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Biomedical subjects

M Lawler

Publications and source records attributed to M Lawler.

At least 55 records · Page 3Linked to original sources
PubMed1996

Recombinant human erythropoietin: effect on the functional performance of anemic orthopedic patients.

OBJECTIVE: To determine whether rapid correction of anemia improves the functional and cognitive performance of postoperative orthopedic patients. DESIGN: A randomized, double-blind, placebo-controlled clinical trial. SETTING: A rehabilitation institute. PATIENTS: Persons having orthopedic surgery at least 2 weeks previously, and a hemoglobin concentration < 10g/dL. INTERVENTIONS: Recombinant human erythropoietin (rH-EPO) or the EPO vehicle for up to 8 weeks. All patients received ferrous sulfate. MEASUREMENTS: Blood counts were performed at weekly intervals, and functional and cognitive tests at baseline and weeks 4 and 8. RESULTS: In patients receiving vehicle only, hemoglobin levels increased from a mean of 9.0 at baseline to 11.0 at 4 weeks and 11.7 at 8 weeks; corresponding values for rH-EPO were 8.8 (p = NS), 12.6 (p = .02), and 13.5 (p = .01). However, functional improvement in dressing, toileting, and mobility was similar between groups, and the results of neuropsychological tests showed no trends favoring rH-EPO. CONCLUSIONS: Although hemoglobin increases more rapidly in anemic orthopedic patients treated with rH-EPO, equally rapid functional improvement occurs in those who receive only iron therapy.

Activities of Daily Living↗
PubMed1996

Sorting out mix-ups. The provenance of tissue sections may be confirmed by PCR using microsatellite markers.

Standard identification systems usually ensure that biopsy material is correctly associated with a given patient. Sometimes, as when a tumor is unexpectedly found, the provenance (proof of origin) of a tissue sample may be questioned; the tissue may have been mislabelled or contaminated with tissue from another patient. Techniques used to confirm tissue provenance include comparing either tissue markers of gender or ABO blood groups; however, these methods have weak confirmatory power. Recently, the use of DNA-based polymerase chain reaction (PCR) techniques has been reported. Paired, formalin-fixed, paraffin-embedded, 10 microns tissue sections were selected from 17 patients, 8 of whom had carcinoma, either by dividing a biopsy section, using sequential biopsies, or sequential biopsy and autopsy tissue. The resulting 36 samples were coded before analysis. In two additional cases, 1-mm fragments of tumor from one patient were included in the tissue block of benign tissue from another patient, the tumor fragments were identified on hematoxylin-and-eosin-stained sections, separately scraped off the glass slide, and analyzed. Tissue from two clinical cases, one of suspected mislabelling and one with a suspected carry-over of malignant tissue were also investigated. Short tandem repeat sequences (STR) or microsatellites, are 2-5 base pair repeats that vary in their repeat number between individuals. This variation (polymorphism) can be assessed using a PCR. A panel of markers of 3 STRs; ACPP, INT 2, and CYP 19 (on chromosomes 3, 11, and 15, respectively) were used. DNA was isolated from the samples after xylene deparaffinization and proteinase digestion, and was then amplified in a radioactive PCR using primers selected to give a product size ranging from 136-178 bases. Amplified products were electrophoresed on denaturing polyacrylamide gels, dried, and autoradiographed. DNA segments were successfully extracted from all samples but one, which was fixed in Bouin's fluid. By comparing allele sizes from the panel, all tissue pairs (other than the Bouin's pair) were successfully matched, the 1-mm tumor fragments were correctly assigned, and the two clinical problems were solved. STRs are highly informative and robust markers, well suited to PCR of small portions of tissue sections, and are an effective method to confirm the provenance of benign and malignant biopsy and autopsy material.

Acid Phosphatase↗
PubMed1996

Multifocal remitting-relapsing cerebral demyelination twenty years following allogeneic bone marrow transplantation.

We report a case study of a female who received an allogeneic bone marrow transplantation (BMT) from a sex-mismatched related donor and who, after a twenty-year interval, developed an acute fulminant biopsy-proven demyelinating disorder of cerebral white matter which followed a remitting-relapsing chronic course. In situ hybridization studies using Y-chromosome-specific markers revealed Y-chromosome-positive mononuclear cells in biopsy samples of white matter. Magnetic resonance imaging (MRI) studies of the asymptomatic healthy male donor showed multiple white matter lesions. These observations suggest that donor lymphocytes were sensitized to central nervous system (CNS) antigens prior to or at the time of transplantation but remained dormant for 20 years before becoming activated to cause widespread demyelination.

Adult↗
PubMed1996

PCR amplification of short tandem repeat sequences allows serial studies of chimaerism/engraftment following BMT in rodents.

Animal models of bone marrow transplantation (BMT) allow evaluation of new experimental treatment strategies. One potential strategy involves the treatment of donor marrow with ultra-violet B light to allow transplantation across histocompatibility boundaries without an increase in graft rejection or graft-versus-host disease. A major requirement for a new experimental protocol, particularly if it involves manipulation of the donor marrow, is that the manipulated marrow gives rise to long-term multilineage engraftment. DNA based methodologies are now routinely used by many centres to evaluate engraftment and degree of chimaerism post-BMT in humans. We report the adaptation of this methodology to the serial study of engraftment in rodents. Conditions have been defined which allow analysis of serial tail vein samples using PCR of short tandem repeat sequences (STR-PCR). These markers have been used to evaluate the contribution of ultraviolet B treated marrow to engraftment following BMT in rodents without compromising the health of the animals under study. Chimaerism data from sequential tail vein samples and bone marrow from selected sacrificed animals showed excellent correlation, thus confirming the validity of this approach in analysing haemopoietic tissue. Thus the use of this assay may facilitate experimental studies in animal BMT.

Animals↗
PubMed1996

Campath-1G in vivo confers a low incidence of graft-versus-host disease associated with a high incidence of mixed chimaerism after bone marrow transplantation for severe aplastic anaemia using HLA-identical sibling donors.

We have evaluated the effect of in vivo Campath-1G on engraftment and GVHD in 23 patients with severe aplastic anaemia transplanted from HLA-identical sibling donors. In 14 patients Campath 1g was given pre-transplant for up to 9 days in an attempt to overcome graft rejection (group 1). In nine patients Campath-1G was given pre-transplant, but also continued post-transplant until day +5 to reduce GVHD (group 2). There were three patients with late graft failure in group I following initial neutrophil engraftment, and four cases of grade II+ GVHD. In group II, two patients had early graft failure (no take), and there were no cases of acute GVHD out of seven evaluable patients. One patient in group I developed chronic GVHD of the liver, and two patients (one in each group) had transient localised chronic GVHD. PCR of short tandem repeats was used to evaluate chimaeric status in 13 patients. Of 11 patients with initial neutrophil engraftment, only one had 100% donor haemopoiesis at all times. The remaining patients had either transient mixed chimaerism or persistence of recipient (< 20%) cells. We conclude that in vivo Campath-1G is associated with a high incidence of mixed chimaerism which tips the balance away from GVHD but towards graft rejection.

Adolescent↗
PubMed1996

Rejection of the second allogeneic graft in a patient with severe aplastic anemia reversed by antilymphocyte globulin and donor lymphocyte infusions.

Rejection after allogeneic BMT for aplastic anemia is a complication with a high risk of mortality. We describe a patient who, following a second episode of rejection after a second BMT entered a third durable remission subsequent to treatment with ALG, donor lymphocyte infusions, GM-CSF, and erythropoietin. Therapy was well tolerated. At 5 years after rejection treatment, his hematopoiesis is of complete donor origin as determined by analyses of short tandem repeats. Thus, donor lymphocyte infusions can be considered as a therapy option for marrow rejection after allogeneic BMT for aplastic anemia.

Adult↗
PubMed1995

Studies on hemopoietic chimerism following allogeneic bone marrow transplantation in the molecular biology era.

Donor hematopoiesis or donor chimerism in the host following allogeneic bone marrow transplantation (BMT) has appeared crucial to the engraftment process. However, as molecular techniques exploiting neutral variation in human genetic material have been used in the study of chimerism, the detection of residual host cells or mixed hemopoietic chimerism has indicated that donor chimerism is not obligatory following BMT. This review focuses on the detection and significance of mixed chimerism (MC) in patients transplanted for both malignant and non-malignant hemopoietic disease and attempts to tease out the contribution of MC to engraftment, leukemia relapse, graft rejection and long-term disease-free survival.

Anemia, Aplastic↗
PubMed1994

Infection of donor lymphocytes with human T lymphotrophic virus type 1 (HTLV-I) following allogeneic bone marrow transplantation for HTLV-I positive adult T-cell leukaemia.

Human T lymphotrophic virus type 1 (HTLV-I) associated leukaemia has a poor prognosis even with chemotherapy. We describe a patient with adult T-cell leukaemia treated with allogeneic bone marrow transplantation from an HTLV-I negative identical sibling donor. During follow-up after bone marrow transplantation, HTLV-I could be repeatedly isolated inspite of anti-viral prophylaxis. The patient died of an acute encephalitis and HTLV-I could be detected in autopsy material from the brain. By a PCR-based technique using short tandem repeats (STRs) it was shown that the patient's haemopoiesis was of donor origin. This shows the infection of donor cells in vivo by an aetiological agent which has been implicated in the leukaemogenic process for adult T-cell leukaemia.

Bone Marrow↗
PubMed1994

Adenovirus 12 E1A gene detection by polymerase chain reaction in both the normal and coeliac duodenum.

A 12 amino acid sequence from the adenovirus 12 E1B protein is homologous at the protein level with a similar 12-mer derived from the wheat protein A-gliadin. It has been suggested that exposure to Ad 12 could sensitise individuals to gliadins with resultant gluten sensitive enteropathy. In this study, the polymerase chain reaction (PCR) was used to analyse duodenal biopsy tissue from patients with coeliac disease for the presence of Ad 12. The sensitivity of the assay system was at least 1 in 10(5) cells and specificity was confirmed both by probing with an internal oligonucleotide and by direct sequencing. Ad 12 sequences were detected in three of 17 patients with adult coeliac disease and in five of 16 adult controls with normal duodenal biopsies. Since exposure to the virus would be predicted to occur in infancy we also studied patients with childhood coeliac disease diagnosed at less than 1 year of age. Ad 12 was positive in three of 10 childhood coeliac patients and one of seven controls. In addition, we studied a cohort of patients who presented with a diarrhoeal illness and associated anti alpha gliadin antibodies in 1983. These patients had duodenal biopsies performed at this time. One of three patients with abnormal histology had detectable Ad 12 while two of 14 with normal findings were positive for Ad 12. Finally, the potential oncogenic nature of Ad 12 prompted examination of a group of patients with intestinal tumours. Ad 12 DNA was, however, in only two of 19 tumour samples tested. These data indicate that Ad 12 can be successfully detected using PCR on paraffin embedded tissue. Furthermore, Ad 12 was detected at a relatively high level in normal duodenum. The results do not, however, support the hypothesis that prior exposure to Ad 12 is implicated in the pathogenesis of coeliac disease.

Adenocarcinoma↗
PubMed1994

Ultraviolet irradiation for the prevention of graft-versus-host disease and graft rejection in bone marrow transplantation.

This review describes an approach to the prevention of graft-versus-host disease (GVHD) and graft rejection following allogeneic BMT that differs from conventional methods. Ultraviolet (UV) irradiation inhibits the proliferative responses of lymphoid cells to mitogens and alloantigens by inactivation of T lymphocytes and dendritic cells, and in animal models this can prevent both GVHD and graft rejection. It is important that the marrow repopulating capacity of haemopoietic stem cells is not damaged by the irradiation process. We have found that polymorphic microsatellite markers are a sensitive way of assessing the impact of UV irradiation on chimerism after BMT in rodents.

Antigen-Presenting Cells↗
PubMed1994

Successful bone marrow transplant for Fanconi anaemia in transformation.

We present a patient who was diagnosed as suffering from Fanconi anaemia at the age of 36 years. At the time of diagnosis his bone marrow showed features of pre-leukaemic transformation. He received an allogeneic bone marrow transplant (BMT) from his HLA-identical sibling. The post-transplant course was unremarkable with evidence of trilineage engraftment at day +32 and no acute or chronic GVHD. He is well with sustained engraftment and no haematological evidence of Fanconi anaemia 18 months post-transplant.

Adult↗
PubMed1994

Donor leukemia following allogeneic bone marrow transplantation.

Although allogeneic bone marrow transplantation has been shown to be a highly effective treatment for acute and chronic leukemia, leukemic relapse remains a significant problem. Leukemic relapse occurs in recipient cells in the majority of cases, but the paucity of donor cell leukemias may reflect the sensitivity of the investigative technique. We have developed a highly sensitive technique to identify the origin of all hematopoietic cells in the post transplant state which is based on PCR amplification of microsatellites, polymorphic tandem repetitive elements. We have identified donor leukemia (AML M5) following a sex matched BMT for severe aplastic anemia, verified a previously reported case of donor leukemia following BMT for chronic granulocytic leukemia and recently identified an acquired cytogenetic abnormality(del 11q23) in donor cells four years following an apparently successful BMT for AML. In all cases the donors have remained healthy. Postulated mechanisms include transfer to the transplanted marrow of a dormant oncogene residing in the DNA of either a virus, the chromosomes of degenerating irradiation damaged host leukemic cells or in the marrow stroma which is radioresistant and host in origin following BMT. Using sensitive techniques donor leukemia has been shown to be a more common event than was previously thought and an understanding of its pathogenesis may allow us to elucidate leukemogenic mechanisms in man.

Adolescent↗
PubMed1993

Recurrence of Philadelphia chromosome-positive leukemia in donor cells after bone marrow transplantation for chronic granulocytic leukemia.

Allogeneic bone marrow transplantation has been shown to be a very effective therapy for Chronic Granulocytic Leukemia with long term disease free survivals in excess of 60%. Relapse rates remain low at 15% following histocompatible sibling transplants and lower rates following matched unrelated donor grafts. Relapse rates however, are higher if BMT is carried out in transformation or blast crisis. Leukemic relapse in donor cells following transplantation for CGL is a rare event. The occurrence of donor leukemia however, may be under reported as accurate and sensitive investigation of the origin of relapsed leukemia following BMT requires DNA based technologies. A possible mechanism of donor leukemia in CGL is transfection of donor cells with the chimeric gene which is unique to this disease. It is possible that the malignant cells found in transformed or blast crisis of CGL may have a greater potential to transfect donor haematopoietic material. Careful evaluation of the incidence of donor leukemia using molecular biology methods may elucidate the frequency of this event following BMT for CGL.

Animals↗
PubMed1993

Successful second unrelated donor BMT in a child with juvenile chronic myeloid leukaemia: documentation of chimaerism using the polymerase chain reaction.

A 3-year old child with juvenile chronic myeloid leukaemia received a T cell-depleted BMT from a male unrelated donor. There was early graft failure associated with increasing splenomegaly and hypersplenism. Splenectomy was performed 53 days post-transplant and was followed by autologous marrow recovery with return of leukaemia. A second unrelated donor BMT was performed 9 months later using T cell-replete marrow from a similarly matched female donor. Grade 2 GVHD involving the skin and gut responded to treatment with steroids. Chimaerism was assessed using Y-specific polymerase chain reaction (PCR) and microsatellites. Samples taken at the time of splenectomy showed no donor marrow engraftment but there was significant engraftment in the spleen. Following the second transplant, donor-type haematopoiesis was documented using a panel of microsatellite probes. The patient remains well 6 months after transplant. Splenectomy should be considered prior to transplant in patients with significant splenomegaly and hypersplenism. Partial chimaerism in the spleen, but not bone marrow, post-BMT, has not previously been documented. PCR technology is a useful and highly sensitive way to assess chimaerism post-BMT and is informative in sex-matched cases, whilst the small amount of material required is advantageous in paediatric patients.

Bone Marrow Transplantation↗
PubMed1993

Mixed chimaerism; detection and significance following BMT.

Residual recipient haematopoietic cells may coexist with donor haemopoietic tissue following BMT. This is known as mixed chimaerism. The incidence of mixed chimaerism varies with the sensitivity of the detection system used; DNA based methodologies are the most sensitive. The influence of mixed chimaerism on leukaemia relapse and graft rejection is unclear. The lineages in which mixed chimaerism occurs may affect outcome.

Anemia, Aplastic↗