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Biomedical subjects

T C Pearson

Publications and source records attributed to T C Pearson.

At least 73 records · Page 4Linked to original sources
PubMed1997

Spleen sizing by ultrasound in polycythaemia and thrombocythaemia: comparison with SPECT.

Detection of non-palpable early splenic enlargement may aid diagnosis of primary polycythaemia (PP) and primary thrombocythaemia (PT). In this study linear spleen sizing by ultrasound has been compared with spleen volume estimation by single photon emission computerized tomography (SPECT) in 26 patients. Spleen length by ultrasound correlated well with SPECT volume estimation. Ultrasound spleen length was also measured in 60 normal control subjects where the upper limit of the 95% reference range was 11.6 cm. Changes in spleen length with both age and body weight were substantial and overshadowed the imperfect reproducibility of this method. Therefore, interpretation of an individual's measured spleen length should be in relation to that predicted for adults of the same age and weight, particularly at the extremes of the younger, heavier patients and also the older, lighter patients. Ultrasound spleen lengths of different patient groups (21 PP, 26 PT, 17 idiopathic erythrocytosis, 12 secondary polycythaemia, nine apparent polycythaemia) were compared both using the measured overall reference range and the differences from the values predicted for their age and weight. The comparison showed that almost all patients with PP whose spleens were not palpable had spleen lengths greater than the upper limit for the normal control group, but separation from the other patient groups was incomplete. Detection of non-palpable splenomegaly by ultrasound length should remain a 'minor' criterion amongst the 'proposed modified diagnostic criteria' of PP.

Adult↗
PubMed1997

Hemorheologic considerations in the pathogenesis of vascular occlusive events in polycythemia vera.

Polycythemia vera (PV) commonly presents with vascular occlusion. Untreated patients have a poor prognosis due to the occurrence of thromboses. Treatment outcomes in PV and thrombotic events in other forms of polycythemia and in primary thrombocythemia lead to the conclusion that both raised packed cell volume (PCV) values and quantitative/qualitative platelet changes play a role in the pathogenesis of these vascular occlusive events. In vitro blood viscosity values are predominantly affected by the PCV, particularly at low shear rates and are thus high in untreated PV. Generally, under physiologic conditions blood flow is not governed by blood viscosity due to a number of factors, such as prevailing high shear rates, red cell axial migration, and adaptive vessel diameter changes. Peripheral blood flow is low in untreated PV. Whereas some untreated patients maintain adequate oxygen transport to the tissues, this may not apply in those with cardiac or local vessel disease. There is evidence that low flow rates predispose to occlusive events. Under pathologic low blood flow or static conditions, the rheologic blood changes of untreated PV, demonstrated in vitro, play a role in producing a more deleterious outcome of an occlusive event. Under blood flow conditions, red cell axial migration occurs. This leaves a plasmatic zone at the vessel wall into which platelets are dispersed and where shearing forces are maximal. These forces lead to platelet activation. Increased PCV values reduce the width of the plasmatic zone and lead to an increased possibility of platelet activation, platelet-platelet contact and platelet-vessel wall interaction, particularly when the platelet count is raised as well. These effects increase the likelihood of the initiation of thrombus formation in PV.

Blood Platelets↗
PubMed1997

The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency.

Total body water (TBW) is reduced in adult GH deficiency (GHD) largely due to a reduction of extracellular water. It is unknown whether total blood volume (TBV) contributes to the reduced extracellular water in GHD. GH and insulin-like growth factor I (IGF-I) have been demonstrated to stimulate erythropoiesis in vitro, in animal models, and in growing children. Whether GH has a regulatory effect on red cell mass (RCM) in adults is not known. We analyzed body composition by bioelectrical impedance and used standard radionuclide dilution methods to measure RCM and plasma volume (PV) along with measuring full blood count, ferritin, vitamin B12, red cell folate, IGF-I, IGF-binding protein-3, and erythropoietin in 13 adult patients with GHD as part of a 3-month, double blind, placebo-controlled trial of GH (0.036 U/kg.day). TBW and lean body mass significantly increased by 2.5 +/- 0.53 kg (mean +/- SEM; P < 0.004) and 3.4 +/- 0.73 kg (P < 0.004), respectively, and fat mass significantly decreased by 2.4 +/- 0.32 kg (P < 0.001) in the GH-treated group. The baseline RCM of all patients with GHD was lower than the predicted normal values (1635 +/- 108 vs. 1850 +/- 104 mL; P < 0.002). GH significantly increased RCM, PV, and TBV by 183 +/- 43 (P < 0.006), 350 +/- 117 (P < 0.03), and 515 +/- 109 (P < 0.004) mL, respectively. The red cell count increased by 0.36 +/- 0.116 x 10(12)/L (P < 0.03) with a decrease in ferritin levels by 39.1 +/- 4.84 micrograms/L (P < 0.001) after GH treatment. Serum IGF-I and IGF-binding protein-3 concentrations increased by 3.0 +/- 0.43 (P < 0.001) and 1.3 +/- 0.15 (P < 0.001) SD, respectively, but the erythropoietin concentration was unchanged after GH treatment. No significant changes in body composition or blood volume were recorded in the placebo group. Significant positive correlations could be established between changes in TBW and TBV, lean body mass and TBV (r = 0.78; P < 0.04 and r = 0.77; P < 0.04, respectively), and a significant negative correlation existed between changes in fat mass and changes in TBV in the GH-treated group (r = -0.95; P < 0.02). We conclude that 1) erythropoiesis is impaired in GHD; 2) GH stimulates erythropoiesis in adult GHD; and 3) GH increases PV and TBV, which may contribute to the increased exercise performance seen in these patients.

Adult↗
PubMed1997

Drainage of the exocrine pancreas in clinical transplantation: comparison of bladder versus enteric drainage in a consecutive series.

The purpose of this study was to define the incidence of urologic and metabolic complications after simultaneous kidney/pancreas transplantation (SKPT) with bladder drainage (BD). Review of 55 SKPT with BD performed between 1989 and 1995 demonstrated patient, kidney, and pancreas survival rates of 95%, 89%, and 78%, respectively, with a mean follow-up of 41 months (range 12-78 months). Over this follow-up period 78% of these patients experienced a urinary tract infection, 27% had hematuria, and 38% had at least one hospital admission for dehydration. Recent experience with primary enteric drainage of the exocrine secretions of the transplanted pancreas (n = 11) has demonstrated the total absence of these complications (follow-up range 2-12 months). These results suggest the value of continuous re-evaluation of surgical techniques as the care of transplant patients evolve.

Acidosis↗
PubMed1996

Interstitial deletion constitutes the major mechanism for loss of heterozygosity on chromosome 20q in polycythemia vera.

An acquired deletion of the long arm of chromosome 20 is a recurrent abnormality in myeloproliferative disorders, particularly polycythemia vera and myelodysplastic syndromes. The association of 20q deletions with myeloid "stem cell" disorders suggests that the deletions mark the site of one or more genes, loss or inactivation of which plays a role in the regulation of normal hematopoietic progenitors. We have recently performed a detailed molecular analysis of 20q deletions in peripheral blood (PB) granulocytes and defined a commonly deleted region of 16 to 21 centimorgan (cM). To further reduce the size of the common deleted region we have searched for small deletions or mitotic recombination events, neither of which would be detected by conventional cytogenetics. We have studied 48 patients with polycythemia vera and four patients with idiopathic myelofibrosis. In each case, cytogenetic analysis had either failed or had shown no abnormalities of chromosome 20. Seventeen microsatellite markers that span the common deleted region were used to search for loss of heterozygosity in granulocyte DNA. No instance of microsatellite instability was observed in a total of 880 comparisons of granulocyte and T-cell DNA. Granulocyte DNA from four patients exhibited allele loss on 20q. In each case the allele loss was caused by an interstitial deletion because heterozygosity at distal markers was retained and because quantitative Southern blotting demonstrated hemizygosity. Loss of heterozygosity in PB granulocytes would be masked by the presence of significant numbers of normal granulocytes not derived from the malignant clone. Therefore, the human androgen receptor assay (HUMARA) was used to determine granulocyte clonality. In 21 of 27 informative female patients the majority of the granulocytes were clonally derived. In 5 patients the granulocytes appeared polyclonal and in 1 patient unilateral X inactivation was observed in both granulocytes and T cells. These results show that, in the vast majority of patients presented here, the failure to detect loss of heterozygosity cannot be attributed to the presence of normal polyclonal granulocytes. Our results therefore show that allele loss on chromosome 20q in polycythemia vera does not commonly involve mitotic recombination or chromosome loss and that microsatellite instability is a rare event in this disorder.

Chromosome Deletion↗
PubMed1996

Analysis of allogeneic and syngeneic rat heart transplants using 23Na magnetic resonance spectroscopy.

This study defines the total sodium-23 magnetic resonance spectroscopy (23Na MRS) signal from in vivo heterotopic rat heart transplants in the early post-transplant period and examines the utility of this noninvasive method for monitoring allograft rejection. Measurements were performed at 4.7 T. Syngeneic (n = 6) and allogeneic (n = 6) donor hearts were transplanted into the neck of recipient rats. There were 27 MRS observations between days 0 and 29 post-transplant. Heart grafts were excised at various intervals post-transplant for histologic examination. Allogeneic heart grafts rejected between days 4 and 5 post-transplant while syngeneic grafts continued to beat. All hearts showed ischemic damage. Allogeneic hearts showed cellular rejection by Day 1. 23Na MRS showed a steady elevation in signal in the 3 days prior to rejection and a sharp rise after rejection. 23Na MRS accurately identified full rejection and was also sensitive to the rejection process.

Animals↗
PubMed1996

Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways.

The receptor-ligand pairs CD28-B7 and CD40-gp39 are essential for the initiation and amplification of T-cell-dependent immune responses. CD28-B7 interactions provide 'second signals' necessary for optimal T-cell activation and IL-2 production, whereas CD40-gp39 signals co-stimulate B-cell, macrophage, endothelial cell and T-cell activation. Nonetheless, blockade of either of these pathways alone is not sufficient to permit engraftment of highly immunogenic allografts. Here we report that simultaneous but not independent blockade of the CD28 and CD40 pathways effectively aborts T-cell clonal expansion in vitro and in vivo, promotes long-term survival of fully allogeneic skin grafts, and inhibits the development of chronic vascular rejection of primarily vascularized cardiac allografts. The requirement for simultaneous blockade of these pathways for effective inhibition of alloimmunity indicates that, although they are interrelated, the CD28 and CD40 pathways are critical independent regulators of T-cell-dependent immune responses.

Abatacept↗
PubMed1996

CTLA4-Ig plus bone marrow induces long-term allograft survival and donor specific unresponsiveness in the murine model. Evidence for hematopoietic chimerism.

Allograft rejection is dependent on T cell activation, which requires both the engagement of the T cell receptor by antigen in the context of the MHC molecules and costimulatory signals delivered by cell surface molecules such as B7-CD28/CTLA4 pathway. CTLA4-Ig is a fusion protein that blocks this pathway and has previously been shown to prolong both allograft and xenograft survival. The current study demonstrates markedly prolonged murine cardiac allograft survival and specific prolongation of secondary skin grafts using a combination of CTLA4-Ig plus donor bone marrow. A role for hematopoietic chimerism in the establishment of CTLA4-Ig-induced transplantation tolerance was investigated using reverse transcriptase polymerase chain reaction analysis of recipient tissues. Expression of donor-specific MHC class II transcripts in both peripheral and lymphoid tissues was demonstrated at greater than 200 days after transplant. To investigate the functional significance of this observation, heart donors, and donor bone marrow were irradiated before transplantation in CTLA4-Ig-treated recipients. A reduction in allograft survival was associated with irradiation of both the donor heart and the bone marrow. These results suggest that there may be a donor-derived radiosensitive element that enhances allograft survival in this model. Reverse transcriptase polymerase chain reaction analysis of allografts of tolerant and control animals at days 5, 8, and 12 after transplantation failed to demonstrate a dramatic difference in the expression of interleukin (IL)-2, IL-4, IL-10, and interferon-gamma message. Cytotoxicity effector transcripts were largely intact in CTLA4-Ig + bone marrow-treated recipients as they showed no decrease in intragraft granzyme, perforin, Fas, or Fas ligand transcripts during thr first 8 days after transplant. These results imply that complex mechanisms may be important for the induction and maintenance of transplantation tolerance in the CTLA4-Ig plus bone marrow murine cardiac allograft model.

Abatacept↗
PubMed1996

CD40-gp39 interactions play a critical role during allograft rejection. Suppression of allograft rejection by blockade of the CD40-gp39 pathway.

Studies in vivo have documented the importance of CD40-gp39 interactions in the development of T-dependent antibody responses to foreign and auto-antigens. In this report, we demonstrate that allograft rejection is also associated with strong induction of CD40 and gp39 transcripts. When treatment was initiated at the time of transplant, MR1, a mAb specific for gp39, induced markedly prolonged survival of fully disparate murine cardiac allografts in both naive and sensitized hosts. However, when therapy was delayed until postoperative day 5, anti-gp39 failed to prolong graft survival. Allografts from recipients treated with MR1 from the time of transplantation showed decreased expression of transcripts for the macrophage effector molecule, inducible nitric oxide synthase, but essentially unaltered expression of B7 molecules and T cell cytokine transcripts (interleukin [IL]-2, interferon-gamma, IL-10, and IL-4) relative to control allografts. In addition, alloantibody responses in the MR1-treated mice were profoundly inhibited. However, our studies using B cell-deficient mice indicated that the ability of MR1 to prolong allograft survival was not dependent on B cells. These data suggest that blockade of CD40-gp39 interactions may inhibit allograft rejection primarily by interfering with T cell help for effector functions, rather than by interference with T cell activation.

Animals↗
PubMed1996

Polycythemia.

Plethora ('a morbid condition due to excess of red corpuscles') has been recognized since antiquity as a manifestation of disease. The use of leeches and blood letting, which was for centuries the mainstay of therapy in many clinical situations, reflected the importance then attached to having too much blood. Greater knowledge has achieved greater precision, so that measurement of packed cell volume (PCV) or hematocrit now defines polycythemia (> 0.51 in men and > 0.48 in women, when blood is sampled without venous occlusion). Clinical and laboratory investigations, mainly in the last 30 years, have enabled the subdivision of polycythemia into different subtypes of radically different etiology which will be described in this Chapter. The last decade, however, has seen the advancing edge of research in this field passing from clinical and routine laboratory testing to studies of cellular proliferation at the molecular level. Detailed understanding is, however, as always elusive, with each new finding revealing deeper layers which in turn need elucidation. The field of polycythemia is nevertheless moving slowly into the molecular era.

Bone Marrow↗
PubMed1996

Analysis of effector mechanisms in murine cardiac allograft rejection.

Multiple effector cells have been implicated in transplant rejection, including cytotoxic T cells, B cells, macrophages and NK cells. The purpose of this study was to examine the effector pathways which are critical to murine cardiac allograft rejection. RT-PCR (reverse transcriptase-polymerase chain reaction) analysis of syngeneic and allogeneic vascularized heterotopic cardiac grafts at 5, 8 and 12 days following transplantation demonstrate constitutive expression of Fas in both the syngeneic and allogeneic grafts as well as in normal heart. However, FasL, granzyme, and perforin expression were shown to be up-regulated on days 5-12 in the allograft with no expression in syngeneic grafts or in normal hearts. We have recently analyzed the functional significance of T cell cytotoxic pathways and found that neither the Fas nor CD8+ cytotoxic pathways are required for murine cardiac allograft rejection. In light of these results, we investigated the functional significance of other effector cells in the rejection process. B cell deficient C57BL/10-IgHtm1Cgn mice rejected cardiac allografts from normal donors at control rate. Finally, RT-PCR was used to analyze the expression of macrophage effector transcripts in allograft rejection. Transcripts for iNOS (inducible nitric oxide synthase) and TNF alpha (tumor necrosis factor-alpha) were up-regulated on days 5-12 in untreated allografts with undetectable expression in normal heart or syngeneic grafts. These results demonstrate that effective allograft rejection can occur in the absence of B cells and T cell cytotoxicity pathways suggesting that other effector pathways, such as delayed-type hypersensitivity responses by macrophages, may be critical for allograft rejection.

Animals↗
PubMed1996

Experience with the Port-A-Cath in sickle cell disease.

Peripheral vein access is often a problem in patients with sickle cell disease (SCD). Totally implantable venous access devices (TIVAD) have offered other groups of patients safe long-term venous access. We reviewed our own experience with the use of a Port-A-Cath device in five patients with SCD undergoing exchange transfusion programmes. All five lines required removal due to infection associated with SBE, septic arthritis, pulmonary embolus and axillary vein thrombosis. The organisms involved were Staphylococcus aureus (3), Staphylococcus epidermidis (1) and Streptococcus sp. (1). The median working life of the catheters was 240 days (range 61-428). The median length of time from presentation to the diagnosis of a line-associated infection was 29 days (range 1-58). The rate of complications (0.4 per 100 patient days) in this small group of patients contrasts with the lower rates in patients with HIV and malignancy (0-0.1 per 100 patient days). Our results suggest that patients with SCD suffer an unacceptable incidence of infective complications associated with the Port-A-Cath. Bone infection is more common where there is pre-existing infarcted tissue. While these systems provide a valuable tool, our experience has led us to discontinue the use of TIVADs in SCD.

Adult↗
PubMed1996

Investigation of patients with polycythaemia.

Polycythaemia may complicate or be the presenting feature of a wide variety of different pathologies. Early diagnosis and treatment of primary polycythaemia will significantly reduce the morbidity and mortality associated with this condition. Patients with a raised packed cell volume are divided into those with a raised red cell mass (absolute polycythaemia), and those with a red cell mass within their normal range (apparent polycythaemia). A standard investigative approach of an absolute polycythaemia enables patients with primary and secondary polycythaemia to be identified, leaving a group termed idiopathic erythrocytosis. There are a number of physiological situations and pathological events associated with idiopathic erythrocytosis and apparent polycythaemia. Careful follow-up of both groups of these patients is essential to identify possible causative mechanisms.

DNA Probes↗
PubMed1996

Essential thrombocythemia and pregnancy.

A review of the literature disclosed 106 pregnancies (preg.) in 57 women with essential thrombocythemia (ET). The success rate (baby alive) was 57% (60 live births/106 preg.), the rate of miscarriage 43% (46 miscarriages/106 preg.). The most frequent complication was spontaneous abortion during the first trimester in 36% (38 abortions/106 preg.). Other complications such as intrauterine death and stillbirth after the 28th week, which occurred in 5% (7/106), premature delivery in 8% (8/106), pre-eclampsia in 4% (4/106), and fetal growth retardation in 4% (4/106) were rarer events. Placental infarction due to thrombosis seems to be the most consistent pathological event as far as the fetus is concerned. Maternal hemorrhage occurred in 4% (3 minor and 1 major bleeding) and only 2 minor maternal thrombotic episodes have been observed. Interestingly, a decline in platelet count has been observed in 14 women and was associated with a successful preg, in 13/14 cases (93%). Aspirin (ASS) was the most frequently used drug in 47 of 93 recorded cases (51%). In 16 evaluable women treated with ASS the live birth rate was higher (12/16 preg., 75%) than for 21 untreated women (9/21 preg., 43%). In 5 cases interferon alpha (IFN) has been used successfully. In summary, 57% of women with ET had a live birth, maternal complications happened in 6%. Promising treatment modalities might be ASS and IFN. However, no definitive answer can be given on the ideal management for women with ET during pregnancy. A European register should be set up.

Abnormalities, Drug-Induced↗
PubMed1996

Diagnostic applications of haemopoietic progenitor culture techniques in polycythaemias and thrombocythaemias.

Clonogenic cultures support the proliferation of haemopoietic cells into colonies of differentiated progeny. Using these techniques it has been established that normal haemopoietic progenitors are dependent upon growth factors for their survival, proliferation and differentiation in vitro. However, progenitors from patients with polycythaemia vera (PV) generate erythroid colonies in cultures deprived of exogenous erythropoietin. These have been termed endogenous erythroid colonies (EEC). Recently, endogenous megakaryocytic colonies (EMC), those arising in assays without megakaryocyte growth factors, have been reported, particularly in patients with primary thrombocythaemia (PT). Many investigators have found an EEC positive culture to have 100% diagnostic specificity and sensitivity for PV. Similarly, EMC have been shown by some to be an unequivocal marker of PT. Accordingly, clonogenic assays for EEC and EMC have been advocated as diagnostic markers of PV and PT. However, the specificity of these assays is not universally attested to as there are some reports of EEC in patients with secondary polycythaemia and of EEC and EMC in normal subjects. Thus, for diagnostic use, EEC and EMC assays must be exhaustively validated for specificity using clinically appropriate controls. Furthermore, clonogenic culture techniques are not amenable to external quality assurance, are technically demanding and are unlikely to be available in most haematology laboratories. These considerations must be taken into account when assigning weighting to EEC and EMC assays as diagnostic criteria in myeloproliferative disorders.

Cell Culture Techniques↗