Induction therapy with an immunomodulatory CD2 antibody does not inhibit allograft vasculopathy after rat heart transplantation.
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Animals↗
Biomedical subjects
R Zimmermann
Publications and source records attributed to R Zimmermann.
Association of viral load in plasma samples of HIV-infected hemophilia patients with autoantibodies and gp120-containing immune complexes on CD4+ lymphocytes.
OBJECTIVE: We investigated whether the induction of antilymphocyte autoantibodies and immune complexes is associated with the activity of HIV replication. METHODS: Viral HIV-1 RNA was measured in the plasma samples of 84 HIV+ hemophilia patients and correlated with the IgM, IgG, IgM/IgG and IgM/IgG/gp120 load of circulating CD4+ lymphocytes, CD4+ and CD8+ cell counts, plasma neopterin levels and in vitro T-cell responses to mitogens and pooled allogeneic stimulator cells. RESULTS: Compared to patients with no immune complexes, on circulating CD4+ lymphocytes, viral load was increased in patients with IgM, IgM/IgG or IgM/IgG/gp120 complexes. Sequential analysis of HIV+ patients showed that peaks of retroviral activity were associated with the subsequent formation of CD4+ lymphocyte-reactive IgM and IgG autoantibodies and gp120-containing immune complexes. CONCLUSION: The induction of autoantibodies and immune complexes attached to CD4+ lymphocytes is associated with periods of increased viral activity in HIV-infected patients.
Antigen-Antibody Complex↗
The interosseous membrane and its influence on the distal radioulnar joint. An anatomical investigation of the distal tract.
From the interosseous membrane of the forearm a tract extends to the dorsal capsule of the distal radioulnar joint. The structure and function of this tract have been investigated. The tract originates from the radius 22 mm proximal to the distal dorsal corner of the sigmoid notch. Central fibres are attached there with fibrous cartilage and superficial bundles mix with the periosteum. The tract is 8 mm wide, 31 mm long and 1 mm thick. Distally it inserts at the capsule of the distal radioulnar joint between the tendon sheaths of extensor digiti minimi and extensor carpi ulnaris. Deep fibres insert directly at the triangular fibrocartilage. The tract of the interosseous membrane is taut in pronation and loose in supination. It strengthens the dorsal capsule of the distal radioulnar joint. During pronation the tract protects the ulnar head in a sling. Its attachment at the triangular fibrocartilage influences the distal radioulnar joint. Its insertion at the triangular fibrocartilage and the support of the weakest part of the dorsal capsule are of interest.
Aged↗
Elevated serum concentrations of cardiac troponin T in acute allograft rejection after human heart transplantation.
OBJECTIVES: This study evaluates the concept and diagnostic efficacy of using serum troponin T for the detection of cardiac graft rejection. BACKGROUND: Cardiac troponin T is a cardiospecific myofibrillar protein, which is only detectable in the circulation after cardiac myocyte damage. It might be expected to be released during acute heart allograft rejection, allowing noninvasive rejection diagnosis. METHODS: In 35 control subjects and in 422 samples from 95 clinically unremarkable heart allograft recipients more than 3 months postoperatively, troponin T serum concentrations were compared to the histological grade of acute graft rejection in concurrent endomyocardial biopsies. RESULTS: Mean troponin T serum concentrations were identical in control subjects (23.2 +/- 1.4 ng/liter) and in heart transplant recipients without graft rejection (International Society for Heart and Lung Transplantation [ISHLT] grade 0; 22.4 +/- 1.7 ng/liter). Mean troponin T concentrations increased in parallel with the severity of graft rejection (ISHLT grade 1: 27.8 +/- 1.8 ng/liter; grade 2: 33.2 +/- 2.7 ng/liter; grade 3A: 54.6 +/- 6.5 ng/liter; grade 3B and 4: 105.4 +/- 53.7 ng/liter; p < 0.001 for grades 3 and 4 vs. grades 0 and 1). The proportion of positive samples also increased in parallel with rejection severity, reaching 100% in rejections of grade 3B and 4. Sensitivity and specificity for the detection of significant graft rejection (ISHLT grade 3/4) were 80.4% and 61.8%, respectively. The negative predictive value was most remarkable with 96.2%. Intraindividual longitudinal analysis of troponin T levels and biopsy results in 15 patients during long-term follow-up confirmed these findings. CONCLUSIONS: The present data demonstrate that acute allograft rejection after human heart transplantation is often associated with increased serum concentrations of troponin T. All cases of serious forms of graft rejection would have been detected before the development of clinical symptoms. Measurement of troponin T levels may become a useful ancillary parameter for noninvasive rejection diagnosis, being most valuable in the exclusion of severe cardiac graft rejection.
Acute Disease↗
HIV-induced IL-6/IL-10 dysregulation of CD4 cells is associated with defective B cell help and autoantibody formation against CD4 cells.
To analyse CD4 cell cytokine secretion and helper/suppressor function at a clonal level we established 446 CD4+ T cell clones (TCC) in four healthy controls, three HIV- haemophilia patients, four CDC II,III and four CDC IV patients. Spontaneous TCC secretion of Th1 cytokines (IL-2, interferon-gamma (IFN-gamma)) and Th2 cytokines (IL-4, IL-6, IL-10) was determined by ELISA. TCC helper and suppressor functions were tested in a pokeweed mitogen (PWM)-stimulated allogeneic co-culture system using a reverse haemolytic plaque assay for assessment of B cell responses. There was a significant association of TCC surface marker expression (Leu-8, CD45RA) with TCC IL-6 secretion in healthy controls (P < 0.01), HIV- patients (P < or = 0.001) and CDC II,III patients (P < or = 0.01) but not in CDC IV patients. Likewise, TCC expression of Leu-8 and CD45RA was significantly associated with TCC suppressor function in healthy controls (P < or = 0.0005) but not in HIV-infected patients. A reduced TCC helper frequency (< or = 10% of TCC) and an enhanced TCC suppressor frequency (> 80% of TCC) were detected only in those HIV-infected patients who showed an excessively increased TCC IL-6 secretion (> 70% of TCC) together with a significantly diminished TCC IL-10 secretion (< or = 10% of TCC). CD4 cell autoantibodies also were found only in patients with this type of cytokine dysregulation. These data indicate that CD4 cell surface markers lose their functional relevance in HIV-infected patients. HIV-induced IL-6/IL-10 dysregulation of CD4+ T cells, i.e. the up-regulation of spontaneous IL-6 and down-regulation of spontaneous IL-10 secretion, appears to be involved in inducing CD4 helper defects and may promote autoantibody formation against CD4 cells.
Autoantibodies↗
A survey of blood utilization in children and adolescents in a German university hospital.
There are no detailed data on blood use with regard to diagnoses of recipients during infancy, childhood and adolescence. Available information on this issue is incomplete and no longer current. We conducted a survey of blood component use in children and adolescents in an acute-care university hospital in the greater area of Nuremberg between June 1994 and September 1996. Packed red blood cells (RBCs), fresh-frozen plasmas (FFPs) and platelet (PLT) components were evaluated for the recipients discharge diagnoses. Source study files were extracted from the hospital transfusion service and the medical records department. Transfused units were listed by broad diagnostic categories and leading diagnostic groups formed from principal diagnoses of the recipients according to the International Classification of Diseases, 9th edn (ICD-9). 34.3% of 2869 RBC cell units, 35.0% of 1095 FFP units and 5.0% of 1028 PLT components were used in patients with congenital diseases, mainly cardiac defects. The disease category neoplastic diseases was next most frequently associated with blood transfusion diagnosed in recipients of 23.9% of all RBCs, 15.6% of all FFP units and in 66.4% of all PLT units. Malignant diseases and benign haematological diseases (diagnostic categories II and IV) accounted for 68.9% of all costs of blood component transfusion. These findings demonstrate the increased importance of platelet transfusion for the organization of local and regional blood donation programmes and for cost analysis exercises. The study shows that detailed information on local blood use may be obtained quickly using available data collections of transfusion services and medical record departments.
Adolescent↗
Effects of nitric oxide synthesis on reperfusion injury and catecholamine responsiveness in a heterotopic rat heart-transplantation model.
Global myocardial ischemia and reperfusion injury play a major role in early postoperative graft dysfunction. In this study, the influence of nitric oxide (NO) on reperfusion injury and catecholamine sensitivity after ischemia was investigated in a heterotopic rat heart-transplantation model. After a 1-h ischemic preservation, reperfusion was started either after application of saline vehicle (control, n = 8) or nitro-L-arginine methyl ester (L-NAME; 10 mg/kg, n = 8) for inhibition of NO synthesis or NO-precursor L-arginine (L-Arg; 40 mg/kg, n = 8), or L-NAME plus L-Arg (n = 8), respectively. After 60 min of reperfusion, continuous dobutamine infusion (5 microg/kg/min) was started. Myocardial blood flow was assessed by the hydrogen-clearance method. An intraventricular balloon was used to measure pressure-volume relations: peak left ventricular pressure, the rate of pressure development (dP/dt), end-diastolic pressure, and isovolumic relaxation constant. Myocardial blood flow was significantly reduced after L-NAME and increased after L-Arg in comparison with control (p < 0.05). The L-NAME group showed decreased systolic and diastolic functional recovery in comparison with control. Simultaneous infusion of L-Arg and L-NAME reversed these effects. L-Arg alone led to a further improvement of cardiac functional recovery. Whereas myocardial blood flow remained unchanged in the L-NAME group with dobutamine infusion, it significantly increased in the control group (p < 0.05). L-Arg antagonized this effect of L-NAME. Dobutamine increased peak left ventricular pressure and dP/dt and shortened the isovolumic relaxation constant in all groups; however, the changes of systolic hemodynamic indices were significantly smaller in the L-NAME group (p < 0.05) and significantly higher in the L-Arg group (p < 0.05). These results indicate that (a) NO production within the graft during reperfusion has a significant beneficial effect on graft function, and (b) NO formation may play an important role in beta-adrenergic responses after heart transplantation.
Adrenergic beta-Agonists↗
Routine ultrasound has not been shown to be more accurate than the calendar method.
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Female↗
Cofactor-induced modulation of the functional specificity of the molecular chaperone Hsc70.
Molecular chaperones differ in their ability to stabilize nonnative polypeptides and to mediate protein folding, defining 'holding' and 'folding' systems. Here we show that the mammalian cytosolic and nuclear chaperone Hsc70 can act as both, as a 'holding' and a 'folding' system, depending on the chaperone cofactors which associate with Hsc70. In conjunction with the cofactor Hsp40, Hsc70 stabilizes heat-denatured firefly luciferase. The stabilizing activity turns into a folding activity in the additional presence of the Hsc70-interacting protein Hip. In contrast, the cofactor BAG-1 abrogates the 'holding' function of the Hsc70/Hsp40 system and blocks the action of Hip on Hsc70. Our study sheds light on the molecular mechanisms that determine the functional specificity of Hsc70 in the mammalian cell.
Adenosine Triphosphatases↗
Bacterial contamination of autologous bone marrow: reinfusion of culture-positive grafts does not result in clinical sequelae during the posttransplantation course.
OBJECTIVES: Microbiological cultures and posttransplantation course were analyzed in order to investigate the incidence and clinical significance of bacterial contamination of autologous bone marrow (BM) grafts. METHODS: Cultures were obtained from BM after collection, BM concentrate after processing, contaminated/cryopreserved BM at thawing, and from peripheral blood (PB) following autologous BM transplantation (ABMT). The posttransplantation course of patients grafted with culture-positive BM was recorded and compared with patients who underwent ABMT with noncontaminated BM grafts. RESULTS: In 239 BM grafts processed, the incidence of microbiological contamination was 26.4% (n = 63). Fifty marrow grafts were contaminated by bacteria from the skin flora: coagulase-negative Staphylococcus (CNSC), Propionibacterium, and Corynebacterium species (79%). Thirty-eight patients underwent ABMT (day 0) with cryopreserved culture-positive BM, and 32 patients were evaluable for microbiological cultures at thawing: in 10 of 32 BM grafts CNSC was found prior to reinfusion. Following ABMT, PB cultures revealed CNSC in 5 of 38 patients between days +4 and +12. However, the late occurrence of positive PB cultures after BM reinfusion made a relationship between BM CNSC and PB CNSC unlikely. In 33 of 38 patients, no graft-contaminating bacteria were detected in PB. Comparison of the posttransplantation course of patients who received contaminated BM with that of patients grafted with noncontaminated BM showed no significant differences concerning time to engraftment, febrile days, and days on antibiotics. CONCLUSION: (1) Collection and/or ex vivo processing can result in microbiological contamination of BM grafts predominantly with bacteria from the skin flora, and (2) only CNSC can be cultured at thawing from previously contaminated/cryopreserved BM. Since patients undergoing ABMT usually receive oral antibiotics from beginning of the conditioning regimen which are active against CNSC, no further administration of antibiotics is recommended for the reinfusion of bacterially contaminated BM grafts.
Adolescent↗
The role of molecular chaperones in protein transport into the mammalian endoplasmic reticulum.
Molecular chaperones belonging to the Hsp70 protein family play various roles in posttranslational protein transport into the yeast endoplasmic reticulum (ER): (i) Cytosolic Hsp70 (Hsc70) together with the J-domain containing Hsp40 preserves the transport competent state of presecretory proteins; (ii) ER-lumenal Hsp70 (Kar2p or Lhs1p) triggers the initial insertion of precursor proteins into the core of the protein translocase in the ER-membrane and cooperates with a J-domain containing membrane protein (Sec63p); (iii) the ER-lumenal Hsp70 and its membrane receptor also are involved in completion of translocation. Here a working model is presented for the putative roles of molecular chaperones in post- as well as cotranslational protein transport into the mammalian ER.
Animals↗
Evaluation of a platelet apheresis technique for the preparation of leukocyte-reduced platelet concentrates.
OBJECTIVES: Reduction of the white blood cell (WBC) contamination in platelet concentrates (PC) protects patients from the immunological and infectious side effects of platelet transfusion caused by WBC. This can be done either by filtration of the PC or by improved apheresis techniques that yield WBC-poor preparations. METHODS: To evaluate an improved technique for platelet collection, we carried out 201 separations in 89 healthy cytapheresis donors using the new COBE Spectra leukoreduction system (LRS) and compared the results with those of standard dual-needle separations obtained with the same cell separator. RESULTS: A small but statistically significant difference was found in platelet collection efficiency in comparison with the standard non-LRS software procedures (LRS: 52.6 vs. 56.3% for the reference). However, median WBC contamination was only 0.01 x 10(6) WBC per LRS product. This significant (p < 0.0005) improvement corresponds to a 10-fold reduction of WBC as compared with the standard dual-needle technique. CONCLUSIONS: The COBE Spectra LRS system produced PCs with a platelet collection efficiency nearly equal to previous techniques and with a residual WBC content satisfying even the most stringent criteria for WBC-depleted blood components. As this purity is achieved without important platelet loss, conventional fiber filtration no longer seems necessary in this kind of PC.
Centrifugation↗
Adjuvant treatment with ursodeoxycholic acid may reduce the incidence of acute cardiac allograft rejection.
BACKGROUND: The nontoxic bile acid, ursodeoxycholic acid (UDCA), is an effective drug for the treatment of different cholestatic conditions. Furthermore, an immunomodulatory capacity of UDCA has been reported in vitro, as well as in vivo, in different immune-mediated liver diseases and after liver transplantation. METHODS: In this retrospective study, the influence of UDCA on heart transplant rejection was investigated in 21 cardiac allograft recipients receiving UDCA for cyclosporine-induced cholestasis (500 mg administered twice daily, start of therapy within the first postoperative month, duration >8 weeks). Thirty-one patients not receiving UDCA served as control subjects. All patients received triple-maintenance immunosuppression (cyclosporine, azathioprine, prednisolone). For quantitative comparison of rejection severity, the following score was applied: 0, no specific therapy; 1, temporary increase in oral steroids; 2, intravenous steroids; 3, ATG or OKT3 therapy. RESULTS: During the first 6 postoperative months, the number of acute rejection episodes requiring specific anti-rejection therapy was significantly lower in the UDCA group as compared with control subjects (1.38 +/- 1.36 vs 2.74 +/- 1.83 rejection episodes per patient, p = 0.005). The cumulative score was significantly lower in the UDCA group as compared with control subjects (2.38 +/- 2.29 vs 5.06 +/- 3.61, p = 0.004). CONCLUSIONS: These initial data indicate a beneficial effect of adjuvant UDCA treatment in the early phase after heart transplantation probably related to immunomodulating properties of UDCA, which may be used therapeutically after organ transplantation.
Acute Disease↗
The extracellular matrix in hibernating myocardium--a significant factor causing structural defects and cardiac dysfunction.
Recently, we described chronic intracellular degeneration accompanied by fibrosis as typical structural features of hibernating myocardium and we concluded that cellular degeneration as a sign of the incomplete adaptation to the reduced blood flow is characteristic of hibernation. This study has been extended by analyzing the composition of the extracellular matrix proteins of the diseased myocardium. Areas of hibernating myocardium were identified in 38 patients by angiography, multigated radionuclide ventriculography, thallium scintigraphy with reinjection and low-dose dobutamine echocardiography. These areas were biopsied at cardiac surgery and were studied by electron microscopic and immunofluorescence techniques. Electron microscopy showed an enlarged extracellular space containing numerous particles of cellular debris, macrophages, fibroblasts, homogeneous matrix material and collagen fibrils. The basement membrane of the cardiomyocytes was thickened by an augmentation of laminin, fibronectin and collagen VI, but these proteins also were present in the matrix itself. Collagen fibrils were numerous and macrophages (CD68) and fibroblasts (vimentin) were increased. In situ hybridization showed an increase in mRNA for laminin, fibronectin and collagen. This observation is consistent with the conclusion that fibrotic scar formation was occurring continuously. It is postulated that fibrosis is the consequence of myocyte loss due to chronic underperfusion in the hibernating tissue. This will further injure myocytes so that a vicious cycle is established that leads to progressive loss of structural integrity and functional capacity. Since these changes are progressive, revascularization should be performed at the earliest time point possible in patients with areas of hibernating myocardium.
Aged↗
Modulation of the CD2 receptor and not disruption of the CD2/CD48 interaction is the principal action of CD2-mediated immunosuppression in the rat.
CD48, the murine homolog of human CD58, binds to CD2 in rats and mice. Whereas inhibition of CD2 signaling leads to profound immunosuppression, no information is available on CD48-targeted therapy in the rat. We could show that anti-CD2 treatment (OX34) efficiently inhibited TCR-driven as well as CD2-mediated proliferation, whereas blocking of ligand binding (OX45) remained completely uneffective. Inhibition of allogeneic MLR by OX45 turned out to be due to induction of unspecific suppressive mechanisms. In vivo, OX45 failed to prolong rat heart allograft survival in contrast to that seen with OX34. Grafts were rejected despite persistent and complete downmodulation of CD48 on lymphocytes without any cell depleting effect, rendering receptor/ligand interactions physically impossible. Combined application of CD2 and CD48 mAb did not enhance immunosuppression induced by CD2 mAb alone. Provided that there is no alternative CD2 ligand in the rat, we conclude that CD2-directed immunotherapy is mediated by suppressive events induced by modulation of the CD2 receptor ("negative signaling") rather than by mere disruption of the CD2-CD48 interaction.
Animals↗
Hibernating myocardium: an incomplete adaptation to ischemia.
BACKGROUND: We tested the hypothesis that hibernating myocardium represents an incomplete adaptation to a reduced myocardial oxygen supply. METHODS AND RESULTS: In 38 patients, areas of hibernating myocardium were identified by angiography, multigated radionuclide ventriculography, thallium scintigraphy with reinjection, and low-dose dobutamine echocardiography. Biopsies removed at cardiac surgery showed structural degeneration characterized by a reduced protein and mRNA expression and disorganization of the contractile and cytoskeletal proteins myosin, actin, desmin, titin, alpha-actinin, and vinculin by electron microscopy, immunohistochemistry, and in situ hybridization. Additionally, an increased amount of extracellular matrix proteins resulting in a significant degree of reparative fibrosis was present. Dedifferentiation, ie, expression of fetal proteins, was absent. Apoptosis indicating suicidal cell death was found by the terminal deoxynucleotidyl transferase end-labeling method and electron microscopy. Radionuclide ventriculography showed improvement of regional function at 3 months postoperatively compared with preoperative values (mean values, 23.5% and 48%, respectively), and the echocardiographic wall-motion score index decreased from 3.4 to 1.8. The degree of severity of the morphological changes (three stages) correlated well with the extent of postoperative functional recovery: more advanced clinical improvement was observed in patients with slight and moderate morphological degeneration (stages 1 and 2), but recovery was only partial in severe degeneration (stage 3). CONCLUSIONS: Cellular degeneration rather than adaptation is present in hibernating myocardium. The consequence is progressive diminution of the chance for complete structural and functional recovery after restoration of blood flow. The practical consequence from this study should be early revascularization in patients showing areas of hibernating myocardium.
Adaptation, Physiological↗
Attenuated progression of coronary artery disease after 6 years of multifactorial risk intervention: role of physical exercise.
BACKGROUND: It was the aim of this study to assess the long-term effects of physical exercise and low-fat diet on the progression of coronary artery disease. At the beginning of the study, 113 male patients with coronary artery disease were randomized to an intervention group (n=56) or a control group (n=57); 90 patients (80%) could be reevaluated after 6 years. METHODS AND RESULTS: Patients in the intervention group (n=40) showed a reduction in total serum cholesterol (6.03+/-1.03 versus 5.67+/-1.01 mmol/L; P<.03) and triglyceride levels (1.94+/-0.8 versus 1.6+/-0.89 mmol/L; P<.005) and maintained their initial body mass index (26+/-2 versus 27+/-2 kg/m2; P=NS), but results were not statistically different from the control group (n=50) (total serum cholesterol, 6.05+/-1.02 versus 5.79+/-0.88 mmol/L; triglycerides, 2.25+/-1.28 versus 1.85+/-0.96 mmol/L [both P=NS]; body mass index, 26+/-2 versus 28+/-3 kg/m2 [P<.0001]). In the intervention group, there was a significant 28% increase in physical work capacity (166+/-59 versus 212+/-89 W; P<.001), whereas values remained essentially unchanged in the control group (165+/-51 versus 170+/-60 W; P=NS; between groups, P<.05). In the intervention group, coronary stenoses progressed at a significantly slower rate than in the control group (P<.0001). Energy expenditure during exercise was assessed in a subgroup; patients with regression of coronary stenoses spent an average of 1784+/-384 kcal/wk (approximately 4 hours of moderate aerobic exercise per week). Multivariate regression analysis identified only physical work capacity as independently contributing to angiographic changes. CONCLUSIONS: After 6 years of multifactorial risk intervention, there is significant and persistent improvement in lipoprotein levels and physical work capacity, which results in a significant retardation of disease progression. These beneficial effects appear to be largely due to chronic physical exercise.
Adult↗
New families with von Willebrand disease type 2M (Vicenza).
The variant von Willebrand disease (vWd) variant type 2M (Vicenza) was identified in 13 patients of 7 unrelated families. 11 patients were from different parts of germany and 2 patients from Turkey. Hitherto this variant of vWd has been described only in two families originating from the province of Vicenza in Northern Italy. Characteristically this type of vWd shows the supranormal multimers of von Willebrand factor (vWf) in plasma similar to those seen in normal plasma after desmopressin infusion. Clinically, the patients present with bleeding symptoms. Other laboratory abnormalities include reduced values for vWf antigen (vWf: Ag), factor VIII coagulant activity (VII:C), ristocetin cofactor activity (RiCof) and collagen binding activity (vWf: CBA). The hereditary transmission of this variant is consistent with an autosomal dominant mode of inheritance. The patients with vWd type 2M (Vicenza) could be allocated into two subgroups: type "platelet normal" with normal vWf properties in platelets and type "platelet low" with reduced vWf: Ag levels in platelets.
Adult↗