Showing papers on "Transplantation published in 1983"

The Clinical Significance of Positive Blood Cultures: A Comprehensive Analysis of 500 Episodes of Bacteremia and Fungemia in Adults. II. Clinical Observations, with Special Reference to Factors Influencing Prognosis

Abstract: Among 500 patients with bacteremia and fungemia, total mortality was 42%; about half of all deaths were attributable directly to infection. Mortality increased with age, but deaths unrelated to infection itself were responsible in part for this increase. Mortality was 2.6% among obstetric-gynecologic patients, 42% among medical patients, 49% among surgical patients, and 60% among transplant patients. The risk of death was especially high with enterococcal, facultative gram-negative, fungal, polymicrobial, or hospital-acquired sepsis; in the presence of shock, leukopenia, absolute granulocytopenia, or defined predisposing conditions (neoplasia, cirrhosis, and combinations of factors such as surgery and renal failure); and with a primary infected focus in the respiratory tract, the skin, a surgical wound, an abscess, or an unknown site. Body temperature was inversely related to mortality. Survival was increased by the use of appropriate antibiotics and, where applicable, additional therapeutic maneuvers (e.g., drainage). Multivariate analysis defined seven variables that independently influenced outcome: microorganism, blood pressure, body temperature, primary focus of infection, place of acquisition of infection, age, and predisposing factors. Although some adverse prognostic factors are not amenable to intervention, prevention of nosocomial bacteremia and fungemia and early reversal of hypotension may reduce the death rate from sepsis.

Isolation and nucleotide sequence of a cDNA encoding the precursor of mouse nerve growth factor

Abstract: Nerve growth factor (NGF) is a polypeptide that enhances survival, nerve fibre outgrowth and neurotransmitter biosynthesis in sympathetic and sensory neurones. Administration of antibodies against NGF to developing animals leads to atrophy of the sympathetic system. NGF is not normally detectable in innervated tissues but ablation of the innervating neurones leads to the production of measurable NGF in the target tissue. After transplantation of the denervated tissue, reinnervation occurs, then NGF decreases to undetectable levels. Thus NGF seems to act as a neurotrophic messenger and its level is regulated by innervating neurones. Because of the minute levels present it is very difficult to study NGF biosynthesis in innervated tissue. However, NGF can be isolated from male mouse submaxillary glands, where it exists in inexplicably high levels. Its amino acid sequence has been determined, and the synthesis of NGF and its larger precursors has been demonstrated in cultured submaxillary glands. We report here the nucleotide sequence of a submaxillary cDNA encoding the mouse NGF precursor (preproNGF). In contrast to previous suppositions the NGF moiety is situated near the carboxyterminus of the polyprotein precursor. It is flanked at the amino-terminus by 187 amino acids which may be cleaved at dibasic residues to generate three peptides; there are only two additional amino acids at the carboxy-terminus.

Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings. Beneficial effect of a protective environment.

Abstract: One hundred thirty patients with severe aplastic anemia were conditioned with cyclophosphamide for transplantation of marrow from HLA-identical siblings. The patients were selected for the present analysis according to the criterion of sustained marrow engraftment. Of the 130 patients, 97 are now alive between 1.4 and 11 years (median, 5) after transplantation. Twenty-nine of the thirty-three who died had either acute or chronic graft-versus-host disease (GVHD). Our analysis was directed at identifying factors predicting GVHD and survival after transplantation in patients. Our key findings were that moderately severe to severe acute GVHD had a strong adverse influence on survival; that a protective environment significantly reduced mortality, which corresponded in part to a reduction in and delayed onset of acute GVHD; that refractoriness to random-donor platelet infusions at transplantation adversely influenced survival, particularly among patients with acute GVHD; and that increasing age was associated with increased mortality.

Epstein-Barr virus (EBV) induced polyclonal and monoclonal B-cell lymphoproliferative diseases occurring after renal transplantation. Clinical, pathologic, and virologic findings and implications for therapy.

Abstract: Nineteen renal allograft recipients developed B-cell lymphoproliferative diseases. Clinically there were two groups: a) young patients (mean age, 23 years) who presented soon (mean, 9 months) after transplantation or antirejection therapy with fever, pharyngitis, and lymphadenopathy resembling infectious mononucleosis, and b) older patients (mean age, 48 years) who presented later (mean, 6 years) after transplantation with localized tumor masses. Histologically, the diseases were classified as polymorphic diffuse B-cell hyperplasia (PDBH) or polymorphic B-cell lymphoma (PBL). Immunologic cell typing revealed either polyclonal or monoclonal B-cell proliferations. Malignant transformation of polyclonal proliferations in two patients was suggested by the finding of clonal cytogenetic abnormalities. Epstein-Barr virus (EBV) specific serology, staining of biopsy specimens for the Epstein-Barr nuclear antigen, and EBV DNA molecular hybridization studies implicated EBV as the cause of both PDBH and PBL. Acyclovir, an antiviral agent that blocks EBV replication in vitro, inhibited oropharyngeal shedding of EBV and caused complete remission in four patients with polyclonal B-cell proliferations. The monoclonal tumors were acyclovir resistant. We suggest that surgical treatment, radiotherapy, or chemotherapy may be more appropriate therapy in selected patients with acyclovir resistant tumors. Therapeutic decisions require not only documentation of the viral etiology of these tumors, but also immunologic and cytogenetic analysis to determine the stage of tumor evolution in individual patients.

Remission of Essential Hypertension after Renal Transplantation

Abstract: Six patients in whom "essential hypertension" led to nephrosclerosis and kidney failure received kidney transplants from normotensive donors. After an average follow-up of 4.5 years, all were normotensive and had evidence of reversal of hypertensive damage to the heart and retinal vessels. These six patients, all of whom were black, and six control subjects matched for age, sex, and race were admitted to the General Clinical Research Center for 11 days for observation of their blood pressure and their responses to salt deprivation and salt loading. Mean arterial pressure (+/- S.E.M.) among the patients who had previously had essential hypertension was similar to that of the normal controls (92 +/- 1.9 vs. 94 +/- 3.9; P not significant), and both groups had similar responses to salt deprivation and salt loading. Thus, essential hypertension in human beings is shown to be similar to the hypertension seen in spontaneously hypertensive rats in that both can be corrected by transplantation of a kidney from a normotensive donor. This observation supports the concept of the primary of the kidney in causing essential hypertension.

Solution to the "Char problem" based on Arctic char (Salvelinus alpinus) in Norway

Abstract: Rearing and transplantation experiments demonstrate that three coexisting forms of Arctic char Salvelinus alpinus (anadromous, small and large freshwater residents) belong to the same gene pool. Th...

Replication of Epstein–Barr virus in human epithelial cells infected in vitro

Abstract: Epstein-Barr virus (EBV), a member of the herpes group of viruses and the aetiological agent of infectious mononucleosis, is usually thought of as a lymphotrophic virus with the ability to transform B lymphocytes. So the association of EBV with nasopharyngeal carcinoma is puzzling, especially given the lack of success of attempts to infect epithelial cells with EBV in culture and the apparent lack of EBV receptors on epithelial cells. Circumvention of the apparent requirement for membrane receptors by techniques of transfection, microinjection and receptor transplantation has clearly demonstrated that there is no inherent barrier to EBV replication in nonlymphoid cells, including epithelial cell types. Our ability routinely to detect EBV DNA by in situ hybridization in epithelial cells of the oropharynx from persons with acute infectious mononucleosis suggests that, in vivo, EBV regularly gains access to and replicates lytically in epithelial cells. We report here in vitro evidence for direct infection by EBV and replication of the virus in cultured normal human epithelial cells.

Prevention of Cytomegalovirus Infection by Cytomegalovirus Immune Globulin After Marrow Transplantation

Abstract: In an effort to prevent cytomegalovirus infection among seronegative patients having marrow transplants, a globulin with high antibody levels against cytomegalovirus was given before and for 11 weeks after transplantation in a randomized trial. Among 36 patients who received no prophylactic granulocyte transfusions, globulin recipients had significantly fewer infections than controls (2 of 17 versus 8 of 19, p = 0.05 by Fisher's exact test and p = 0.03 by Mantel-Cox test). Conversely, infection rates were high and unchanged by globulin use among patients who received granulocytes from seropositive donors (7 of 8 recipients versus 6 of 7 controls). The lack of effect of the globulin among patients receiving transfusions of granulocytes from seropositive donors may suggest that the dose of antibody was insufficient or that antibody is ineffective against virus transmitted in granulocytes. We conclude that cytomegalovirus infection can be prevented by immunoprophylaxis in seronegative patients having marrow transplants who are not given granulocyte transfusions.

Survival with dialysis and transplantation in patients with end-stage renal disease.

Abstract: We examined the survival experience of 1038 white patients with end-stage renal disease to compare transplantation with maintenance dialysis. A mathematical model was used that permitted adjustment for the confounding effects of age and morbidity at the start of treatment as well as for the year in which treatment began. For patients with all kinds of renal disease, survival was related to age and morbidity but not to the year of starting treatment. Transplantation with a graft from a living related donor was associated with significantly better survival than either transplantation with a cadaveric graft (relative risk, 0.54) or dialysis (relative risk, 0.55). No significant difference in survival was found between treatment by dialysis and by cadaveric transplantation (relative risk, 1.01). In view of this experience, the decision about whether a patient on dialysis should receive a cadaveric transplant should be based on evaluation of the differences in complications associated with the two treatments and the potential effects of these on the patient's general life style, opportunity for rehabilitation, and family and social responsibilities. Whether the use of cyclosporine will change this assessment in the future remains to be seen.

Transplantation of CNS Fragments into the Brain of Shiverer Mutant Mice: Extensive Myelination by Implanted Oligodendrocytes

Abstract: Solid fragments of olfactory bulb from new-born normal (B6CBA and C57BL6) mice were implanted into new-born shiverer (shi/shi) brains. The shiverer mouse being characterized by the absence of myelin b

The response to chemotherapy of a variety of human tumour xenografts.

Abstract: The results of a series of projects on the cytotoxic drug response of human tumour xenografts are compared. All were performed in one laboratory, using conventional CBA mice that were usually immunosuppressed by thymectomy, cytosine arabinoside treatment, and whole-body irradiation. Results on human tumours arising in 9 anatomical sites are included, with the main emphasis on colo-rectal, pancreas, breast, lung and testis carcinomas, also melanomas. Growth acceleration during successive passage of most of these tumour types was observed. When therapeutic response was measured by a growth-delay method there were wide differences in response to chemotherapy. Testicular teratomas and small-cell lung tumours responded well; breast tumours showed modest response; melanomas, colo-rectal tumours and non-small-cell lung tumours responded poorly. Studies of clonogenic cell survival were made in 11 xenografted tumour lines. They confirmed the range of responsiveness and tendency towards individuality of the growth delay data. Cell survival in most cases was exponentially related to drug dose. This compilation of a large amount of experimental data supports the belief that human tumour xenografts broadly maintain the level of chemotherapeutic responsiveness of the source tumours in man.

Intraocular Transplantation in Rodents: A Detailed Account of the Procedure and Examples of its Use in Neurobiology with Special Reference to Brain Tissue Grafting

Abstract: Publisher Summary This chapter focuses on an in oculo technique with emphasis on technical details and step-by-step procedures and presents an analysis of various types of grafts. The two most obvious advantages of the in oculo approach are that it provides a chamber in which grafts can exist without being squeezed by or exerting pressure on host tissues and the transparency of the cornea through which grafts can be noninvasively observed. The grafted tissue that acts as a receptor of nerves from the host iris may itself be nervous tissue. The chapter presents a demonstration of partial phenotypic transformation of adult chromaffin cells to neuron-like cells as fiber outgrowth from chromaffin cells grafted to sympathetically denervated irises. Intraocular grafting, when properly performed, is probably among the least harmful types of experimental surgery that can be performed on a rat.

Accelerated atherosclerosis in cardiac transplantation: role of cytotoxic B-cell antibodies and hyperlipidemia.

Abstract: Accelerated coronary atherosclerosis remains a potential rate-limiting problem to longterm survival in cardiac transplantation. In order to gain insight into this problem, we have formulated the hypothesis that chronic immune injury (cytotoxic B-cell antibodies) and/or hypercholesterolemia (increase in total cholesterol/high-density lipoprotein cholesterol) predispose to accelerated coronary atherosclerosis. Fourteen long-term survivors of cardiac transplantation (>6 months) were longitudinally followed for the presence of cytotoxic B-cell antibodies, hyperlipidemia, and the development of coronary atherosclerosis. Three patients who received transplants for treatment of cardiomyopathy remained antibody negative, maintained normal serum lipids, and have no coronary disease. Eleven patients developed hyperlipidemia (one receiving transplant for idiopathic cardiomyopathy, 10 for ischemic cardiomyopathy). Six of these patients developed cytotoxic B-cell antibodies and all six developed severe, diffuse, tubular atherosclerosis and died within 8 to 30 months. The presence of cytotoxic B-cell antibodies combined with hyperlipidemia was a predictor of early myocardial infarction and/or sudden death (<2.5 years; p = .004). Histologically, the disease was characterized by severe atherosclerosis with the presence of lymphocytic and monocytic infiltrates. In the remaining five hyperlipidemic patients who did not develop cytotoxic B-cell antibodies, late graft atherosclerosis developed (>3 years), characterized by more proximal discrete lesions and only one death from myocardial infarction at 6.5 years. We conclude that hypercholesterolemia (increase in total cholesterol/high-density lipoprotein) and the presence of cytotoxic B-cell antibodies results in the development of graft atherosclerosis, early myocardial infarction, and death. Hypercholesterolemia in the absence of cytotoxic B-cell antibodies is a risk factor for the development of late graft atherosclerosis that is more proximal in nature. Circulaton 68 (suppl II), II-94, 1983. AFTER the first year after cardiac transplantation, the incidence of acute cell-mediated allograft rejection significantly declines. Rider et al.' have calculated the rate of decline in acute, cell-mediated rejection to be from one episode per 23 patient days during the first 3 months after cardiac transplantation to an incidence of one episode per 325 patient days during years 2 through 5. Thus, it now appears that the factor limiting long-term survival of the cardiac allograft recipient is the development of chronic rejection, which is manifested by the development of accelerated coronary atherosclerosis with subsequent myocardial infarction.2 In the cardiac transplantation programs at the Medical College of Virginia and Stanford University, the development of clinically significant coronary atherosclerosis has been documented as early as 13 to 15 months after orthotopic cardiac transplantation.34 From the Cardiac Transplantation Program, Medical College of Virginia, Departments of Medicine and Surgery, Richmond. Supported in part by RR00065 to Clinical Research Center, American Heart Association grant 79772, and National Institutes' of Health grant AI-12822. Address for correspondence: Michael L. Hess, M.D., MCV Station, Box 281, Medical College of Virginia, Richmond, VA 23298. 11-94 The pathogenesis of this form of malignant coronary atherosclerosis has not been completely elucidated. In a preliminary report Hess et al.5 identified a subpopulation of cardiac allograft recipients who developed significant hypercholesterolemia, a major risk factor in the development of native coronary atherosclerosis.6 In the field of renal transplantation, Mohanakumar et al.7 I demonstrated circulating anti-B-cell antibodies during chronic allograft rejection. These renal graft eluates containing the anti-B-cell antibody reacted to kidney cell antigens and endothelial cells. What is not known is the role of the chronic immunologically induced coronary endothelial injury possibly related to circulating anti-B-cell antibodies and the potential synergistic effect of hyperlipidemia in this disease process. In order to gain insight into this problem, we have followed 14 long-term survivors of cardiac transplantation for the development of lipid abnormalities, cytotoxic B-cell antibodies, and coronary atherosclerosis and asked the following question: Is the development of either cytotoxic B-cell antibodies or hypercholesterolemia associated with clinically significant coronary atherosclerosis in patients who have had oth-

Intracerebral grafting of neuronal cell suspensions. III. Activity of intrastriatal nigral suspension implants as assessed by measurements of dopamine synthesis and metabolism

Abstract: The activity of intrastriatal grafts of nigral cell suspensions has been monitored biochemically, using radioenzymatic assays of dopamine, its major acidic metabolite, DOPAC, and DOPA accumulation after DOPA-decarboxylase inhibition. Implants of 4-9 microliter of nigral cell suspension restored striatal DA levels by an average of 13-18%, with the highest individual values reaching about 50% of control. DOPAC was restored from about 5% in the lesioned controls to about 20% of normal in the grafted animals. The DOPAC: DA ratios and the DOPA accumulation measures indicated that the grafted DA neurons were spontaneously active and that the transmitter turnover rate was on the average some 50-100% higher than the intact intrinsic nigrostriatal DA neurones. These results thus provide evidence that the intrastriatal nigral suspension grafts are capable of restoring dopaminergic neurotransmission in the previously denervated striatum.

Association of herpesvirus infections with T-lymphocyte-subset alterations, glomerulopathy, and opportunistic infections after renal transplantation.

Abstract: We studied the interrelation among herpes-virus infections, T-lymphocyte subsets, opportunistic infections, and renal histopathology in 28 recipients of renal allografts. All primary or reactivated herpesvirus infections occurring in the first three months after transplantation in recipients of cadaveric grafts accompanied persistent inversions in the ratio of OKT4 (helper/inducer) to OKT8 (cytotoxic/suppressor) lymphocytes. In the less heavily immunosuppressed recipients of organs of living related donors, these inversions were seen only in association with clinically apparent cytomegalovirus infections. Five of seven opportunistic infections occurred in patients with OKT4/OKT8 ratios of less than 1.0. Biopsy specimens from patients with renal dysfunction occurring in association with a low OKT4/OKT8 ratio frequently revealed glomerular damage rather than acute cellular rejection. Monitoring of T-lymphocyte subsets provides early evidence of herpesvirus infections and identifies patients at increased risk for opportunistic infection after renal transplantation.

Frequency and Significance of Acyclovir-Resistant Herpes Simplex Virus Isolated from Marrow Transplant Patients Receiving Multiple Courses of Treatment with Acyclovir

Abstract: The sensitivity to acyclovir of virus isolates from 52 consecutive marrow transplant patients who received acyclovir for herpes simplex virus infections was studied in vitro. The median sensitivity of viruses obtained during first, second, third, and fourth recurrences was similar, and the median duration of virus positivity (three days) was the same for first and second treatment courses. However, acyclovir-resistant virus was recovered from one of 52 patients (1.9%) during the initial treatment course and from two of 22 patients (9.1%) treated for second recurrences. All three strains had reduced thymidine kinase activity. None caused severe infection. Three other patients remained virus-positive during treatment despite the isolation of acyclovir-sensitive virus. Although continuing surveillance is necessary, these data may suggest that acyclovir-resistant virus will not be the cause of significant clinical illness among immunosuppressed patients. In addition, not all instances of "resistance," defined by the persistence of virus during treatment, will be caused by virus strains that are resistant to acyclovir in vitro.

A minor transplantation antigen detected by MHC-restricted cytotoxic T lymphocytes during graft-versus-host disease

Abstract: Transplantation of bone marrow can give rise to graft-versus-host desease when donor T lymphocytes; mismatched with the host for major histocompatability (MHC) antigens, become sensitized and attack host tissues. However, graft-versus-host desease can also arise between donor and host with compatible MHC antigens but mismatched for a minor histocompatability antigen1–3. We report here on the occurrence of severe acute graft-versus-host disease in a male patient with acute myeloid leukaemia who had received bone marrow matched for MHC (HLA) antigens from his sister. Strong cytotoxicity of the post-transplantation (that is, donor) lymphocytes against the patient's pretransplantation lymphocytes was found. Thus, the transplanted lymphocytes differed in a non-HLA antigen from the patient. The possible role of this strong cytotoxic minor histocompatability antigen in the development of graft-versus-host disease in man is being evaluated. Furthermore, with the use of cytotoxic T-cell lines, derived from the patient's 6 day effector cells, we are now able to type for it before grafting.

Primary and reactivated toxoplasma infection in patients with cardiac transplants. Clinical spectrum and problems in diagnosis in a defined population.

Abstract: We have attempted to define the serologic criteria for diagnosis of toxoplasmosis in heart transplant recipients. Of 31 patients who were seronegative before transplantation, 4 received a heart from a seropositive donor, and 3 of these 4 had seroconversion and developed life-threatening toxoplasmosis; the remaining 27 did not have seroconversion or develop clinical toxoplasmosis. Of 19 patients who had antibodies to Toxoplasma before transplantation, 10 developed significant increases in test titers of the dye test or double-sandwich IgM enzyme-linked immunosorbent assay but did not develop a clinical illness that could be attributed to toxoplasma infection. Significant serologic changes occurred more often in patients who received azathioprine, corticosteroids, and antithymocyte globulin than in those who received cyclosporine, corticosteroids, and antithymocyte globulin (p less than 0.05). These data show the wide clinical spectrum and differences in kinetics of antibody response of patients who develop toxoplasma infection after transplantation, and suggest that clinical disease occurs in those who have seroconversion but is rare in patients with preexisting antibody who have serologic evidence of recrudescence.

Factors associated with graft rejection after HLA-identical marrow transplantation for aplastic anaemia.

Abstract: Summary. One hundred and seventy-five consecutive patients with severe aplastic anaemia were given high-dose cyclophosphamide followed by marrow grafts from healthy, HLA-identical family members, and 168 lived long enough to show engraftment. In 38 patients the graft was rejected and 29 of these died. This analysis, using a binary logistic regression model, was aimed at identifying factors that predicted marrow graft rejection. Five factors correlated with graft rejection: (1) previous blood transfusion; (2) a positive relative response in mixed leucocyte culture indicating sensitization of patient against donor; (3) a low number of marrow cells used for transplantation; (4) marrow grafts from male donors; and (5) lack of infusion of viable donor buffy coat cells in addition to the marrow for transfused patients. The findings confirm the importance of transplanting early before transfusion and indicate that the greatest possible amount of donor marrow (supplemented by stem cells/lymphoid cells derived from the peripheral blood) should be obtained.