UMLS:C0432222 - FACTA Search

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The functional status of immune cells within human transplanted lungs was analyzed during cytomegalovirus (CMV) pneumonia complicating lung and heart-lung transplantations. The expression of interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) genes is a marker for the activation of macrophages as is that of serine esterase B (SE-B) gene for cytotoxic cells. The levels of expression of these genes by bronchoalveolar lavage (BAL) cells were determined by in situ hybridization. Eight cases of CMV pneumonia were included in this study. BAL cells from either rejection episodes (eight cases) or control transplanted patients experiencing neither infection nor allograft rejection (eight cases) were analyzed in parallel. In the control patients, virtually no cells expressed the IL-1 beta, the IL-6, or the SE-B genes. In contrast, these three genes were all expressed in samples from patients with CMV pneumonia. IL-1 beta gene-expressing cells were abundant in all infected patients (mean +/- SEM: 898 +/- 449 positive cells per 10(4) cells, p less than 0.001, compared with those in control patients). IL-6 gene-expressing cells were less numerous (92 +/- 74 positive cells per 10(4) cells) and present in five of the eight cases of CMV pneumonia. Activated cytotoxic cells were detected in seven of the eight cases of CMV pneumonia (36.5 +/- 19 SE-B gene-expressing cells per 10(4) cells, p less than 0.001). During allograft rejections (eight cases) IL-1 beta gene-expressing cells were present in all but one patient.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of macrophages and cytotoxic cells during cytomegalovirus pneumonia complicating lung transplantations. 131 30

Ganciclovir (DHPG) was used in 32 renal transplant recipients with proven cytomegalovirus (CMV) disease. Mean time of CMV occurrence from grafting was 49 days. CMV disease was recognized on the combination of both clinical signs and histological or virological findings. DHPG treatment, adapted to renal function was given for 14 days and a pharmacokinetic study was performed at days 1, 7 and 14. Twenty nine patients, 10 of whom has severe to moderate disease, were improved by treatment. Three patients died, 2 of them with severe pulmonary and hepatic diseases. Few adverse effects were observed (leucopenia: n = 7, thrombopenia: n = 2, abdominal pain: n = 1). CMV was no longer found in virological samples in 80 percent of the patients. Maximal plasma concentration of DHPG (9.3 +/- 0.3 micrograms/ml, m +/- SEM) was reached at the end of the one hour infusion and decreased according to a biexponential model. The half life of elimination was 3.35 +/- 0.32 hours, the metabolic clearance 128 +/- 7 ml/min and the distribution volume about 50 percent body weight (0.48 +/- 0.02 l/kg). The clearance of DHPG was greater than creatinine clearance, and was linearly correlated with it, suggesting that renal elimination was important, both by glomerular filtration and tubular secretion. These results indicate that DHPG is effective and well tolerated for the treatment of CMV disease in renal transplant recipients. Renal elimination of the drug requires dosage adjustment to renal function.
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PMID:[Treatment of cytomegalovirus infections with ganciclovir in kidney transplant recipients. Clinical and pharmacokinetic study]. 166 77

From January 1987 through July 1989, nine patients (eight male, one female) underwent bridge to transplantation and were managed with a modified immunosuppression regimen based around the monoclonal antibody OKT3. Six patients were bridged with the Jarvik-7 70 cc total artificial heart, four patients with centrifugal ventricular assist devices, and one patient with a Novacor left ventricular assist system. In two patients two devices were used. There was one patient death at 29 days after transplantation because of acute rejection. One other patient had a rejection episode 368 days after transplantation, for an overall rejection incidence of 0.22 episodes/patient. Four infections occurred, and all were viral--three cytomegalovirus and one mumps. Posttransplant complications involving other organ systems were minimal. In follow-up, from 2 to 29 months, six patients are in New York Heart Association functional status class I and one is in class II. Six patients are not taking steroids. The serum cholesterol level in the patients not receiving steroids at 6 and 12 months is 151 +/- 11 and 171 +/- 23 mg/dl (+/- SEM), respectively. Because of these results we have expanded our indications for the modified regimen using OKT3 in patients with preoperative organ system dysfunction, in diabetic patients, in pediatric patients, in female patients, and in posttransplant patients who require mechanical assistance.
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PMID:Induction immunosuppression for patients bridged to transplantation. 211 95

Serum levels of alpha 1 microglobulin (s-alpha 1 m) in 92 recipients of renal transplants were elevated during pretransplant uremia (P less than 0.001), acute rejection (P less than 0.01), and cyclosporin-induced nephrotoxicity (P less than 0.01). In patients with stable renal function, those treated with cyclosporin had higher s-alpha 1 m than those receiving azathioprine: 81 +/- 4 and 64 +/- 3 mg/l (mean +/- SEM), respectively (P less than 0.05). The serum creatinine levels were 127 +/- 5 and 115 +/- 7 mumol/l (mean +/- SEM), respectively (N.S.). Two of the patients with normal serum creatinine had normal s-alpha 1m levels. There were positive linear correlations between s-alpha 1m and serum creatinine levels during stable renal function, rejection, cyclosporin-induced nephrotoxicity, and cytomegalovirus infections (r = 0.7-0.8, P less than 0.01-0.001) and between s-alpha 1m and beta 2 microglobulin (beta 2m) during the same conditions (r = 0.5-0.8, P less than 0.01-0.001). During infections, serum creatinine and beta 2m increased (P less than 0.001), but s-alpha 1m did not. S-alpha 1m values did not distinguish between rejection and cyclosporin-induced nephrotoxicity. It is concluded that s-alpha 1m might be a valuable complement to serum creatinine levels in the evaluation of renal function in renal transplant recipients.
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PMID:Serum levels of alpha-1 microglobulin in recipients of renal allografts. 247 19

To study the effectiveness and nephrotoxic side-effects of cyclosporin A (CsA) in renal transplant recipients, a prospective randomised trial was designed to compare CsA with azathioprine (Aza). Each treatment group consisted of 40 patients; in the CsA group, 18 were randomly selected for conversion to Aza after 3 months. The 1-year graft survival for CsA-treated patients was 87% compared with 66% for the Aza group (P = 0.033). Anti-rejection therapy was administrated to 78% of the patients in the Aza group and 47% of those in the CsA group (P less than 0.01). There was no difference in the incidence of primary non-functioning kidneys, cytomegalovirus infections, hypertension, or degree of proteinuria between the two treatment groups. At 3 months the mean creatinine clearance was 42 +/- 2 ml/min (mean +/- SEM) for the CsA group compared with 56 +/- 4 ml/min for the Aza group (P less than 0.01), whereas the mean creatinine clearances at 6 months for both the converted and the non-converted CsA-treated patients did not differ from that found in the Aza-treated group. At 1 year, the mean creatinine clearance for CsA-treated patients who were converted to Aza was higher than that found for Aza-treated patients (62 +/- 7 vs 50 +/- 6 ml/min; P less than 0.05). Furthermore, the increment in creatinine clearance observed after conversion from CsA to Aza at 3 months showed a linear relationship (r = 0.9061) with the CsA trough levels before discontinuation of the drug. This indicates that CsA treatment induces a dose-dependent, nephrotoxic side-effect which is probably reversible.
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PMID:A prospective randomised comparative study on the influence of cyclosporin and azathioprine on renal allograft survival and function. 311 Jun 62

We treated 73 patients with hematologic malignancies in first complete remission (acute lymphoblastic leukemia = 23 patients; acute non-lymphoblastic leukemia = 25 patients; chronic myelogenous leukemia in first chronic phase = 20 patients, and high grade lymphoma = five patients) with a uniform preparative regimen consisting of fractionated total body irradiation (1,320 cGy) and high dose cyclophosphamide (100 mg/kg), followed by allogeneic bone marrow transplantation. By radiation dosimetry we demonstrated that the calculated doses were delivered accurately and reproducibly. Actuarial survival rates (+/- SEM) in complete remission were as follows: Acute lymphoblastic leukemia = 74 +/- 9%; acute nonlymphoblastic leukemia = 50 +/- 11%; and chronic myelogenous leukemia = 55 +/- 11%. Actuarial relapse rates for these three diagnoses were 19 +/- 9%, 17 +/- 11%, and 0% respectively. Three of the five lymphoma patients are alive in complete remission at 22+, 28+, and 54+ months. Overall probability of survival for the 73 patients was 59 +/- 7%. Interstitial pneumonia, usually associated with cytomegalovirus infection and graft-versus-host disease, and relapse of the underlying malignancy were the major causes of death.
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PMID:Fractionated total body irradiation and high dose cyclophosphamide: a preparative regimen for bone marrow transplantation for patients with hematologic malignancies in first complete remission. 329 91

The cellular composition and T-lymphocyte subpopulations of bronchoalveolar lavage (BAL) fluid from 12 patients with acquired immunodeficiency syndrome (AIDS) and active pneumonitis were examined. Differential cell counts were performed on BAL specimens from each patient and from 25 normal subjects. The BAL and peripheral blood (PB) lymphocytes were isolated from 8 patients and 11 subjects. Leu 4 (mature T), Leu 2 (T suppressor), and Leu 3 (T helper) markers were identified by fluorescein-labeled monoclonal antibody agents and counted in an automated flow cytometer. Infectious pneumonitis caused by Pneumocystis carinii and/or cytomegalovirus and/or Mycobacterium avium-intracellulare was diagnosed in all but 1 patient. All but 2 patients demonstrated lymphocytosis in the BAL fluid; only 3 had greater than 1% neutrophils. The BAL cell differentials were not predictive of the type of pneumonitis. The Leu 3/Leu 2 ratios were (mean +/- SEM): 0.08 +/- 0.03, patients' BAL fluid; 1.55 +/- 0.21, subjects' BAL fluid; 0.18 +/- 0.06, patients' PB; 1.42 +/- 0.12, subjects' PB. The marked decrease in Leu 3/Leu 2 ratios primarily reflected severely diminished proportions of Leu 3 positive cells (3 +/- 1.3% compared with a control value of 35 +/- 4.0%), although the proportion of Leu 2 positive cells tended to be elevated as well (46 +/- 7.9% compared with a control value of 22 +/- 2.2%). Bronchoalveolar lavage specimens from patients with AIDS and these types of pneumonitis may contain increased proportions of lymphocytes. The accumulation of lymphocytes, however, does not reflect homing of helper T-lymphocytes to the site of pulmonary infection.
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PMID:Cellular and T-lymphocyte subpopulation profiles in bronchoalveolar lavage fluid from patients with acquired immunodeficiency syndrome and pneumonitis. 609 55

Two distinct types of tumor necrosis factor receptors (TNF-R) have been identified (TNF-R55 and TNF-R75). Both TNF-R also exist in soluble forms (TNF-sR), resulting from the release of the extracellular domains (TNF-sR55 and TNF-sR75). TNF-sR may play an important role in vivo as they can bind to TNF alpha and prevent ligand binding to the cellular TNF-R, thus acting as naturally occurring inhibitors of TNF alpha. Sera from lung allograft recipients with cytomegalovirus (CMV) pneumonitis (12 patients) were assayed for TNF-sR55 and TNF-sR75. The concentrations were compared with those from either control lung recipients displaying neither rejection nor infection (12 patients), or lung recipients with allograft rejection (12 patients). Serum TNF-sR55 and TNF-sR75 concentrations were measured by enzyme-linked immunologic binding assay. Serum TNF-sR55 and TNF-sR75 concentrations were significantly higher during CMV pneumonitis (mean +/- SEM: 13.7 +/- 4.7 ng/ml, and 11.7 +/- 2.7 ng/ml, respectively) than during allograft rejection (3.7 +/- 0.3 ng/ml, p < 0.001, and 2.6 +/- 0.6 ng/ml, p < 0.001, respectively). They were also higher than in control subjects (3.6 +/- 0.3 ng/ml, p < 0.001, and 1.9 +/- 0.5 ng/ml, p < 0.001, respectively). Serum TNF alpha concentration was low in case of rejection or in control subjects (< 20 pg/ml). Conversely increased levels of TNF alpha were detected in the serum of six out of the 12 patients with CMV pneumonitis (p < 0.03 versus rejection and control subjects). Ganciclovir treatment of CMV pneumonitis led to a dramatic decrease of TNF alpha, TNF-sR55, and TNF-sR75 serum levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Soluble TNF receptors (TNF-sR55 and TNF-sR75) in lung allograft recipients displaying cytomegalovirus pneumonitis. 800 30

Clinical and experimental studies have established the accelerating role of cytomegalovirus (CMV) infection on cardiac allograft arteriosclerosis, ie, chronic rejection. We have investigated the mechanisms behind the interaction between CMV infection and chronic rejection. In the first part of the study, 762 endomyocardial biopsy specimens obtained from 47 heart allograft recipients were analyzed. Of these, 28 patients developed CMV infection during the first postoperative year. In 24 of 28 CMV patients, mononuclear inflammatory cells (endothelialitis) were seen in the subendothelium of small intramyocardial arterioles. In CMV-free recipients, only five of 19 had any subendothelial inflammation in the vascular structures P < 0.0001 when compared with CMV patients). The subendothelial inflammation demonstrated an intensive peak at the onset of CMV infection, subsiding slowly thereafter. Morphologically, the inflammatory cells in the subendothelium were small lymphocytes. Only few activated pyroninophilic lymphocytes were seen. Immunohistochemistry revealed that the lymphocytes were mostly T cells (UCHL1+). In the second part of the study, we investigated if a similar endothelialitis could be induced experimentally in allografted rats. We performed rat aortic allografts from the DA (AG-B4, RT1a) donors to the WF (AG-B2, RT1v) recipients and infected the recipients with 10(5) plaque-forming units of rat CMV Maastricht strain 1 day after transplantation. In rat CMV-infected aortic allografts, the frequency of subendothelial leukocyte common antigen (LCA, OX1) positive leukocytes, 1.7 +/- 0.1 (SEM) point score units, was significantly higher when compared to noninfected allografts, 0.8 +/- 0.1 point score units (P < 0.05), and they were most prominent in the intimal space during and following acute infection. During subsequent weeks, the LCA-positive leukocytes were replaced by alpha-actin-positive smooth muscle cells. Instead, most of the cells in intima of CMV-free grafted rats stained positively to alpha-actin from the beginning and were smooth muscle cells. Practically no leukocytes were seen. In rat CMV-infected aortic allografts most subendothelial inflammatory cells represented T cells (W3/25+) and cells of the monocyte/macrophage lineage (OX42+). In conclusion, acute CMV infection is associated with an subendothelial inflammation (endothelialitis) of allograft vascular structures both in human and in rat. Nonactivated T lymphocytes and monocytes predominate the inflammatory lesion in the subendothelium. The results suggest that the virus-linked vascular wall inflammation may play a role in the immune injury toward allograft vascular structures, particularly to endothelium, and thus contribute to allograft arteriosclerosis.
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PMID:Acute cytomegalovirus infection induces a subendothelial inflammation (endothelialitis) in the allograft vascular wall. A possible linkage with enhanced allograft arteriosclerosis. 829 11

There is no consensus regarding the optimal induction immunosuppression regimen after lung transplantation (LT). In addition to the potential benefit of a reduced incidence of early acute allograft rejection, cytolytic induction immunosuppression may impact on long-term allograft function. We retrospectively assessed our incidence of obliterative bronchiolitis syndrome (OBS) stages Ia and IIa in LT survivors given two different cytolytic induction immunosuppression regimens: (between March 1989 and October 1990) OKT3 (5 mg/d)x10 to 14 days (n=11) vs (between November 1990 and April 1993) Minnesota antilymphocyte globulin (MALG) (10 to 15 mg/kgdx5 to 7 days. Cyclosporine (CSA) (whole blood polyclonal assay=600 to 800 ng/mL), azathioprine (1 to 2 mg/kg/d), and maintenance prednisone (0.2 mg/kg/d) were similar. Surveillance spirometry was performed monthly, in accordance with accepted American Thoracic Society criteria. Fiberoptic bronchoscopy with transbronchial biopsies (TBBs) were performed for clinical indications. Surveillance TBBs were not performed during the era of this study. As defined by the ISHLT "Working Formulation for the Standardization of Nomenclature and for Clinical Staging of Chronic Dysfunction in Lung Allografts," latencies to development of OBS stages Ia and IIa were determined by Kaplan-Meir analysis. Stepwise regression (Cox proportional hazards model) was performed for the variables: cytolytic induction regimen, episodes cytomegalovirus (CMV) pneumonitis, episodes CMV infection, serologic CMV donor (+): recipient (-) mismatch, prior pregnancy, HLA (A,B,DR +/- DQ) mismatches, episodes greater than grade A1 acute cellular rejection (ACR). We found that the OKT3 cohort experienced longer latencies for OBS stages Ia and IIa. Latencies to OBS stages Ia for OKT3 ve MALG were 962 +/- 65 vs 354 +/- 85 days (X +/- SEM) respectively. Brookmeyer-Crowley 95% confidence intervals for median latencies were 744 to 1,180 vs 266 to 510 days for OKT3 vs MALG, respectively. The Cox model was significant only for the variable of the induction cytolytic immunosuppression regimen (p=0.0015). By physiologic criteria, a longer course of OKT3 appeared superior to the short-course MALG protocol in delaying chronic lung allograft dysfunction. These effects may be related either to inherent differences in the antilymphocyte preparations or, alternatively, the difference in duration of treatment between groups. Surveillance TBB and treatment of detected occult ACR may serve to negate the observed differences in latencies for OBS.
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PMID:Delayed development of obliterative bronchiolitis syndrome with OKT3 after unilateral lung transplantation. A plea for multicenter immunosuppressive trials. 863 56

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