-2 protein compared with mature splenic B cells and their resistance to x-rays and corticosteroid could be enhanced by expression of a BCL-2 transgene. These data have important implications for normal lymphopoiesis and for the behavior of leukemic lymphoid precursor cells.
Long-term management after splenectomy. Lifelong penicillin unproved in trials...
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Inhibition of prostacyclin release by endothelial binding anticardiolipin antibodies in thrombosis-prone patients with systemic lupus erythematosus and the antiphospholipid syndrome.
IgG from 18 patients with SLE, eight with the primary antiphospholipid syndrome and 19 controls was examined for its effect on thrombin-induced prostacyclin (PGI2) release from human umbilical vein endothelial cells in relation to both the titre of anticardiolipin (ACA) and antiendothelial activity (AEA) and clinical thrombotic events. Although no significant inhibition of PGI2 release was found overall, examination of subgroups revealed that IgG from patients with ACA produced significant inhibition of PGI2 release (mean stimulation index IgGM, 0.74 +/- 0.12, P = 0.02) when compared with patients without ACA (1.18 +/- 0.12). Further analysis revealed a significant positive correlation between ACA and AEA (r = 0.52, P = 0.006) in the total patient group which was reflected in significant negative correlations between inhibition of PGI2 release and increasing titre of both ACA (r = -0.42, P = 0.032) and AEA (r = -0.57, P = 0.002). However, only increasing titre of AEA showed a significant negative correlation with inhibition of PGI2 release when patients with (r = -0.74, P = 0.0005) and without (r = 0.23, N.S.) thromboses were compared. The titre of ACA failed to show any significant correlation with inhibition of PGI2 release in either patients with (r = -0.42, N.S.) or without (r = -0.16, N.S.) thromboses. These findings suggest that previous, sometimes conflicting, reports of an association between inhibition of PGI2 release and ACA may be explained by the co-incidence of AEA with ACA.
High resolution computed tomography of the lungs in patients with rheumatoid arthritis and interstitial lung disease.
We performed high resolution computed tomography (HRCT) on the lungs of 20 patients with RA and clinical and radiological evidence of interstitial lung disease (ILD). A case control group of patients with RA but without evidence of ILD were similarly studied and all patients underwent detailed pulmonary function testing. Clinical findings, drug therapy, smoking status, the presence/absence of SS and disease activity were also assessed. HRCT showed a range of abnormalities among patients thought to have ILD. Interstitial fibrosis was confirmed in 16 but was frequently associated with emphysema. Ground glass opacification was present in seven, while basal honey-combing was also evident in seven patients. Both these features were present in two patients with ILD. Bronchiectasis was identified in six patients and was the predominant finding in two patients previously thought to have ILD. Among the control patients, HRCT was normal in only five. Clinically unsuspected ILD was present in four patients, while a further four had bronchiectasis. Pleural disease was identified in seven controls. Pulmonary function tests were generally poor predictors of HRCT findings, although a reduced residual volume (RV) [> 1 S.D.] was 83% specific for the presence of ILD and a raised RV [> 1 S.D.] was 64% specific for emphysema. Smoking did not correlate with the presence of either ILD or emphysema and there were no correlations between disease activity and HRCT findings. RA patients with evidence of ILD have abnormalities on HRCT which cannot be confidently predicted on any other non-invasive test.(ABSTRACT TRUNCATED AT 250 WORDS)
Use of granulocyte colony-stimulating factor (G-CSF) for mobilizing peripheral blood stem cells: risk of mobilizing clonal myeloma cells in patients with bone marrow infiltration.
Peripheral blood stem cells have been used for autologous reconstitution of haemopoiesis after high dose cytotoxic therapy and produce similar disease response rates as autologous bone marrow transplants. Peripheral blood stem cell transplants are an especially attractive option for patients in whom marrow harvest is not feasible due to bone marrow damage or infiltration. Recombinant growth factors mobilize adequate numbers of stem cells from the marrow but their effect on tumour cell circulation kinetics is not known. We report a patient with multiple myeloma and bone marrow infiltration in whom the use of G-CSF for stem cell mobilization led to release of plasma cells into the peripheral circulation and contamination of the stem cell harvest.
Reversal of diabetes associated with escape of myeloma: evidence for inappropriate IGF-II secretion.
We report the sudden and dramatic reversal of maturity onset diabetes in a 57-year-old woman in association with relapse of IgA myeloma diagnosed 3 years earlier. Prior to the relapse of the myeloma, twice daily insulin had been administered at a dose which had been stable for 3 years. However, the same dose produced hypoglycaemic coma at the time of relapse and, subsequently, blood glucose was controlled by diet alone. There had been no significant change in weight or renal function prior to the hypoglycaemic episode. Investigations showed a suppressed fasting serum insulin level in association with an inappropriately high serum level of IGF-II compared with IGF-I and a 'big' IGF-II concentration at the upper end of the normal range. Pituitary, adrenal and liver disease, as well as the autoimmune insulin syndrome, were excluded. The findings are consistent with the hypothesis that the plasma cell tumour was associated with excessive production of insulin-like peptides with consequent reduction in the blood glucose level.
The development of antiphospholipid antibodies in haemophilia is linked to infection with hepatitis C.
In haemophilia the presence of antibodies to antiphospholipid has been linked with HIV infection, but other possibilities have not been fully explored and the specificity for various phospholipids not established. In order to investigate further the pathogenesis and clinical significance of these antibodies, we have determined IgG and IgM antibodies to a variety of phospholipids, including cardiolipin, in the serum of 52 haemophiliacs, and related our findings to the presence of antibodies to HIV and hepatitis C virus (HCV), as well as to clotting factor concentrate usage and blood markers of liver biochemistry. Our results demonstrate that the presence of infection with hepatitis C virus is strongly associated with raised serum levels of antiphospholipid antibody even in the absence of HIV infection. They suggest that earlier conclusions on the relationships of antiphospholipid to HIV infection in haemophilia should be revised and that chronic infection with the hepatitis C virus should be added to the list of infective causes for the development of antiphospholipid antibody.
Breathlessness with bumps, lumps, and humps.
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Failure to tolerate high affinity IgE receptors: a novel mechanism in the pathogenesis of diseases that result from abnormal cell activation.
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A natural history for pediatric acute leukemia.
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In utero rearrangements in the trithorax-related oncogene in infant leukaemias.
The majority (approximately 75%) of infant acute leukaemias have a reciprocal translocation between chromosome 11q23 and one of several partner chromosomes. The gene at 11q23 (named MLL, ALL-1, HRX or HTRX-1; refs 2-6) has been cloned and shares homology with the Drosophila developmental gene trithorax. Rearrangements of this gene (called HRX here) occur in introns and cluster in a region of approximately 10 kb; individual patients have different breakpoints. Here we describe three pairs of infant twins with concordant leukaemia who each share unique (clonal) but non-constitutive HRX rearrangements in their leukaemic cells, providing evidence that the leukaemogenic event originates in utero and unequivocal support for the intra-placental 'metastasis' hypothesis for leukaemia concordance in twins.
Anticoagulants in pregnancy.
Pregnancy is associated with a prethrombotic state. Pulmonary embolism is the major cause of maternal mortality. Anticoagulant prophylaxis and therapy are therefore commonplace in pregnant women. Those with inherited and acquired thrombophilic conditions are at increased risk and special considerations arise in management. Heparin has recently become the favoured anticoagulant drug in pregnancy. Its use carries risks of osteopaenia and thrombocytopaenia, as well as haemorrhage, in the mother. Warfarin is teratogenic and may also cause haemorrhagic complications in mother and fetus. Few clinical trial data exists for guidance on optimal anticoagulant regimes during pregnancy and the puerperium and details of management will depend upon the personal preferences of patient and clinician, after due consideration of the perceived risks and benefits in the individual clinical situation.
Stimulation of von Willebrand factor antigen release by immunoglobulin from thrombosis prone patients with systemic lupus erythematosus and the anti-phospholipid syndrome.
The level of von Willebrand factor antigen (vWF) released by endothelial cells in response to IgG isolated from 18 patients with systemic lupus erythematosus (SLE), eight patients with the anti-phospholipid syndrome (APS) and 22 controls has been measured. Incubation with IgG from the combined patient group resulted in a significantly greater release of vWF (mean stimulation index +/- SEM, 4.57 +/- 0.78) when compared with controls (1.96 +/- 0.22, P = 0.003). Furthermore, IgG from 17 patients who had had a history of thrombosis induced higher levels of vWF release (5.33 +/- 1.09) when compared with the controls (P = 0.008). These findings suggest that IgG from patients with SLE or APS is capable of stimulating vWF release and that this ability may be implicated in the thrombotic events that are observed in these conditions.
Thromboxane and prostacyclin synthesis in experimental pancreas transplantation. Changes in parenchymal and vascular prostanoids.
The principal causes of failure of a pancreas transplant are rejection and vascular thrombosis. There is an unusually high attrition rate for pancreas transplants, but study models have been difficult to develop. In a rat model that allows study of acute rejection to the exclusion of nonspecific effects of transplant surgery on the pancreas, in vitro synthesis of prostacyclin (PGI2) and thromboxane A2 (TXA2) by transplanted pancreas and the blood vessels transplanted with it was measured using an RIA for their stable hydrolysis products 6-keto-prostaglandin F1 alpha and thromboxane B2 (TXB2). TXB2 synthesis was significantly greater in allotransplanted pancreas than isotransplanted pancreas from the 5th day after transplantation. Rejection was complete in the allografted group 7-9 days after transplantation. 6-Keto-prostaglandin F1 alpha synthesis was similar in the pancreas for both allografts and isografts. Similar changes were seen in aorta, celiac artery, superior mesenteric artery, and portal vein transplanted with the pancreas. In the transplanted aorta, TXB2 was significantly greater in the allograft group from the third posttransplant day. A group of CsA-treated allografts sampled after 9 days had transplanted pancreatic parenchymal and vascular prostanoid synthesis in the isograft range. The changes in PGI2 and TXA2 synthesis that accompany cellular rejection may mediate vascular failure in rejecting pancreas transplants, and changes in PGI2 and TXA2 synthesis in blood vessels transplanted with the pancreas could promote early vascular thrombosis.
Spontaneous remission of chronic pure red cell aplasia after failure of immunosuppressive therapy.
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