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Biomedical subjects

D C Linch

Publications and source records attributed to D C Linch.

At least 217 records · Page 12Linked to original sources
PubMed1988

Uptake of antibody directed cytotoxic liposomes by CD3 on human T cells.

Using polyclonal human T cells and anti-CD3 monoclonal antibodies we have shown that small unilamellar liposomes covalently coupled with protein A become bound to T cells and not to B cells and that the binding was a specific liposome-antibody-receptor interaction. Intracellular delivery of liposome contents was demonstrated by the use of encapsulated carboxyfluorescein and flow cytometry and the transfer of membrane-bound liposomal carboxyfluorescein was virtually complete in 30 min. Liposomes containing methotrexate inhibited the growth of PHA-stimulated peripheral blood lymphocytes by 90%, after 48 h incubation. Potential applications are proposed in the study of the behaviour of surface membrane components and in T cell depletion and purging of bone marrow.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1987

Membrane phenotype and response to deoxycoformycin in mature T cell malignancies.

The adenosine deaminase inhibitor deoxycoformycin was used in low doses to treat 19 patients with clinically aggressive T cell malignancy with a mature membrane phenotype. The patients comprised eight with prolymphocytic leukaemia, two with chronic lymphocytic leukaemia, four with adult T cell leukaemia-lymphoma, three with Sézary syndrome, and two with T cell lymphoma. Two thirds of the patients had been resistant or minimally responsive to combination chemotherapy. Complete remission was obtained in five patients (two with prolymphocytic leukaemia and one each with chronic lymphocytic leukaemia, adult T cell leukaemia-lymphoma, and Sézary syndrome) and partial remission in two others. Unmaintained complete remission lasting more than one year was seen in three patients. Responses were obtained only in patients with CD4+,CD8-membrane markers (seven out of 10), and no responses were recorded in any of the nine patients with a different phenotype. In this series remission appeared to correlate with the membrane phenotype of the neoplastic cell and not with the cytopathological diagnosis. Future studies should establish the biochemical basis for the greater sensitivity of CD4+ lymphoid cells to deoxycoformycin.

Adult↗
PubMed1987

Comparison of the sensitivity of normal and leukaemic myeloid progenitors to in-vitro incubation with cytotoxic drugs: a study of pharmacological purging.

The sensitivity of myeloid leukaemic colony forming cells (AML-CFC), to five cytotoxic drugs has been compared in two culture systems with the sensitivity of normal myeloid progenitor cells (GM-CFC). No increased sensitivity was found for AML-CFC to any of the chemotherapeutic agents studied. AML-CFC were significantly less sensitive than normal GM-CFC to mafosfamide at the doses commonly used to purge bone marrow autografts. It is suggested that AML cells probably display similar sensitivity to cytotoxic agents as normal myelopoietic cells at a similar stage of differentiation. Hence complete elimination of the leukemic clone by pharmacological purging may be incompatible with bone marrow re-engraftment. We conclude that purging AML autografts with any of the agents examined has little scientific basis.

Antineoplastic Agents↗
PubMed1987

Interactions between prostacyclin analogue ZK 36374 and heparin in their effects upon platelet function.

Prostacyclin and heparin can be administered to patients concurrently, with the aim of maximizing anticoagulant effect. It has been suggested that the two agents may interact in their effects upon platelet function. We have therefore studied this parameter in the presence of ZK 36374, a chemically stable analogue of prostacyclin and heparin, alone and in combination. Platelet responses to ADP and thrombin have been studied by standard aggregometry, and intra-platelet calcium mobilization has simultaneously been recorded after loading the cells with the fluorescent calcium indicator, Quin 2. ZK 36374 alone consistently inhibited platelet aggregation and calcium mobilization in response to ADP and thrombin, in a dose-dependent fashion. Heparin alone did not significantly alter the responses to ADP but consistently reduced those to thrombin. Pre-mixture of ZK36374, with heparin, was shown to interfere with the ability of the prostacyclin analogue to inhibit platelet aggregation and calcium flux in response to ADP. In contrast, ZK 36374 inhibition of platelet responses was markedly enhanced when thrombin was the agonist.

Adenosine Diphosphate↗
PubMed1987

Incidence and mechanism of neutropenia and thrombocytopenia in patients with human immunodeficiency virus infection.

The incidence of lymphopenia, thrombocytopenia and neutropenia was studied in 105 homosexual men with HIV infection. Lymphopenia was common in patients with AIDS (75%), but its incidence in PGL (24%) was not significantly different from that in asymptomatic anti-HIV positive (15%) homosexual men. Neutropenia and thrombocytopenia were found in patients with AIDS or PGL, but not in asymptomatic anti-HIV positive homosexuals. The study suggests that the neutropenia and thrombocytopenia in these patients were due to autoimmune destruction of neutrophils and platelets.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Pyrimethamine in the myeloproliferative disorders: a forgotten treatment?

Eight patients with myeloproliferative disorders, five with polycythaemia rubra vera (PRV) and three with essential thrombocythaemia (ET), have been treated with the anti-folate drug Pyrimethamine for periods ranging from 1 to 24 years. In PRV this treatment was comparable in efficacy to that achieved with Busulphan or radioactive phosphorus, but required more frequent supervision. One patient was controlled on Pyrimethamine, having failed on conventional treatment. The major side effect was thrombocytopenia which was rapidly reversible on stopping the drug. In ET, Pyrimethamine produced satisfactory control of the platelet count and thrombocytopenia did not arise. No neurological sequelae were encountered. One patient developed a non-Hodgkin's lymphoma of the gut, but there were no other cases of secondary malignancy. Pyrimethamine may still have a role in the treatment of selected cases of myeloproliferative disorders.

Adult↗
PubMed1987

The value of staging bone marrow trephine biopsy in Hodgkin's disease.

A retrospective study of pre-treatment bone marrow biopsies was undertaken to examine the value of bone marrow staging in Hodgkin's Disease. Bone marrow biopsy revealed infiltration in 40 out of 613 cases, (6.5%). These patients were not significantly different from stage 4 patients without marrow involvement with regard to age, sex, anaemia or survival. Peripheral blood lymphopenia and lymphocyte depleted histopathological type were more common in patients with marrow involvement. Bone marrow biopsy altered individual patient management in less than 1% of 613 patients and can no longer be recommended as part of the routine staging in Hodgkin's Disease.

Biopsy↗
PubMed1987

Incidence and clinical importance of bone marrow eosinophilia in Hodgkin's disease (BNLI Report No 29). British National Lymphoma Investigation.

A retrospective study of 136 bone marrow aspirates was undertaken before treatment to evaluate the importance of bone marrow eosinophilia in Hodgkin's disease. This occurred in 28 patients (21%) but did not correlate with age, sex, B symptoms, histopathological type or peripheral blood count. It also had no effect on survival. Bone marrow eosinophilia, therefore, seems to represent a common but non-specific reaction to Hodgkin's disease.

Adolescent↗
PubMed1987

Selective peripheral blood eosinophilia associated with survival advantage in Hodgkin's disease (BNLI Report No 31). British National Lymphoma Investigation.

A peripheral blood eosinophilia was found at presentation in 193 of 1260 (15%) patients with Hodgkin's disease who had been entered into clinical studies by the British National Lymphoma Investigation (BNLI). Eosinophilia as a component of a general leucocytosis conferred no survival advantage. Eosinophilia without a general leucocytosis was present in 95 patients, and this selective eosinophilia was associated with a clear survival advantage. The association of selective eosinophilia and improved survival was limited to patients with mixed cellularity and grade I nodular sclerosis histology. Selective eosinophilia was found to be a good prognostic indicator both in local and generalised disease. Its survival advantage seemed to lie in the response to second line treatment following relapse.

Eosinophilia↗
PubMed1987

Autologous bone marrow transplantation for patients with acute myeloid leukaemia and acute lymphoblastic leukaemia--a comparison.

Forty-two patients with acute leukaemia were treated with autologous bone marrow transplantation (ABMT) using a combination chemotherapy protocol for bone marrow ablation. The response to high-dose chemotherapy and ABMT and its associated morbidity and mortality have been compared in 24 patients with acute myeloid leukaemia (AML) and 18 patients with acute lymphoblastic leukaemia (ALL). In 16 patients with AML treated with ABMT during first complete remission (CR), ten patients (62.5%) remain in unmaintained remission; median follow up is 32 months. In eight patients with ALL treated in first CR, only one remains in remission 32 months post-ABMT, with three patients dying non-leukaemic deaths. Fourteen of 18 patients (AML and ALL) treated after first remission have died of recurrent leukaemia, two died non-leukaemic deaths and two remain well 31 and 55 months post-ABMT; both have ALL. The length of hospital stay and the amount of blood product support were similar in both groups. Haematological recovery post-ABMT was delayed in patients with AML compared to patients with ALL but this difference was not significant. Rapidly progressive lung infection was thought to be the cause of four early deaths (4/18) in patients with ALL but none in patients with AML. Severe gram-negative infections were significantly more common in patients with AML.

Adolescent↗
PubMed1987

Autologous bone marrow transplantation in acute leukaemia.

Intensive chemoradiotherapy with autologous bone marrow rescue has been widely explored as treatment for acute myeloblastic and acute lymphoblastic leukaemia. Encouraging preliminary results have been reported but in no situation has this modality of therapy been proved to be superior to conventional chemotherapy. Attempts to remove minimal residual disease from the harvested marrow have been made by both immunological and pharmacological means, but the value of such procedures has not been tested rigorously. Determination of the precise role of autologous bone marrow transplantation in the treatment of acute leukaemia must await the outcome of randomised controlled trials and will take several years.

Bone Marrow Transplantation↗
PubMed1986

The relationship between mitogen-induced membrane potential changes and intracellular free calcium in human T-lymphocytes.

We have investigated the effects of mitogenic lectins on human T-lymphocytes, isolated from peripheral blood, and cells from the T-cell clone, HPB-ALL, using the fluorescent dyes, bis-thiobarbiturate tri-methineoxonol (bisoxonol) and quin2 to sense changes in membrane potential and intracellular free [Ca2+], respectively. The resting potential of both cell types is close to the K+ equilibrium potential. Changes from the resting level occur when mitogenic concentrations of either concanavalin A or phytohaemagglutinin are added. T-lymphocytes undergo a decrease in emission, maximal at 1 to 2 min, corresponding to a small membrane hyperpolarization. This is followed by a depolarization to approximately the resting level. HPB-ALL cells, on the other hand, respond to the mitogens by a sustained increase in fluorescence, denoting a depolarization, that is maximal at 4 to 5 min and 7 to 9 min, respectively. The Ca2+-dependence of these phenomena indicates that the membrane potential response, in both cell types, is the resultant of two opposing effects: a Ca2+-sensitive ion movement tending to hyperpolarize the cells and a Ca2+-insensitive effect that generates a depolarization. Our results suggest that Ca2+-activated K+ channels are responsible for the first effect and that an inward Na+ movement accounts for the depolarization signal in T-lymphocytes. In HPB-ALL cells only part of the depolarization is Na+-dependent. Although the effects elicited by phytohaemagglutinin occur more slowly than those produced by concanavalin A, similar membrane potential and [Ca2+]i changes occur.

Aminoquinolines↗
PubMed1986

CD2 and CD3 antigens mobilize Ca2+ independently.

Antigen-induced stimulation of T cells is mediated via the CD3 antigen receptor (Ti) complex and monoclonal antibodies (mAb) reacting with CD3 and Ti result in rapid intracellular Ca2+ mobilization, followed by monocyte-dependent proliferation. Combinations of mAb to CD2, the sheep red blood cell receptor, also mobilize calcium and induce mitogenesis and purified phytohemagglutinin (PHA) stimulates T cells predominantly by interaction with this molecule. It has been suggested that activation via CD2 requires the presence of CD3 and that the hydrophobic epsilon chain of CD3 is the T cell calcium channel. To investigate this further we have obtained large numbers of natural killer (NK) cells which express CD2 but not CD3 from a patient with a chronic expansion of this lymphocyte subpopulation. It is shown that calcium mobilization can be induced in these cells by mAb to CD2 and purified PHA but not by anti-CD3 mAb. This indicates that calcium mobilization can be induced via the CD2 molecule in NK cells not expressing CD3 and that activation through CD2 is separate from the antigen receptor CD3 pathway.

Aminoquinolines↗
PubMed1986

Very high dose chemotherapy with autologous bone marrow rescue in adult patients with resistant relapsed lymphoma.

Seventeen patients with advanced lymphoma were treated with high-dose chemotherapy with autologous bone marrow rescue. In 11 patients with non-Hodgkin's lymphoma (NHL) there were 2 complete remissions (CRs) and 2 partial remissions (PRs), and in 6 patients with Hodgkin's disease there were 5 CRs. Three patients remain well in unmaintained remission (days 874, 446 and 351), and a further 2 are alive and still receiving treatment (days 650 and 558). This type of therapy appears useful and should now be considered earlier in the course of the disease.

Adult↗