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Biomedical subjects

T C Pearson

Publications and source records attributed to T C Pearson.

At least 109 records · Page 6Linked to original sources
PubMed1994

Idiopathic erythrocytosis--additional new study techniques suggest a heterogenous group.

25 patients with idiopathic erythrocytosis (absolute increase in red cell mass without conventional criteria of primary polycythaemia or known underlying cause) have been further studied for evidence of primary or secondary polycythaemia. Additional non-conventional criteria used were: platelet distribution width, platelet nucleotide ratio, serum erythropoietin, clinical evidence of ischaemic vascular disease and erythroid culture variables in serum-free system. All had been used in an earlier study in score form to assist in the diagnosis of primary polycythaemia. These patients were also newly assessed for the presence of hypoxia (supine oximeter values, history suggestive of sleep apnoea), for renal lesions and for splenic enlargement (impalpable) by ultrasound or computerized tomography. 7 patients had erythroid culture scores suggesting primary polycythaemia but the addition of non-culture criteria did not result in any scores more strongly predictive of primary polycythaemia. Supine oximeter values < 92% suggested hypoxaemia as the mechanism of polycythaemia in 3 patients in whom it had not previously been suspected. Some splenic enlargement (impalpable) was demonstrated in 6 patients, only 1 of whom had erythroid culture scores suggesting primary polycythaemia. 12 patients had confirmed, raised erythropoietin levels. We conclude that idiopathic erythrocytosis refers to a heterogenous group of patients. Features of primary or secondary polycythaemia may be demonstrated in some of them by additional new study techniques. The raised erythropoietin values found in half the patients were unexpected.

Adolescent↗
PubMed1994

Circulating megakaryocytic progenitor cells in patients with primary thrombocythaemia and reactive thrombocytosis: results using a serum-deprived culture assay and a positive detection technique.

A serum-free culture method was used to study the growth of megakaryocytic progenitor cells (CFU-Meg) from patients with elevated platelet counts. The culture technique was combined with immunocytochemistry (APAAP, CD61) for the identification of CFU-Meg derived cells in cytopreparations of cells eluted from the culture dishes. Twenty-six patients with primary thrombocythaemia (14 untreated patients, UPT, 12 treated patients, TPT), 14 patients with reactive thrombocytosis (RT) and 9 normal individuals were studied. Unstimulated growth of CD61-positive cells was detected in 8/14 UPT, 8/12 TPT, 12/14 RT and 5/9 normal subjects (with mean CD61-positive cell counts of 75, 579, 236 and 7 per cytopreparation respectively). Cultures supplemented with interleukin 3 contained CD61-positive cells in 11/14 UPT, 7/12 TPT, 14/14 RT and 5/9 normal subjects (with mean CD61-positive cell counts of 157, 589, 250 and 7 per cytopreparation respectively). Thus, this serum-free culture technique combined with sensitive positive identification of CFU-Meg derived cells failed to discriminate between PT and RT. These results cast doubt on the usefulness of serum-free culture assays for the detection of unstimulated CFU-Meg growth in the differential diagnosis of patients with elevated platelet counts.

Antibodies, Monoclonal↗
PubMed1993

The assessment of transplantation tolerance induced by anti-CD4 monoclonal antibody in the murine model.

Transplantation tolerance can be induced in the adult mouse by the selective manipulation of the CD4+ T cell subset. C3H/He recipients with prolonged survival (> 120 days) of C57BL/10 cardiac allografts induced by treatment, at the time of transplantation, with the anti-CD4 mAb, YTS 191.1, were skin grafted simultaneously with donor-specific and third-party (BALB/c) skin. The development of donor-specific tolerance was proved by the specific prolongation of C57BL/10 skin graft survival, while third-party grafts were rejected. Further investigation of recipients with long-term surviving primary heart allografts showed that donor-specific tolerance was associated with organ-specific differences. Secondary cardiac allografts were universally accepted, even at 42 days after the primary heart transplant, while prolonged survival of donor-specific skin grafts was not obtained until more than 120 days after primary cardiac transplantation. Analysis of leukocyte reactivity in the mixed leukocyte culture (MLC) showed no correlation between the proliferative response of recipient T cells in vitro to either donor or third-party alloantigen and the survival of either heart of skin allografts. These results illustrate the significant challenge presented when attempting to define and assess accurately the state of transplantation tolerance.

Animals↗
PubMed1993

Lymphocyte changes associated with prolongation of cardiac allograft survival in adult mice using anti-CD4 monoclonal antibody.

This study investigated the effect of anti-CD4 MoAb treatment on lymphocyte phenotype and function and correlated these changes with the prolongation of cardiac allograft survival in adult mice. Indefinite survival of heterotopic cardiac allografts was obtained in several fully allogeneic strain combinations when two doses of the anti-CD4 MoAb, YTS 191.1, were given at the time of transplantation. A dose response analysis in the C57BL/10 to C3H/He strain combination showed that very low doses of YTS 191.1 (25 micrograms/dose) were able to induce prolonged allograft survival when administered perioperatively. At the time of transplantation the immunosuppression induced by administration of the anti-CD4 MoAb is not antigen-specific, as heart grafts from different donor strains, mismatched for both major and minor histocompatibility antigens, showed prolonged survival in treated recipients. Immunocompetence was restored by 6 weeks after MoAb treatment, as recipients regained the ability to reject a cardiac allograft transplanted at this time point. However, while recovery of immunocompetence could be demonstrated in vivo, leucocytes isolated from the peripheral lymphoid organs of treated mice continued to be hyporesponsive in mixed leucocyte culture (MLC). Phenotypic analysis of the peripheral lymphoid tissues showed that C3H/He recipients treated with 25 micrograms/dose of YTS 191.1 had a marked, but not complete, elimination of the CD4+ subset at the time of transplantation, which was gradually restored to 50% of normal by 6 weeks after treatment. Thus, complete elimination of the CD4+ subset was not required to achieve indefinite allograft survival, and immunocompetence, as assessed in vivo, returned even when the CD4+ subset was present at half the normal level. Low doses of anti-CD4 MoAb (25 micrograms) had no effect on the expression of the CD4 molecule by thymocytes, and yet thymocytes were hyporesponsive to alloantigen in vitro. At higher doses of YTS 191.1, immature CD4+8+ thymocytes were selectively depleted. These results suggest that anti-CD4 MoAb therapy may modulate the intrathymic T cell selection process. These studies provide further insight into the mechanism of action of low dose, depleting anti-CD4 MoAb therapy in allograft rejection, and form a basis from which rational modifications to therapeutic protocols in transplantation models can be made.

Animals↗
PubMed1993

Apparent polycythaemia: diagnosis, pathogenesis and management.

The term "apparent polycythaemia" is applied to a group of patients who have a raised PCV (> 0.51 in males, > 0.48 in females) but a normal red cell mass (less than 25% above their predicted mean normal value). Some have additionally a marked reduction in plasma volume and can be defined as a subgroup: relative polycythaemia. Smoking, hypertension and to a lesser extent obesity, excessive alcohol, low-dose diuretic therapy and hypoxaemia have all been associated with apparent polycythaemia but the mechanism is both uncertain and likely to be complex. This group of patients is unlikely to be uniform in pathogenesis and may well include some normal individuals. Investigation requires exclusion of factors associated with other types of polycythaemia. The possibility of an increased vascular occlusive risk is uncertain in these patients except at the higher PCV values. Reduction of PCV by venesection is sensible at PCV > 0.54 or where there is perceived to be an increased risk of vascular occlusion. The remaining patients should be managed by regular observation to detect further rise in PCV or evolution to absolute polycythaemia (raised red cell mass). In some, the PCV returns to normal.

Erythrocyte Volume↗
PubMed1993

Primary polycythaemia: diagnosis by non-conventional positive criteria.

Patients with polycythaemia and normal controls have been studied to establish and subsequently test non-conventional criteria for the diagnosis of primary polycythaemia (primary proliferative polycythaemia, polycythaemia vera) as compared with conventional Polycythaemia Vera Study Group (PVSG) assessment. One criterion was erythroid colony formation from peripheral blood in a serum-free system, assayed alone and with the addition of recombinant human erythropoietin (Epo), interleukin 3 (IL3), or alpha interferon (alpha-IFN) (Dudley et al. 1990). The remaining criteria were non-culture associated and comprised platelet distribution width (PDW), platelet nucleotide ratio (ATP:ADP), serum erythropoietin and clinical evidence of ischaemic vascular disease. The combination of culture associated and non-culture associated variables, by use of a simple additive scoring system, gave no false positive and only 6% false negative results in distinguishing primary polycythaemia from other polycythaemias and normal controls in those (34 patients Group A) used in its derivation. Testing the scoring system in a newly presenting group (25 patients Group B) was highly satisfactory with no false positives and only a few false negative results (14%). Use of these non-conventional criteria should allow more confident diagnosis of primary polycythaemia, where conventional clinical and laboratory assessment is inconclusive.

Adenosine Diphosphate↗
PubMed1993

Double blind trial of recombinant human erythropoietin in preterm infants.

Twenty four infants between 27 and 33 weeks' gestation were recruited into a double blind study to investigate the use of recombinant human erythropoietin (r-HuEpo) for the prevention of anaemia of prematurity. Between 50 and 150 U of r-HuEpo (n = 16) or placebo was administered subcutaneously twice a week from 7 days of age until discharge. There was a significant increase in the reticulocyte count in infants receiving r-HuEpo sustained from the second week of treatment until discharge compared with placebo. There was a reduction in the number of transfusions required in the r-HuEpo group with only 47% requiring a transfusion compared with 87% in the placebo group. During treatment with r-HuEpo there was a significant rise in the red cell folate concentration, a significant fall in the ferritin concentration, and a significantly higher percentage of haemoglobin F at discharge suggesting active erythropoiesis. The study provides strong evidence for the efficacy of r-HuEpo in stimulating erythropoiesis and reducing the requirement for transfusions for anaemia of prematurity.

Anemia, Neonatal↗
PubMed1993

Renal failure caused by leukaemic infiltration in chronic lymphocytic leukaemia.

A case of B-CLL which was complicated by chronic renal failure due to leukaemic infiltration of the kidney is reported. Treatment with chlorambucil, prednisolone, and renal bed irradiation resulted in a substantial improvement in renal function which persisted until the the patient's death from marrow failure some eight years later. The temporal association between treatments and response suggested that renal bed radiotherapy had contributed to the improvement in renal function. This case is one of only two reported cases in which chronic renal failure due to CLL has been treated with radiotherapy. It is unique in that the renal response was shown histologically. Leukaemic infiltration of the kidney is common in CLL but, characteristically, is not associated with renal impairment. An improvement in renal function has been described in two patients with acute renal failure after chemotherapy.

Chlorambucil↗
PubMed1993

Serum erythropoietin and circulating BFU-E in patients with multiple myeloma and anaemia but without renal failure.

In 30 patients with multiple myeloma (MM) and mild to moderate anaemia (mean Hb 107 g/l, 95% confidence limit (CL) 102-113) but no evidence of renal failure (serum creatinine < 110 mumol/l), serum erythropoietin (EPO) showed significant inverse logarithmic correlation with the haemoglobin level (r = -0.57, p = 0.001). The observed/expected ratio of log-EPO in patients with MM (mean 0.96, CL 0.89-1.04) was similar to that of 119 subjects (mean 1.01, CL 0.96-1.05) with or without anaemia (mean Hb 116 g/L, CL 110-121) but without renal failure. The concentration of circulating erythroid progenitors (BFU-E) in 10 MM patients in plateau phase was significantly reduced (mean 0.70 x 10(5)/l of blood, CL 0.34-1.06) compared to that of 8 normal controls (mean 3.57, CL 1.60-5.55, p = 0.011) In vitro sensitivity of the BFU-E to EPO in the patients with MM was comparable to that of the normal controls. It appears that in MM there is an appropriate EPO response to anaemia but even in the plateau phase the number of circulating BFU-E is reduced, reflecting a degree of marrow failure. However, the progenitors are normally sensitive to EPO in such patients, and therapeutic doses of EPO may correct the anaemia by a pharmacological rather than a physiological effect.

Anemia↗
PubMed1992

Functional expression of the costimulatory molecule, B7/BB1, on murine dendritic cell populations.

Whereas dendritic cells (DC) are known to be potent activators of T cells both in vitro and in vivo, the critical costimulatory molecules expressed on DC are not well characterized. Using immunocytochemical and molecular techniques we find that splenic DC express B7/BB1, the counter-receptor for CD28. Moreover, expression of B7/BB1 is upregulated on epidermal Langerhans cells (LC) during their functional maturation into potent T cell stimulators. In blocking experiments, we find that participation of B7/BB1 is required for optimal proliferation of unprimed, allogeneic T cells in DC-driven, primary mixed leukocyte reactions. These data demonstrate that the regulated expression of B7/BB1 on DC may be important in the initiation of a primary T cell response.

Animals↗
PubMed1992

Induction of transplantation tolerance in adults using donor antigen and anti-CD4 monoclonal antibody.

The T-cell-mediated immune response usually results in the rapid destruction of organ allografts transplanted between murine strains incompatible for major and minor histocompatibility antigens. This response may be modified by pretreatment with either donor-specific antigen or anti-CD4 monoclonal antibody. Previous work by others has shown that combined treatment of mice with soluble protein antigens and anti-CD4 monoclonal antibody can produce antigen-specific B cell unresponsiveness that continues long after the nonspecific immunosuppressive effect of the mAb treatment has resolved. Following this principle we have shown that adult C3H/He mice can be made specifically unresponsive to vascularized C57BL/10 cardiac allografts by pretreating the recipient with donor alloantigen under the cover of a brief course of mAb against CD4. A full-dose response analysis shows that the dose of mAb is critically important for the successful induction of tolerance. Tolerance induction using this protocol is dependent on treatment with donor major histocompatibility complex antigens and occurs in the presence of marked depletion but not complete elimination of the CD4+ T cell subset. The unresponsiveness to alloantigen is antigen specific, as determined by the ineffectiveness of third-party (C57BL/10) alloantigen when combined with anti-CD4 mAb to induce long-term survival of BALB/c allografts in C3H/He recipients. The tolerant state is specific and effective in the long-term as indicated by the specific acceptance of C57BL/10 skin grafts in recipients with surviving C57BL/10 cardiac allografts. This study provides a simple method for the successful induction of specific transplantation tolerance in the adult across a full H-2 major and minor antigen mismatch strain combination. The results illustrate the important role of the CD4 molecule in the T cell response to alloantigen in vivo and suggest possibilities for the therapeutic manipulation of complex immune reactions.

Animals↗
PubMed1992

Red blood cells from patients with sickle cell disease exhibit an increased adherence to cultured endothelium pretreated with tumour necrosis factor (TNF).

Red blood cells (RBCs) from 24 patients with sickle cell disease were more adherent to cultured endothelium pretreated with the inflammatory cytokine, tumour necrosis factor (TNF) than RBCs from 22 healthy subjects. The enhanced sticking was apparent in RBC preparations from patients who were in crisis (mean 190% increase from controls) and out of crisis (mean 220% increase) and was not related to the number of circulating RBCs, reticulocytes, platelets, leucocytes or haemoglobin levels. When irreversibly sickled RBCs, enriched by centrifugation on density gradients, were added to TNF-treated endothelium they were found to be significantly more adherent (mean 411% increase; P < 0.001) than the unfractionated RBCs from the same patients. There was no difference between the adherent properties of sickle RBCs and normal RBCs for untreated endothelium. Contributing factors to the enhanced adhesion to TNF-treated endothelium may be the low surface change of sickle RBCs, and increased levels of fibrinogen and von Willebrand's factor (vWF) in the patients' plasma. By acting on vascular endothelium to increase its adhesiveness for sickled RBCs, it is concluded that inflammatory cytokines such as TNF may have a prominent role in mediating the events that lead to microvascular occlusions in sickle cell disease.

Anemia, Sickle Cell↗
PubMed1992

The in vitro effect of high-dose recombinant human erythropoietin on granulocyte-macrophage colony production in premature infants using a defined serum deprived cell culture system.

Recent reports of neutropenia associated with the use of recombinant human erythropoietin (r-HuEpo) in preterm infants with the anaemia of prematurity have raised concern over the clinical use of this hormone. The present studies were undertaken to determine whether high-dose r-HuEpo has an effect on granulocyte production in vitro. The studies used a serum deprived, optimized semi-solid cell culture system to investigate the effect of lineage specific and non-specific granulocyte and erythroid colony stimulating factors on circulating peripheral blood granulocyte-macrophage colony forming units (CFU-GM), erythroid burst forming units (BFU-E) and multilineage colonies (CFU-Mix) from nine premature infants and seven healthy adults. CFU-GM were grown in the presence of interleukin 3 (IL3) 8 ng/ml, granulocyte-macrophage colony stimulating factor (GM-CSF) 20 ng/ml and granulocyte colony stimulating factor (G-CSF) 15 ng/ml alone and combinations of G-CSF with GM-CSF or IL3. The number, size and differentiation of CFU-GM colonies were then analysed in the presence and absence of high dose r-HuEpo (4 U/ml). High-dose r-HuEpo did not exert any significant modulatory effects on the number of CFU-GM colonies produced in the presence of IL3, GM-CSF and G-CSF alone or in combination. The number of cells within each CFU-GM colony did not change significantly, nor was there a significant change in the degree of differentiation. The combined number of BFU-E, CFU-GM and CFU-Mix colonies increased with r-HuEpo in both adults (1.8 x) and preterm infants (1.4 x), almost exclusively due to an increase in BFU-E derived colonies. Thus, no evidence was found for an r-HuEpo mediated redirection of multipotential haemopoietic stem cells into committed erythroid precursors at the expense of myeloid precursors.

Cell Differentiation↗