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Biomedical subjects

R Zimmermann

Publications and source records attributed to R Zimmermann.

At least 307 records · Page 17Linked to original sources
PubMed1993

[Fetal and neonatal alloimmune thrombocytopenia].

Alloimmune thrombocytopenia (AIT) in fetuses and newborn, a disease resembling Rh incompatibility, is caused by transplacental transfer of an IgG-class antibody against fetal platelets. In humans five different platelet antigen systems are so far known which lead to AIT. The disease occurs in 1:2000-1:5000 deliveries. In contrast to Rh disease, immunization occurs in the first pregnancy in the majority of cases. The main significance of AIT lies in the occurrence of fetal (-10%) and neonatal (-20%) intracranial hemorrhage. Newborns are treated with compatible platelets, if necessary in combination with immunoglobulins. The high rate of fetal intracranial hemorrhage justifies therapy during pregnancy as well. Antenatal measures include treatment of the mother with high-dose immunoglobulin, treatment of the fetus with immunoglobulin by cordocentesis, and fetal platelet transfusions. However, all therapeutic measures involving the fetus remain in the experimental stage at present. International cooperative studies are necessary to evaluate cost-benefit of intervention during pregnancy.

Blood Platelets↗
PubMed1993

3',5'-Cyclic nucleotide phosphodiesterase in tumor cells as potential target for tumor growth inhibition.

Isoenzymes of 3',5'-cyclic nucleotide phosphodiesterase (PDE) have been characterized in B16 murine melanoma cells and MCF-7 human mammary carcinoma cells. Separation of soluble phosphodiesterase activity by fast protein liquid chromatography on a Mono-Q column resolved three isoenzymes, MCF-7 cells contained a cyclic GMP-specific isoenzyme (PDE-V), a cyclic GMP-activable isoenzyme (PDE-II), and a cyclic AMP-specific isoenzyme (PDE-IV). B16 cells contained a cyclic GMP-specific isoenzyme (PDE-V), a Ca2+/calmodulin-activated isoenzyme (PDE-I), and a cyclic AMP-specific isoenzyme (PDE-IV). A series of PDE inhibitors was tested for their activity spectrum on PDE isoenzymes. Inhibition of PDE activity in B16 cells by the new compound DC-TA-46, was found to result specifically from PDE-IV inhibition [50% inhibition (IC50) = 0.03 microM]. Much lower inhibitory activity was observed for DC-TA-46 toward PDE-I (IC50 = 5 microM) and PDE-V (IC50 = 14 microM). DC-TA-46 was found to inhibit growth of B16 melanoma and MCF-7 mammary carcinoma cells dose dependently (B16: IC50 = 1.7 microM, MCF-7: IC50 = 2 microM). At 2 microM concentration, growth inhibition of B16 melanoma cells was 60%, concomitant with a decrease in PDE activity of 63% and an increase in cAMP level of 59%. In contrast, incubation with inhibitors specific for PDE-I and PDE-V resulted only in marginal or undetectable growth inhibition. The results suggest a correlation between PDE-IV inhibition and growth inhibition. PDE-IV thus appears to be a potential new target for antiproliferative treatment.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1993

Hsc70, immunoglobulin heavy chain binding protein, and Hsp90 differ in their ability to stimulate transport of precursor proteins into mammalian microsomes.

Ribonucleoparticle-independent transport of precursor proteins into mammalian microsomes is stimulated by 70-kDa heat shock proteins (Hsc70) and an additional cytosolic protein. Here we addressed the question of whether other molecular chaperones can replace Hsc70 in facilitating protein transport into the endoplasmic reticulum. Specifically, we asked if members of the same family of stress proteins, i.e. the microsomal protein immunoglobulin heavy chain binding protein or the bacterial protein DnaK, can substitute for Hsc70. Furthermore, we investigated whether molecular chaperones with a proven role in protein folding and belonging to the other two major families of stress proteins, i.e. Hsp60 or Hsp90, can substitute for Hsc70. We show that none of these stress proteins was able to substitute for Hsc70 in facilitating protein transport into mammalian microsomes. GroEL (the bacterial member of the Hsp60 family) and Hsp90, however, competed with Hsc70 for binding of the non-native precursor protein. Therefore, we conclude that there are both substrate and functional specificity in the action of molecular chaperones.

Animals↗
PubMed1993

The role of molecular chaperones in protein transport into the endoplasmic reticulum.

In eukaryotic cells export of the vast majority of newly synthesized secretory proteins is initiated at the level of the membrane of the endoplasmic reticulum (microsomal membrane). The precursors of secretory proteins are not transported across the microsomal membrane in their native state. Typically, signal peptides in the precursor proteins are involved in preserving the transport-competent state. Furthermore, there are two alternatively acting mechanisms involved in preserving transport competence in the cytosol. The first mechanism involves two ribonucleoparticles (ribosome and signal recognition particle) and their receptors on the microsomal surface and requires the hydrolysis of GTP. The second mechanism does not involve ribonucleoparticles and their receptors but depends on the hydrolysis of ATP and on cis-acting molecular chaperones, such as heat shock cognate protein 70 (hsc 70). In both mechanisms a translocase in the microsomal membrane mediates protein translocation. This translocase includes a signal peptide receptor on the cis-side of the microsomal membrane and a component that also depends on the hydrolysis of ATP. At least in certain cases, an additional nucleoside triphosphate-requiring step is involved which is related to the trans-acting molecular chaperone BiP.

Adenosine Triphosphate↗
PubMed1993

Lack of associations between fetal and maternal serum-erythropoietin at birth.

Erythropoietin (EPO) is known to be the main regulator of erythropoiesis. We wanted to determine whether EPO production during pregnancy takes place independently in the mother and the fetus, and to identify the factors which set the EPO level. Endogenous EPO levels were determined in simultaneous samples from the umbilical vein, the umbilical artery and a maternal vein in 126 mother-child pairs and simultaneously from amniotic fluid (n = 14) in unselected births. Results were related to clinical and biochemical parameters of fetal well-being, mode of delivery, duration of labor, and infant parameters at birth. There was a weak correlation between maternal and fetal log EPO values (umbilical vein: r2 = 0.11; umbilical artery: r2 = 0.08), but a highly significant correlation between log EPO levels in the two umbilical vessels (r2 = 0.91) and between both umbilical blood and amniotic fluid (r2 = 0.41). Maternal EPO levels were lower than fetal levels in 76 cases, higher in 47, and nearly identical in 3. Increased fetal EPO levels were associated with clinical and biochemical indicators of fetal stress. These associations help to explain why EPO concentrations in fetal blood are independent of maternal levels and also indicate that EPO does not cross the placental barrier. These findings are discussed in the light of the animal experimental and in vitro evidence for placental transfer of EPO. Our data, and the work of others, make such a transfer in humans quite unlikely. This observation has therapeutical consequences for the treatment of maternal anemia with recombinant human EPO.

Amniotic Fluid↗
PubMed1993

IgA-anti-Fab autoantibodies and disease progression in AIDS.

There is increasing evidence that autoimmune phenomena contribute to the pathogenesis of the acquired immunodeficiency syndrome (AIDS). We investigated the relationship between IgA autoantibodies directed against the Fab part of the IgG molecule and disease progression in 87 HIV-infected hemophilia patients. AIDS patients demonstrated a significantly higher serum IgA-anti-Fab activity than HIV-positive (HIV+) patients with AIDS-related complex (ARC) (P < 0.02), HIV+ patients without AIDS/ARC (P < 0.0001), HIV negative (HIV-) patients (P = 0.0001), or healthy controls (P < 0.0001). Moreover, an inverse association was observed between serum IgA-anti-Fab activity and CD4+ cell counts (r = -0.396, P < 10(-6)). This close association was confirmed in longitudinal studies of symptomatic patients. IgA-anti-Fab antibodies are suggested to play an important role in the immunopathogenesis of AIDS, and their determination may be helpful in the monitoring of HIV-infected patients.

AIDS-Related Complex↗
PubMed1993

[Early recognition of fetal abnormalities by transvaginal ultrasonography].

Three case reports illustrate situations where transvaginal sonography (TVS) can be important for detecting foetal malformation. In each of these cases a reliable diagnosis was not possible by abdominal ultrasound either because the part of the foetus to be examined lay too low in the pelvis or because it could not be imaged clearly enough due to lack of amniotic fluid. As we would recommend in such cases, diagnosis was then made by TVS. Since the area which can be imaged by TVS is limited mechanically by the anatomical situation, however, it should not be used as the primary method for prenatal screening, whereas in certain selected cases it can provide information not obtainable otherwise.

Abnormalities, Multiple↗
PubMed1993

[Correlation between reduced amniotic fluid volume and Doppler spectra of fetal blood vessels at term].

The aim of this study was to determine, whether foetuses with reduced amniotic fluid in other-wise uncomplicated pregnancies at term show signs of redistribution of blood flow analogous to foetuses with intrauterine growth retardation. In 33 pregnancies > or = 37 gestational weeks with the largest pocket of amniotic fluid < 2 cm, flow velocity waveforms were recorded for the umbilical artery, middle cerebral artery and renal artery and compared with those of foetuses of the same gestational age and normal amniotic fluid volume. No difference was found in the resistance index (umbilical artery and middle cerebral artery), the pulsatility index (renal artery), or for the cerebral-placental ratio between these two collectives. We conclude, that Doppler examination of foetal vessels does not help to clarify the phenomenon of decreasing amniotic fluid volume during the final period of gestation. We suggest, that the decrease is not caused by renovascular changes, but has intra- or extrarenal causes.

Amniotic Fluid↗
PubMed1993

[Syphilis screening in pregnancy].

A review of the effectiveness of antenatal screening for syphilis in the 3 year period 1989 to 1991 was made at the Department of Obstetrics, University of Zurich. In a total of 5640 pregnancies, 30 had a reactive TPHA-result. Using FTA-ABS-test and IgM-tests, 2 were false positive and 27 were considered as seropositive without signs of infection. Only one patient had a serology consistent with a latent syphilis. In Switzerland, every year approx. 9 newborns with positive serology for syphilis are found. Most of them, however, are not infected and the result only reflects the serostatus of the mother. Because of these poor results we doubt the usefulness of an antenatal screening programme for syphilis.

Adult↗
PubMed1993

Defective IL-6 secretion in HIV-infected haemophilia patients.

To study the role of IL-6 in HIV-induced B cell defects, in vitro B cell responses and IL-6 secretion were determined simultaneously in 67 haemophilia patients. Twenty-three patients were HIV- (Group 1), 27 HIV+ stage CDC II, III (Group 2), and 17 were HIV+ stage CDC IV (Group 3). Pokeweed mitogen (PWM) was used for T cell-dependent and Staphylococcus aureus Cowan I (SAC I) for T cell-independent B cell stimulation. B cell differentiation was assessed in a reverse haemolytic plaque assay and by ELISA determination of IgG and IgM in culture supernatants. An ELISA was used to measure IL-6 in plasma and culture supernatants. HIV- patients showed impaired immunoglobulin-secreting cell (ISC) responses after T cell-independent and T cell-dependent stimulation (P < 0.0001 and P < 0.01, respectively), whereas IL-6 secretion, IgM and IgG responses were comparable to those in healthy controls. HIV+ patients at stage CDC II, III or IV demonstrated significantly reduced mitogen-stimulated IL-6 secretion (P < 0.05, PWM; P < or = 0.001, SAC I) as well as impaired ISC and IgG responses (P < 0.01, PWM; P < or = 0.0001, SAC I). CDC IV patients showed reduced IgM responses in addition (P < 0.02, PWM; P < 0.0005, SAC I). Plasma IL-6 levels were elevated both in HIV+ patients (CDC II, III patients: 165 +/- 73 pg/ml, P < 0.005; CDC IV patients: 58 +/- 18 pg/ml, P < 0.0001) and in HIV- patients (283 +/- 65 pg/ml, P < 0.0001) which appeared to be a T cell effect induced by treatment with haemophilia factor concentrates. Our data provide evidence for different types of B cell deficiencies in HIV- patients (impaired ISC response only) and HIV+ patients (impaired ISC as well as IL-6 and IgM/IgG responses). The defective IL-6 secretion in HIV+ patients is likely to affect terminal B cell differentiation and this may explain the reduced immunoglobulin secretion in these patients in response to antigenic challenge.

B-Lymphocytes↗
PubMed1993

Association of T cell and macrophage dysfunction with surface gp 120-immunoglobulin-complement complexes in HIV-infected patients.

The mechanism of CD4+ cell depletion and functional T helper cell inhibition in HIV-infected individuals is poorly understood. The present study demonstrates that immune complex-covered CD4+ cells are associated with T cell inhibition and macrophage stimulation. We studied 30 patients with ARC/AIDS and 35 asymptomatic HIV+ haemophilia patients. Overall, 20 +/- 3% of peripheral CD4+ lymphocytes were covered with gp120 (range 0-94%). gp120+ cells also exhibited surface-bound IgG (P = 0.0001), IgM (P = 0.0001), and complement (P = 0.0001). Decreased in vitro lymphocyte proliferation was associated with the immune complex load of CD4+ cells. The higher the percentage of CD4+ gp 120+ cells in the blood, the lower the T cell response in vitro (P = 0.001). Moreover, an association was found between immune complex-positive cells and plasma neopterin (P = 0.01). Patients with increased plasma neopterin levels had decreased in vitro responses to pokeweed mitogen (PWM) (P = 0.006), phytohaemagglutinin (PHA) (P = 0.004), concanavalin A (Con A) (P = 0.09), and anti-CD3 MoAb (P = 0.03), and decreased CD4+ cell counts in the blood (P = 0.006). Since maximally 1% of CD4+ lymphocytes are infected with HIV, T cell dysfunction and T cell depletion in HIV-infected patients may also be caused by the release of free gp120 that binds to uninfected CD4+ cells. Our data suggest that the functional inhibition and subsequent elimination of uninfected CD4+ lymphocytes with surface gp120-immunoglobulin-complement complexes may be a pathomechanism in the manifestation of AIDS.

Antigen-Antibody Complex↗
PubMed1993

CD4+ lymphocyte depletion in HIV-infected patients is associated with gp120-immunoglobulin-complement attachment to CD4+ cells.

The mechanism of CD4+ lymphocyte depletion, which is the main immunological feature in HIV-infected patients, is unclear. We investigated whether gp120-immunoglobulin-complement complexes on the surface of CD4+ cells might be involved in the elimination of CD4+ lymphocytes. The results obtained in 63 HIV-infected patients show that gp120 is attached to a variable degree to CD4+ cells. Importantly, the percentage of CD4+gp120+ lymphocytes is inversely associated with CD4+ lymphocyte counts in the peripheral blood (p = 0.0004). CD4+gp120+ blood lymphocytes bind IgM (p = 0.0027) and IgG antibodies (p = 0.0001) and complement (p = 0.0005). These results suggest that immune complex-mediated cell elimination is an important mechanism of CD4+ cell depletion in patients with AIDS.

Antigen-Antibody Complex↗
PubMed1993

Troponin T release after heart transplantation.

BACKGROUND: For the diagnosis of myocardial cell damage the measurement of the serum concentrations of myofibrillar antigens has several potential advantages over the assessment of traditional serological markers. These include the expression of myofibrillar antigens as cardiospecific isoforms and their high intracellular concentrations. Recently a sensitive and specific enzyme immunoassay for cardiac troponin T has been developed that shows little cross-reactivity with skeletal isoforms. OBJECTIVE: To characterise myocardial cell damage after orthotopic heart transplantation, concentration of circulating troponin T were measured prospectively in serial blood samples from 19 consecutive patients taken during the first three months after transplantation. RESULTS: Mean (SD) serum concentrations of cardiac troponin T reached a maximum of 3.6 (1.8) micrograms/l at 7.1 (4.2) days after transplantation and remained higher than 0.5 micrograms/l (twice the detection limit of the assay) in all patients for at least 43 days (mean (SD) 59 (20) days). There was considerable variation in cumulative troponin T release (area under the concentration curve) between the patients (ranging from 27 to 150 micrograms x days/l) that was not related to the total ischaemic time before transplantation or to the patient's renal or hepatic function, preoperative cardiac diseases, major histocompatibility complex matching or the number of complications related to rejection. CONCLUSIONS: Because the half life of cardiac troponin T serum is 2 h the current data show that antigen continued to be released from implanted hearts during the first postoperative months in quantities similar to minor Q wave myocardial infarction. Troponin T release after transplantation continued for much longer than after myocardial infarction or other cardiac surgery. Processes other than perioperative ischaemic damage must be responsible for the considerable individual differences in the release of cardiac troponin T.

Female↗