Biomedical subjects
Publications and source records attributed to R O'Reilly.
Both patients and psychiatric residents are seen to exhibit symptoms as the end of the resident's job rotation approaches and the need arises to transfer the patient's care to a new therapist. These symptoms, collectively known as the "Transfer Syndrome", are examined. An approach to modify these problems is outlined. Finally, the need for repeated transfers of individual patients between psychiatric residents is reviewed in the light of educational necessities.
A case of Capgras syndrome associated with extreme violent behaviour is described. The patient's psychodynamics support the belief that the Capgras delusion initially arises from an altered affective response towards one or more others and proceeds to intolerable ambivalent feelings. This ambivalence is neutralised through the imagined existence of doubles.
Explore the source record for details and available documents.
Retroviruses may be used as genetic vectors to transfer genes into mammalian cells with high efficiency. We have shown that the N2 vector will transfer a functional bacterial gene for neomycin resistance (NeoR) into more than 80% of mouse spleen foci. A derivative of the N2 vector was constructed to study transfer and expression of the human gene for adenosine deaminase (ADA) in mammalian lymphoid and hematopoietic stem cells. This vector, termed SAX, contains the human ADA cDNA with an SV40 promoter in addition to the NeoR gene. The SAX vector was found to efficiently transfer and express the ADA gene in an ADA-deficient human T-cell line. Gene transfer by SAX using an autologous nonhuman primate bone marrow transplant model resulted in expression of the human ADA gene in peripheral blood cells of treated animals. Human bone marrow treated with SAX produced 1%-2% of colonies in vitro that were expressing the vector genes. Transfer of genes into circulating hematopoietic stem cells of fetal sheep in utero was most efficient; vector gene expression was evident in 20%-40% of hematopoietic colonies. Therefore, retroviral vectors are capable of transferring functional genes into a wide variety of mammalian lymphoid and hematopoietic cells. Such vectors may be useful for clinical trials of gene therapy, that is, the correction of genetic diseases by insertion of a normal gene into a patient's defective cells.
Explore the source record for details and available documents.
Chronic graft-versus-host disease (GVHD) is a complex immunological disease which can appear in up to 30% of survivors of allogeneic bone marrow transplantation. Target organs include skin, mucous membranes and liver; eventual mucosal defects, specifically involving secretory IgA, have been observed. In these studies we show that transplant recipients who develop GVHD are more likely to have higher serum antibody titres to bovine casein and circulating immune complexes containing casein than patients who do not develop this complication. The stage of GVHD may be related to the level of antibody to casein. The biological role of immune complexes in relationship to the evolution of this disease is unknown.
Explore the source record for details and available documents.
Lymphomas are an uncommon complication of solid organ transplantation and rarely occur after marrow transplantation. When post-marrow transplant lymphomas have occurred, they have been of donor cell origin and when sought, Epstein-Barr virus DNA has been found in the tumor. A 21-year-old woman developed a poorly differentiated lymphocytic lymphoma 6 months after bone marrow transplantation for acute myeloid leukemia in remission. Cyclosporin A had been used as an immunosuppressant. A chromosomal polymorphism demonstrated that the tumor was of host origin and contained a monoclonal tumor marker, 46,XX INV 4 (p16q12). The tumor did not contain the DNA of the Epstein-Barr virus.
Peripheral blood mononuclear cells from 14 patients with acute leukemia or aplastic anemia undergoing allogeneic bone marrow transplantation were examined for the autologous mixed lymphocyte reaction (AMLR) between T and non-T cells and its relationship with chronic graft-versus-host disease (GVHD). Five of 6 patients with GVHD demonstrated deficiency of the AMLR, whereas only three of 8 patients with no evidence of chronic GVHD had deficient AMLR. The nature of underlying disease had no effect on the AMLR. The significance of these results is discussed.
Fifteen patients with acquired immunodeficiency syndrome (AIDS), lymphoma and immunodeficiency, or severe combined immunodeficiency were treated with highly purified interleukin-2 (IL-2) prepared from human lymphocytes. All patients showed a defect in mitogen-induced T cell proliferation which was partially corrected when IL-2 was added in vitro. IL-2 was administered subcutaneously by daily injection or continuous infusion. The maximum daily dose was 20,000 U/m2, the maximum total dose 855,000 U/m2, and the maximum period of treatment 77 days. An increase in the platelet count was seen in one patient with AIDS, a decrease in the serum level of a monoclonal immunoglobulin in another patient with AIDS, and a minor tumor response in a patient with diffuse histiocytic lymphoma. As no toxicity was observed, further study of IL-2 in the treatment of human immunodeficiency is indicated.
Cytomegalovirus (CMV) was repeatedly isolated from urine and saliva of a 20-month-old male child with recurrent episodes of pneumonia, high fever, rash, lymphadenopathy, oral ulceration, and neutropenia. Immunologic evaluation revealed decreased serum IgG and IgA, increased IgM, depressed T- and B-lymphocyte functions, and decreased natural killer (NK) activity for herpes simplex-type I virus-infected targets. NK activity was augmented following exposure of the patient's lymphocytes to interferon (IF) in vitro. The child was treated with interferon (four courses, dosage varying from 2 million U/day to 1 million U three times/week for periods of 10, 28, 80, and 67 days, respectively, interspersed over 9 months) and hyperimmune plasma infusions every 3 weeks. Toward the end of interferon therapy oral Levamisole was started and a feeding gastrostomy was inserted to provide nutritional support. Clinical recovery was associated with reversal of immunologic abnormalities except for the hypogammaglobulinemia. Aggressive antiviral therapy (e.g., with IF) followed by immunostimulation (e.g., with Levamisole) may prove effective in controlling certain viral infections in immunodeficiency disorders.
The pharmacokinetics and urinary metabolic profile of R and S-warfarin, following administration of a 1.5 mg/kg oral dose of racemic warfarin, alone and 4 days into an oral regimen of 100 mg phenylbutazone three times a day, was investigated in three volunteers using a stereospecific h.p.l.c. fluorescent assay. The mean elimination half-life of S-warfarin was increased from 25 to 46 h during phenylbutazone administration, whilst that of the R-isomer was decreased from 37 to 25 h. The peak unbound concentrations of both warfarin enantiomers were higher during phenylbutazone administration, due to displacement. Displacement was not stereoselective. The unbound clearance of more potent S-warfarin is decreased by four-fold during phenylbutazone administration, due to substantial inhibition of both 6- and 7-hydroxylation, significant pathways of elimination of S-warfarin in the absence of phenylbutazone. The unbound clearance of R-warfarin is almost unchanged during phenylbutazone administration, due to the marginal effect of phenylbutazone on 6- and 7-hydroxylation, themselves minor pathways of elimination of this enantiomer in the absence of phenylbutazone. The stereoselective reduction of S- and R-warfarin, to their respective SS and RS-alcohols, is also substantially inhibited during phenylbutazone administration. Collectively the data point to the complex effect of phenylbutazone administration on warfarin's pharmacokinetics.
Peripheral blood mononuclear cells from 23 patients with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) or aplastic anemia (AA) undergoing allogeneic bone marrow transplantation were examined for spontaneous and Concanavalin A (Con-A)-induced suppressor activities against proliferative response of autologous or allogeneic responder lymphocytes to phytohemagglutinin (PHA) and for its relationship with acute or chronic graft-versus host disease (GVHD). Patients who developed acute GVHD had increased spontaneous and deficient Con A-induced suppressor cell activity, whereas patients who developed chronic GVHD or had no evidence of GVHD had both spontaneous and Con A-induced suppressor cell activity essentially similar to that of healthy controls. The nature of underlying disease (ALL v. AML v. AA) had no relationship with the abnormal suppressor functions. Depletion of adherent monocytes from mononuclear cells from a patient with acute GVHD and deficient Con A-induced suppressor function, restored the suppressor function, demonstrating the role of monocytes for deficient Con A suppressor function in some patients with acute GVHD. Additional mechanisms of abnormal immunoregulatory functions in bone marrow transplant recipients are discussed.
Bulk cultured cell lines with natural killer (NK) activity were derived by in vitro culture with interleukin 2-containing conditioned medium (IL 2-CM) of peripheral blood mononuclear leukocytes (PBL) from patients with primary T cell deficiencies. Lines were developed from three patients with severe combined immunodeficiency (SCID) and one patient with Nezelof's syndrome and contained several populations of cells with distinct phenotypes. All lines contained a cell population expressing the Leu-5 (50K) (sheep red blood cell receptor), 3A1 (40K), and OKT10 antigens, but lacking the pan T cell antigens Leu-1 (67K) and Leu-4 (19K) as well as the markers of T cell subsets Leu-2a (32K) and Leu-3a (56K). These cells failed to express the Leu-7 antigen and only weakly expressed OKM1. In addition, one line contained a population of Leu-5+, 3A1+, OKT10+, Leu-2a+, Leu 1-, and Leu 4- cells. Three of the lines also contained populations with classic T cell (Leu-1 and-Leu 4+) phenotypes. The lines were enriched in NK activity compared with the PBL from which they were derived. Their growth was strictly dependent on IL 2-CM. Highly purified IL 2, lacking any other detectable protein contaminants or lymphokine activities, was capable of supporting the growth of the Leu-5+, 3A1+ "null" cell populations from these lines without alteration in their functional activity or phenotype. Thus, studies of in vitro expanded cell lines from patients with severe disorders of T cell function and thymic involution indicate that this "null" cell population does not require thymic maturation to develop its effector function. This "null" cell population can be maintained in vitro in the presence of IL 2. This finding is analogous to the data obtained from study of NK cells in athymic (nude) mice.
Five children with primary deficiencies of T cell function were studied to assess the effects of highly purified exogenous Interleukin 2 (IL 2) on their in vitro T cell responses. The lymphocytes from one child with Nezelof's T cell deficiency demonstrated absence of endogenous IL 2 production and improved proliferative responses to mitogen or alloantigen in the presence of exogenous IL 2. Moreover, during in vitro mixed lymphocyte culture in the presence of exogenous IL 2, his lymphocytes were able to develop into cytotoxic effector cells. A second child with Nezelof's syndrome demonstrated a different type of defect. The lymphocytes from this child had less impairment of endogenous IL 2 production. Although IL 2 increased the proliferation of his cells in response to PHA, similar augmentation was not seen after stimulation with OKT3 or alloantigen. In cell-mediated cytotoxicity assays, after mixed lymphocyte culture, natural killer-like activity was strongly boosted in the cultures that contained IL 2, but T cell-mediated cytotoxicity was not. The lymphocytes from three patients with severe combined immunodeficiency did not show improved proliferative responses in the presence of IL 2. Thus, only one of the five patients demonstrated the combination of defective endogenous IL 2 production, but preservation of the ability to respond appropriately to exogenous IL 2. This child may therefore have suffered from a T cell defect pathophysiologically similar to that seen in nude or aged mice.
A prolonged partial thromboplastin time in a patient was investigated, as well as those of his family members. One sibling, the mother, and the patient all shared a lupus-like anticoagulant and low Factor XII levels in association with the A 11, Bw 35, DR 4 haplotype previously found in familial lupus erythematosis. The rest of the family had normal coagulation profiles and the entire family had normal findings when tested for ANA, complement and immune complexes. After being confirmed in a second coagulation laboratory, the lupus-like anticoagulants in the three affected members of the family disappeared upon retesting 3-8 weeks later.
Periodic monitoring of plasma drug concentrations has been suggested as a means whereby the toxicity of Cyclosporin A (CyA) can be reduced in patients undergoing bone marrow transplantation. We have developed a sensitive and specific method for the determination of CyA in plasma using reverse phase high pressure liquid chromatography (HPLC). Cyclosporin D was used as the internal standard. The lower limits of detection are 100 ng/ml in biological fluids and 20 ng per injection onto the column. We have analyzed plasma samples from patients who received CyA at doses which ranged from 8 to 15 mg/kg/day. Although all patients experienced toxic or therapeutic effects, plasma concentrations of CyA were consistently less than 100 ng/ml when analyzed by this method. We conclude that analytical methods currently available for the detection of CyA are unsuitable for the monitoring of patients who receive this agent.
Serial echocardiographic (ECHO) studies were obtained on 40 pediatric patients (pts) treated with greater than or equal to 80 mg/kg cyclophosphamide (CPM) (range 80-200 mg/kg) in 1 week. Patients were treated for solid tumors and prior to marrow transplant. Echo changes occurred in 10/13 pts who received CPM greater than or equal to 170 mg/kg over four days, and in 11/19 pts who received 120-140 mg/kg dose over two days and who had previously received greater than or equal to 100 mg/m2 anthracyclines with or without radiation. No changes were seen in eight pts who had 80-160 mg/kg CPM and less than 100 mg/m2 anthracyclines. The observed changes occurred approximately 1 week after CPM and persisted for days to weeks. Pericardial effusion seen in 15 pts was successfully treated with furosemide in 13. Two died with hemorrhagic pancarditis. Other changes seen were increased end diastolic left ventricular diameter, decreased fractional shortening and abnormal left ventricular preejection period/ejection time ratios. Thus, cardiac effects of high dose CPM are not rare in children. Patients receiving greater than 170 mg/kg CPM in 1 week or 120 mg/kg in 1 week after greater than or equal to 100 mg/m2 anthracyclines are at particular risk.