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Biomedical subjects

J D Shepherd

Publications and source records attributed to J D Shepherd.

69 records · Page 4Linked to original sources
PubMed1991

Neurologic complications in allogeneic bone marrow transplant patients receiving cyclosporin.

Regimens using cyclosporin (CSP) and either methylprednisolone (MP) or methotrexate (MTX) have been useful in the prophylaxis of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). However, CSP produces a number of side effects, including neurologic toxicity. A retrospective review of recipients of 239 BMTs given CSP-based prophylactic regimens revealed that 10 patients (4.2%, 95% confidence interval 0% to 10.4%) experienced a syndrome characterized by hypertension, severe visual disturbances, seizures and occipital lobe density changes on brain computed tomography (nine patients) or nuclear magnetic resonance imaging (one patient). Neurologic findings were reversible in all cases, usually after temporary discontinuation of CSP. Univariate analysis identified the following risk factors for neurotoxicity: use of unrelated or HLA-mismatched related donors, administration of etoposide (VP-16) or total body irradiation as part of conditioning, use of corticosteroids for prophylaxis or treatment of acute GVHD, or development of either acute GVHD or clinically significant microangiopathic hemolytic anemia (MAHA) post-BMT. In multivariate analysis, the most important predictors were the use of VP-16 (p = 0.008), the use of a continuous infusion CSP plus MP prophylactic regimen for GVHD (p = 0.003) and the development of MAHA after BMT (p less than 0.001). The strong association with MAHA suggests that endothelial damage is related to the development of this complication.

Adolescent↗
PubMed1991

Allogeneic bone marrow transplantation using unrelated donors: a pilot study of the Canadian Bone Marrow Transplant Group.

Between February 1988 and January 1990, 35 patients underwent allogeneic bone marrow transplantation (BMT) from unrelated donors using measures routinely employed for matched related donors. Median patient age was 34 years (range 2-49). Thirty-two patients had hematologic malignancies, including chronic myelogenous leukemia (CML) in 16; three patients had severe aplastic anemia. Donor-patient pairs were matched at the HLA loci tested serologically (HLA-A, -B, -DR) in 29 cases; mixed leukocyte culture results were variable but often reactive. Five patients died prior to day +28 without evidence of myeloid engraftment, and one patient developed fatal graft failure several months after initial engraftment. Acute graft-versus-host disease (GVHD) occurred in 77% (95% confidence interval [CI] 60-90%) of all patients, and GVHD contributed to the death of 10 patients. Fatal regimen-related toxicity occurred in four patients and another died due to neurologic complications of a process that resembled the hemolytic-uremic syndrome. Two acute leukemia patients relapsed, and a CML patient was found to have a localized non-Hodgkin's lymphoma at necropsy. As of 1 June 1991, 14 patients are alive and in remission at a median follow-up of 1.9 years (range 1.5-3.3); all except one have normal performance scores. The 2-year actuarial event-free survival for all patients is 40% (95% CI 24-56%). Proportional hazards analysis revealed favorable significance for female patient sex, less advanced disease status and shorter interval from diagnosis to BMT. While unrelated-donor transplants need not necessarily duplicate the results of related-donor transplants to be of benefit, the event-free survival in this series was roughly similar to that expected in the related-donor situation, with the high transplant-related mortality somewhat offset by a low recurrence rate. Further studies using unrelated donors, employing new methods of preventing transplant-related complications, are indicated.

Acute Disease↗
PubMed1991

Reversible tricuspid regurgitation in a patient undergoing treatment for acute leukemia.

A 52-year-old female patient treated for acute lymphoblastic leukemia with combination chemotherapy (cyclophosphamide, vincristine, adriamycin and prednisone), broad spectrum antibiotics and amphotericin via a Hickman catheter placed in the superior vena cava, developed echocardiographically confirmed tricuspid regurgitation. A second admission four months later showed only mild tricuspid regurgitation. The authors conclude that the amphotericin given via the central line caused valvulitis of the tricuspid valve.

Amphotericin B↗
PubMed1991

Human hematopoietic stem cells in long-term culture: quantitation and manipulation.

These results suggest a potentially important role for the LTC system, not only in the development of a quantitative assay for hematopoietic cells, but also clinically as a procedure for manipulating autologous marrow in culture in a variety of ways for therapeutic advantage. These include strategies for immune modulation, gene marking and gene therapy, and perhaps eventually for stem cell amplification.

Bone Marrow Transplantation↗
PubMed1991

Distribution of glycoconjugates in the human retinal internal limiting membrane.

The internal limiting membrane (ILM), or basal lamina, of the neural retina is located between the end feet of retinal Müller cells and the vitreous cortex. Recent studies of ILM substructure and histochemistry suggest that the ILM lamina rara externa, a region of the ILM likely to mediate vitreoretinal adhesion, is rich in noncollagen glycoconjugates. To characterize the spatial distribution and temporal expression of ILM glycoconjugates further, fetal and adult human retinas were examined using lectin histochemistry. Eyes from early fetal (13-15 weeks of gestation), midfetal (17-20 weeks of gestation), late fetal (23-26 weeks of gestation), full-term (38-41 weeks of gestation), early adult (17-20 yr of age), and late adult (57-84 yr of age) stages were examined. Although a number of significant observations pertaining to the distribution and temporal expression of ILM-associated glycoconjugates are described, two may have a significant relationship to vitreoretinal adhesion. In contrast to laminin and fibronectin, which are detectable throughout the retinal ILM at both young and older adulthood, erythrina cristagalii (ECA), a lectin with high binding affinity for galactose beta (1,3) N-acetyl-glucosamine, binds strongly to the ILM of young eyes but does not bind to the ILM of eyes from older donors. In addition, dolichos bifloris (DBA), a lectin with high binding affinity for N-acetylgalactosamine, does not bind to the ILM at early fetal stages, but binds at the midfetal stage, a time which corresponds with the onset of tertiary vitreous elaboration. More significantly, the DBA-binding glycoconjugate is neural retina ILM specific; it is not present in the basal lamina of the ciliary epithelium. Based on the known oligosaccharide composition of nonocular forms of human laminin, fibronectin, and collagen type I, and on the distribution of these molecules in the basal laminas of both the retina and ciliary epithelium, the authors conclude that the molecule bound by DBA has not been identified previously as a component of the ILM. Further characterization of ILM-associated molecules will be important to understand vitreoretinal adhesion and clinical disorders where adhesion is anomalous.

Adolescent↗
PubMed1990

Detection of breakpoint cluster region- negative and nonclonal hematopoiesis in vitro and in vivo after transplantation of cells selected in cultures of chronic myeloid leukemia marrow.

Philadelphia (Ph1) chromosome-positive clonogenic progenitors usually disappear within 4 to 6 weeks in long-term cultures established from the marrow of patients with chronic myeloid leukemia (CML). In contrast, coexisting chromosomally normal hematopoietic cells are relatively well maintained. Thus, even though normal cells are initially undetectable, they may become the predominant population. Recently, we have begun to explore the potential of such cultures as a strategy for preparing CML marrow for autografting, and based on cytogenetic studies of the differential kinetics of Ph1-positive and Ph1-negative clonogenic cells, have chosen a 10-day period in culture to obtain maximal numbers of selectively enriched normal stem cells. Here we present the results of molecular analyses of the cells regenerated in vivo for the initial three CML patients to be treated using this approach by comparison with the differentiated cells generated by continued maintenance of an aliquot of the autograft in vitro (using a slightly modified culture feeding procedure to enhance the production and release of cells into the nonadherent fraction after 4 weeks) for the one patient whose genotype made molecular analysis of clonality status also possible. These analyses showed that cells with a rearranged breakpoint cluster region (BCR) gene were not detectable by Southern blotting in either in vitro or in vivo populations of mature cells that might be assumed to represent the progeny of primitive cells present at the end of the initial 10 days in culture. Production of BCR-negative cells was also shown to be temporally correlated with the appearance of nonclonal hematopoietic cells both in culture and in vivo. These findings provide support for the view that prolonged maintenance of CML marrow cells in long-term culture may allow molecular characterization of both the BCR-genotype and clonality status of cells with in vivo regenerative potential.

Bone Marrow↗
PubMed1990

Recombinant GM-CSF in patients with poor graft function after bone marrow transplantation.

Poor graft function after bone marrow transplantation is an infrequent complication that is fatal for most patients secondary to severe infections or to bleeding. Even a second marrow infusion is usually not successful in restoring hematopoiesis. We treated nine patients with recombinant Escherichia coli derived human granulocyte-macrophage colony-stimulating factor (GM-CSF) for delayed engraftment or graft failure after autologous (n = 6) or allogeneic (n = 3) bone marrow transplantation (BMT). Six patients were given a dose of 10 micrograms/kg/d over 30 min; three patients received lower doses of 3-5 micrograms/kg/d. Seven patients lived longer than 3 days after commencing GM-CSF and could be evaluated for their response. Six of them had a marked rise in neutrophil counts; there was no effect on platelet and reticulocyte counts. Two patients died within the first 3 days after starting GM-CSF, although both seemed to have some response to GM-CSF (increasing blood neutrophils in one, and increasing macrophages in the bone marrow on autopsy in the other). Side effects most likely attributable to GM-CSF administration were mild and included diarrhea and abdominal pain, low grade fever and mild rash. Severity of graft-vs-host disease (GVHD) was not enhanced in the recipients of allogeneic marrow. We conclude that recombinant GM-CSF can be safely given to patients with poor graft function after marrow transplantation. In some patients, this may lead to a subsequently sustained neutrophil recovery.

Adolescent↗
PubMed1990

Use of an immunoglobulin preparation enriched for IgM (Pentaglobin) for the treatment of acute graft-versus-host disease.

Pentaglobin is a commercial immunoglobulin preparation which is enriched specifically for IgM and also contains antibodies that are capable of neutralizing endotoxins. Its potential use in treating patients with acute graft-versus-host disease (GVHD) was studied in a phase I/II study. Pentaglobin was administered at a dose of 8 ml/kg/day for 4 days as a continuous infusion to 10 patients after allogeneic marrow transplantation who had histologically documented moderate grade II (n = 8) or moderately severe acute GVHD grade III (n = 2), and who did not require immediate treatment with steroids. There were no side effects related to the infusion of Pentaglobin and in all cases the serum concentrations of IgA, IgG and IgM at least doubled. Improvement of GVHD was seen in five patients with grade II GVHD. Conversely, in three patients with grade II and two patients with grade III GVHD, the disease either progressed during Pentaglobin infusion and required steroid treatment or showed no change and required steroids later in the course. Pentaglobin, therefore, might have some effect on mild and moderate GVHD. Randomized trials should be able to determine whether Pentaglobin could be considered as part of the GVHD prophylaxis or as adjunct treatment for acute GVHD together with low doses of steroids.

Bone Marrow Transplantation↗
PubMed1989

Allogeneic marrow transplantation for refractory Hodgkin's disease.

Eight patients with refractory Hodgkin's disease received intensive combination chemotherapy conditioning with cyclophosphamide, carmustine (BCNU), and etoposide (VP 16-213), and allogeneic marrow transplants. All patients achieved complete responses. Three patients relapsed; two died of Hodgkin's disease and one of chronic graft-v-host disease (GVHD) and infection. In all, four patients died due to transplant-related toxicity. One patient developed a fatal B-cell lymphoproliferative disorder soon after transplantation, and died without evidence of Hodgkin's disease. One patient is alive and free of progression 29 months after transplantation. These data indicate that allogeneic marrow transplantation may be considered as therapy for selected patients with advanced Hodgkin's disease and, despite substantial toxicity, will occasionally result in long-term responses. Better patient selection would likely improve results.

Adolescent↗
PubMed1989

Coronary artery disease following bone marrow transplantation.

A 19-year-old woman died suddenly 30 months after allogeneic bone marrow transplantation for refractory leukemia. On postmortem examination severe coronary artery disease and acute myocardial infarction were found. The patient had previously been given chemotherapy including daunorubicin for treatment of her leukemia. She received high dose cyclophosphamide and total body irradiation (1260 cGy) for her transplant. Diffuse chronic graft-versus-host disease, mainly affecting skin, subsequently developed, and was resistant to various therapies. The possible association of coronary artery disease and allogeneic bone marrow transplantation is discussed.

Adult↗
PubMed1989

Successful autografting in chronic myeloid leukaemia after maintenance of marrow in culture.

We have previously shown that Philadelphia chromosome (Ph1)-positive cells rapidly disappear when marrow from patients with chronic myeloid leukaemia (CML) is cultured under conditions that maintain normal haematopoiesis for many weeks. The ability of marrow maintained in culture for 10 days to serve as an autograft has now been tested in three patients treated with intensive chemoradiotherapy. Two weeks after transplantation, marrow samples from all patients showed trilineage haematopoiesis. Neutrophil counts greater than 1.0 x 10(9)/l were achieved in all patients within 4 weeks, and platelet counts greater than 20 x 10(9)/l were achieved in two patients within 5 weeks. During this period of haematopoietic recovery, marrow cells were exclusively Ph1-negative in two patients and predominantly so in the third. These results suggest that engraftment can occur from Ph1-negative haematopoietic stem cells selected by maintenance of autologous CML marrow in culture for 10 days. Thus, the feasibility of using this approach to allow intensive and potentially curative therapy for CML has been established.

Bone Marrow Cells↗
PubMed1988

Acute graft-versus-host disease of the intestine. A surgical perspective.

The general surgeon may be involved in assessment and treatment of intestinal complications in patients who have undergone bone marrow transplantation. It is important to recognize the major causes of intestinal morbidity in these patients and to be aware of the cause and natural progression of the entity of acute graft-versus-host disease. Of 89 patients who underwent allogeneic bone marrow transplantation over a 6 year period, acute intestinal graft versus host disease developed in 29 (33 percent). Although surgical consultation for abdominal pain and peritonism was requested for 15 of these patients, intestinal perforation did not occur, and only two patients underwent laparotomy, both for obstruction (and hemorrhage in one case). Patients who require operation tend to be in the end stages of the disease, and the chance for salvage appears to be remote.

Bone Marrow Transplantation↗
PubMed1988

Cyclosporine and methylprednisolone for prophylaxis of acute graft-versus-host disease.

Twenty-eight consecutive HLA matched patients undergoing allogeneic bone marrow transplantation received prophylaxis for acute graft-versus-host disease with combined cyclosporine and methylprednisolone. The incidence of grades II-IV acute GVHD was 28.5%, a figure similar to that reported for two other drug regimens. The incidence of chronic GVHD in patients surviving longer than 150 days was 73%. Toxicity, especially renal, was acceptable and a number of potential problems associated with the use of methotrexate were avoided. While this regimen and similar ones have reduced the incidence and severity of acute GVHD the problem remains formidable and newer approaches are clearly needed.

Adolescent↗
PubMed1978

The binding of anti-DNA antibodies as measured fluorometrically by ethidium bromide.

The phenanthridine dye ethidium bromide (EB) intercalates with double-stranded DNA (dsDNA) resulting in an enhancement of fluorescence. Single-stranded DNA (ssDNA) does not show this fluorescent enhancement. Purified IgG from patients with Systemic Lupus Erythematosus (SLE) containing anti-dsDNA antibodies competes with EB for binding to DNA resulting in a decrease in fluorescence. This study has shown that antibodies which bind ssDNA in the Millipore filter radioimmunoassay displace EB from dsDNA showing that antigenic determinants are available for binding in the double-stranded molecule. This study introduces the EB assay and presents a comparison with the Millipore filter assay.

Antibodies, Antinuclear↗