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Biomedical subjects

M Kaufmann

Publications and source records attributed to M Kaufmann.

At least 163 records · Page 9Linked to original sources
PubMed1997

Steroids, fatty acyl-CoA, and sterols are substrates of 80-kDa multifunctional protein.

The 2.9-kb mRNA of 17 beta-hydroxysteroid dehydrogenase IV codes for an 80-kDa (737 amino acids) protein featuring domains that are not present in the other human 17 beta-hydroxysteroid dehydrogenases. The N-terminal part reveals conserved motifs of the short-chain alcohol dehydrogenase family. The central- and C-terminal domains are similar to peroxisomal enzymes for beta-oxidation of fatty acids and to sterol carrier protein 2. The 80-kDa protein is N-terminally cleaved to a 32-kDa fragment (amino acids 1-323). Both the 80-kDa and the N-terminal 32-kDa peptides are able to catalyze the dehydrogenation with steroids at the C17 position and with 3-hydroxyacyl-CoA. The central part of the 80-kDa protein (amino acids 324-596) catalyzes the 2-enoyl-acyl-CoA hydratase reaction with high efficiency. The C-terminal part of the 80-kDa protein (amino acids 597-737) facilitates the transfer of 7-dehydrocholesterol and phosphaidylcholine between membranes in vitro. The unique multidomain structure of the 80-kDa protein permits the catalysis of several reactions previously thought to be performed by complexes of different enzymes.

17-Hydroxysteroid Dehydrogenases↗
PubMed1997

Gemcitabine in ovarian cancer: an overview of safety and efficacy.

The outlook for patients with advanced ovarian cancer is still poor. Less than 30% survive for 5 years. The current standard chemotherapy is cisplatin-based combination treatment which gives response rates up to 70%. However, for patients who are resistant to cisplatin, new drugs are required. Response rates are generally low. Even with paclitaxel, remissions have been documented only in 16-30% of patients and with considerable toxicity. A number of studies using gemcitabine as a single agent in cisplatin-resistant patients have been completed or initiated and response rates of around 20% have been recorded. As gemcitabine is well tolerated, studies using gemcitabine combined with paclitaxel and cisplatin in ovarian cancer are ongoing or planned.

Adult↗
PubMed1997

Tandem high-dose therapy with ifosfamide, epirubicin, carboplatin and peripheral blood stem cell support is an effective adjuvant treatment for high-risk primary breast cancer.

We evaluated the therapeutic efficacy and toxicity of a tandem high-dose therapy with peripheral blood stem cell (PBSC) support in 40 patients with high-risk, primary breast cancer (stage II-III) and involvement of ten or more positive axillary lymph nodes. Their median age was 44 years (range 23-56). Two cycles of cytotoxic chemotherapy with ifosfamide (10000 mg/m2) and epirubicin (100 mg/m2) were administered. Granulocyte colony-stimulating factor (G-CSF) was given to hasten neutrophil reconstitution and to mobilise PBSC during marrow recovery. Leukaphereses were performed following the first and/or second cycle. Tandem high-dose therapy consisted of two cycles with ifosfamide (15 or 12 g/m2) and epirubicin (150 mg/m2), while carboplatin (900 mg/m2) was added for the last 24 patients included. Using an immunocytochemical method, two of 11 patients had cytokeratin-positive tumour cells in three leukapheresis products that were collected following the first G-CSF-supported cycle with ifosfamide and epirubicin, whereas only two harvests obtained following the second cycle in 26 patients contained cytokeratin-positive tumour cells. The number of CD34+ cells/kg re-infused following both high-dose cycles was similar (4.20 +/- 0.29 x 10(6), first cycle and 5.25 +/- 0.63 x 10(6), second cycle), and no notable difference was noted in the speed of haematological reconstitution. An absolute neutrophil count (ANC) of 0.5 x 10(9)/1 was reached after a median time of 13 days, while an unsupported platelet count of 20.0 x 10(9)/1 was achieved after a median time of 8 (first cycle) and 9 (second cycle) days post-transplantation. Patients autografted with more than 7.5 x 10(6) CD34+ cells/kg had platelet counts above 20 x 10(9)/1 within less than 10 days. 6 patients relapsed between 7 and 11 months (median 8 months) post-transplantation. 37 patients are alive and in remission with a median follow-up time of 11 months (range 1-38). This translates into a probability of disease-free survival (DFS) of 77% (95% CI 32-95%) at 38 months. The probability of overall survival is 85%, since 3 patients with local relapse achieved a second complete remission following surgery and involved-field radiotherapy. In conclusion, a sequential high-dose therapy including ifosfamide, epirubicin, carboplatin and PBSC support is well tolerated and effective in patients with high-risk primary breast cancer. Involved-field irradiation should be performed post-transplantation to reduce the risk of local relapse.

Adult↗
PubMed1997

The anaesthesia critical incident reporting system: an experience based database.

To date there have been fewer than a dozen studies on the nature of, and contributory factors in, critical incidents (CI) in anaesthesia. The first of these, by Cooper and colleagues, showed that the vast majority of their CI involved human error [1]. Most recently, the on-going Australian Incident Monitoring Study (AIMS), with now more than 2000 reports, has shows that aspects of 'system failure' may constitute the bulk of the contributory factors, even though some human error may be detected in about 80% of the analysed cases [2]. We set up a Critical Incident Reporting System (CIRS) to collect anonymous CI in anaesthesia using a reporting form on the Internet. CIRS analysis of the first 60 cases corroborates the findings of previous CI studies. In addition, our preliminary results have shown certain important trends, especially those concerning the contributory factor of communication in the Operating Theatre. Although to date we are unable to assess the educational importance of these CI reports, we believe that there is great potential for this aspect of CIRS.

Anesthesia, Conduction↗
PubMed1997

Comparison of intravenous ganciclovir followed by oral acyclovir with intravenous ganciclovir alone for prevention of cytomegalovirus and Epstein-Barr virus disease after liver transplantation in children.

A randomized trial was performed to compare the sequential use of 2 weeks of intravenous ganciclovir (10 mg/[kg.d]) followed by 50 weeks of high-dose oral acyclovir (800 mg/m2 four times daily) with 2 weeks of intravenous ganciclovir alone as prophylaxis for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) disease after pediatric liver transplantation. CMV disease was diagnosed for seven of 24 patients treated with ganciclovir followed by high-dose oral acyclovir compared with two of 24 children treated with ganciclovir alone (P = .048). Similarly, the rate of CMV disease among high-risk patients (CMV-positive donor/CMV-negative recipient) treated with the combination regimen was higher than that among high-risk patients treated with ganciclovir alone (four [57%] of seven vs. zero of five, respectively; vs P < .05). The rate of EBV disease among patients treated with the combination regimen (eight [33%] of 24) was similar to that among patients treated with ganciclovir alone (five [21%] of 24; P = not significant). We conclude that sequential prophylaxis with 2 weeks of intravenous ganciclovir followed by 50 weeks of high-dose oral acyclovir did not decrease the frequency of CMV or EBV disease after pediatric liver transplantation when compared with 2 weeks of intravenous ganciclovir alone.

Acyclovir↗
PubMed1997

A review of endocrine options for the treatment of advanced breast cancer.

It is now 100 years since it was first recognised that altering the endocrine environment can be valuable in patients with inoperable breast cancer. Various ablative endocrine and other treatments have since been developed, but few have resulted in a substantial improvement in clinical efficacy, and the response rates to endocrine manoeuvres remain at about 30%. The benefits of more recent therapies, such as the new generation of aromatase inhibitors, appear to relate to better tolerability and more convenient administration. It is now recommended that the majority of patients with advanced breast cancer should receive endocrine therapy as their first mode of treatment, although it is postmenopausal patients who are likely to gain most benefit from this approach. Tamoxifen is currently the first choice of treatment in the majority of postmenopausal women, although most eventually experience progression of disease, possibly because of the partial oestrogen agonist activity of tamoxifen. Second-line therapy is usually then either an aromatase inhibitor or a progestin. The new-generation selective, non-steroidal aromatase inhibitors are effective and can offer major clinical benefits in terms of fewer side-effects.

Aminoglutethimide↗
PubMed1997

Temporal hemodynamic effects of permissive hypercapnia associated with ideal PEEP in ARDS.

The associated use of permissive hypercapnia (PHY) and high PEEP levels (PEEP(IDEAL)) has been recently indicated as part of a lung-protective-approach (LPA) in acute respiratory distress syndrome (ARDS). However, the net hemodynamic effect produced by this association is not known. We analyzed the temporal hemodynamic effects of this combined strategy in 48 patients (mean age 34 +/- 13 yr) with ARDS, focusing on its immediate (after 1 h), early (first 36 h), and late (2nd-7th d) consequences. Twenty-five patients were submitted to LPA--with the combined use of permissive hypercapnia (PHY), VT < 6 ml/kg, distending pressures above PEEP < 20 cm H2O, and PEEP 2 cm H2O above the lower inflection point on the static inspiratory P-V curve (P(FLEX))- and 23 control patients were submitted to conventional mechanical ventilation. LPA was initiated at once, resulting in an immediate increase in heart rate (p = 0.0002), cardiac output (p = 0.0002), oxygen delivery (DO2l, p = 0.0003), and mixed venous Po2 (p = 0.0006), with a maintained systemic oxygen consumption (p = 0.52). The mean pulmonary arterial pressure markedly increased (mean increment 8.8 mm Hg; p < 0.0001), but the pulmonary vascular resistance did not change (p = 0.32). Cardiac filling pressures increased (p < 0.001) and the systemic vascular resistance fell (p = 0.003). All these alterations were progressively attenuated in the course of the first 36 h, despite persisting hypercapnia. Plasma lactate suffered a progressive decrement along the early period in LPA but not in control patients (p < 0.0001). No hemodynamic consequences of LPA were noticed in the late period and renal function was preserved. A multivariate analysis suggested that these acute hyperdynamic effects were related to respiratory acidosis, with no depressant effects ascribed to high PEEP levels. In contrast, high plateau pressures were associated with cardiovascular depression. Thus, as long as sufficiently low distending pressures are concomitantly applied, the sudden installation of PHY plus PEEP(IDEAL) induces a transitory hyperdynamic state and pulmonary hypertension without harmful consequences to this young ARDS population.

Adult↗
PubMed1997

[Blind prophylactic antibiotic administration in premature rupture of fetal membranes].

In a retrospective study based on patients treated at the Department of Gynecology and Obstetrics of the University of Cologne during 1984-1993, we tested whether antepartal prophylactic application of antibiotics in patients with premature rupture of membranes (PROM) decreases the frequency of maternal or fetal infections. With raising intervals between PROM and birth exceeding 24 hours, the frequency of maternal/fetal infections raised in the total study population (n = 940). The maternal infection rate increased from 4% to 11% and the frequency of fetal sepsis from 4% to 19% with a PROM to birth interval exceeding 24 hours. In the group of patients with prophylactic application of antibiotics the frequency of maternal or fetal infections was not lower than in the group without antibiotics. This holds true for the total study population as well as for subgroups with different gestational ages. In the total study population 12% of antibiotics-treated patients and 22% of their newborns had peripartal infections, whereas in the untreated population 3% of the mothers and 4% of the newborns showed signs of infection. The prophylactic application of antibiotics raises significantly the latency period in combination with or without tocolysis in PROM during 25. and 37. week of gestation.

Antibiotic Prophylaxis↗
PubMed1996

A pathogen-specific epitope inserted into recombinant secretory immunoglobulin A is immunogenic by the oral route.

Oral administration of rabbit secretory IgA (sIgA) to adult BALB/c mice induced IgA+, IgM+, and IgG+ lymphoblasts in the Peyer's patches, whose fusion with myeloma cells resulted in hybridomas producing IgA, IgM, and IgG1 antibodies to the secretory component (SC). This suggests that SC could serve as a vector to target protective epitopes into mucosal lymphoid tissue and elicit an immune response. We tested this concept by inserting a Shigella flexneri invasin B epitope into SC, which, following reassociation with IgA, was delivered orally to mice. To identify potential insertion sites at the surface of SC, we constructed a molecular model of the first and second Ig-like domains of rabbit SC. A surface epitope recognized by an SC-specific antibody was mapped to the loop connecting the E and F beta strands of domain I. This 8-amino acid sequence was replaced by a 9-amino acid linear epitope from S. flexneri invasin B. We found that cellular trafficking of recombinant SC produced in mammalian CV-1 cells was drastically altered and resulted in a 50-fold lower rate of secretion. However, purification of chimeric SC could be achieved by Ni2+-chelate affinity chromatoraphy. Both wild-type and chimeric SC bound to dimeric IgA, but not to monomeric IgA. Reconstituted sIgA carrying the invasin B epitope within the SC moiety triggers the appearance of seric and salivary invasin B-specific antibodies. Thus, neo-antigenized sIgA can serve as a mucosal vaccine delivery system inducing systemic and mucosal immune responses.

Administration, Oral↗
PubMed1996

Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status.

BACKGROUND: Approximately 30% of the patients with primary breast cancer who have no axillary lymph node involvement (i.e., lymph node negative) at the time of surgery will relapse within 10 years; 10%-20% of the patients with distant metastases will be lymph node negative at surgery. Axillary lymph node dissection, as a surgical procedure, is associated with frequent complications. A possible alternative to nodal dissection in terms of prognosis may be the immunocytochemical detection of tumor cells in bone marrow. PURPOSE: In a prospective study, the value of tumor cell detection (TCD) in bone marrow was compared with axillary lymph node dissection in the prognosis of primary breast cancer after surgery. METHODS: Data from 727 patients with primary, operable breast cancer were included in the analysis. All patients had surgery, including axillary lymph node dissection, from May 1985 through July 1994 at the Women's Hospital of the University of Heidelberg (Federal Republic of Germany). Bone marrow aspiration at two sites on each anterior iliac crest was performed immediately after surgery while the patients were under general anesthesia. Most patients received some type of systemic adjuvant therapy. The monoclonal antibody 2E11, directed against the polymorphic epithelial mucin TAG12, was used to detect tumor cells in bone marrow samples. The association of TCD with recognized prognostic indicators was evaluated by means of chi-squared tests. Survival without the development of distant metastases (i.e., distant disease-free survival) and overall survival were estimated by use of the Kaplan-Meier method; the logrank test was used to compare survival curves. A multivariate Cox regression analysis with stratification according to adjuvant treatment type was used to assess the independent prognostic value of TCD in bone marrow in relation to other variables. Reported P values are two-sided. RESULTS: Tumor cells were detected in the bone marrow of 203 (55%) of 367 lymph node-positive patients and in 112 (31%) of 360 lymph node-negative patients. TCD was associated with larger tumors (P < .001), lymph node involvement (P = .001), and higher tumor grade (i.e., more undifferentiated) (P = .002). After a median follow-up of 36 months, patients with tumor cells in their bone marrow experienced reduced distant disease-free survival and overall survival (both P values < .001). TCD was an independent prognostic indicator for both distant disease-free survival and overall survival that was superior to axillary lymph node status, tumor stage, and tumor grade. Among patients with tumors less than 2 cm in diameter, TCD was the most powerful predictor of outcome. CONCLUSIONS AND IMPLICATIONS: TCD in the bone marrow of patients with breast cancer is a valuable prognostic tool associated with negligible morbidity. Prospective randomized studies should be performed to determine whether TCD might replace axillary lymph node dissection in a defined subgroup of patients with small tumors.

Adult↗
PubMed1996

Chromosomal breakage correlates with delayed lethality in normal and ataxia telangiectasia cell lines treated with bleomycin.

Cytogenetic damage and cytotoxicity produced by a range of acute treatments with bleomycin (BLM) were investigated in three B-lymphoblastoid cell lines: EM-OC, PA-AT and CP-NC; established from heterozygous, and homozygous, ataxia telangiectasia (AT) and normal donors, respectively. The following endpoints were studied: (1) the maximum (initial) yields of different classes of chromosomal aberrations (CA) produced in G2-phase; (2) the percentage distributions of cells within bins with different numbers of CA; (3) short-term (0-48 h) viability and proliferation; and (4) (delayed) lethality, as measured by a modified limiting-dilution assay. While only slight losses of short-term viability and proliferation were detectable after standard BLM pulse-treatment at 25 or 100 micrograms/ml (results for latter dose given in parentheses), both regimes subsequently led to intense lethality as follows: CP-NC, 79.3% (95.1%); EM-OC, 90.4% (96.7%) and PA-AT, 98.4% (99.9%). Relative lethality after the respective BLM treatments increased 6.2 x (48.3 x) among PA-AT cells more than in controls-resembling the corresponding ratios for chromosome breaks (csb) of 7.0 x (30.9 x), more than those for chromatid breaks (ctb) of 3.1 x (2.7 x). EM-OC exhibited slightly increased relative lethality after the respective BLM treatments at 2.15 x (1.45), and increased aberration sensitivities for csb of 3.0 x (14.0), while the corresponding ratios for ctb were actually lower at 0.66 x (0.50 x). Significant correlations were observed between lethality and both, the yields of most types of chromosomal aberrations (excepting unambiguous exchanges) and also, the percentages of cells bearing CA.

Antibiotics, Antineoplastic↗
PubMed1996

Allelic imbalance on chromosome 13q: evidence for the involvement of BRCA2 and RB1 in sporadic breast cancer.

Recently, the breast cancer susceptibility gene BRCA2 has been identified in chromosome 13q, a region that also contains the retinoblastoma gene RB1. To elucidate a possible role of BRCA2 and RB1 in sporadic breast tumorigenesis, allelic imbalance (AI) at 13q loci was examined in 78 primary sporadic breast tumors. AI was found in 52-63% of tumors. Nine tumors showed AI only in the BRCA2 region but not at RB1. Six tumors showed AI at RB1 but not in the BRCA2 region. AI in the BRCA2 region correlated significantly with aneuploidy (P = 0.032) and AI at RB1 with small tumor size (P = 0.025). Our data suggest that BRCA2 and RB1 may be both distinct target loci for AI on chromosome 13 in sporadic breast cancer.

Alleles↗
PubMed1996

Cohabiting t(12;22) and inv(3) primary rearrangements in an acute myelomonocytic leukemia (FAB M4) cell line.

We describe the cytogenetic characterization of MUTZ-3, the first continuous cell line to be established from acute myelomonocytic leukemia (FAB M4) cells, exhibiting recurrent chromosomal rearrangements associated with this disease category. MUTZ-3 was established from peripheral blood taken at presentation from a 29-year-old male patient and carries the t(12;22)(p13.2;q11.2) associated with acute myelomonocytic leukemia (AMMoL), the inv(3)(q21.2q26.3) associated with multilineage acute myeloid leukemias (AML), and the inv(7)(p 14q35) associated with ataxia telangiectasia (A-T). There was no evidence that the patient was an A-T heterozygote. The breakpoint on chromosome 22 mapped between 5' BCR and D22S39, consistent with the G-banding assignment. Both inversions were translocation-associated and may be further examples of an association previously described in AML FAB M4eo with inv(16). We suggest that the combination of inv(3)/t(3;3) with t(12;22) may represent a new, nonrandom association in AML.

Adult↗
PubMed1996

Homeostatic regulation of CD8+ T cells after antigen challenge in the absence of Fas (CD95).

The role of Fas in the homeostatic regulation of CD8+ T cells after antigen challenge was analyzed in the murine model of lymphocytic choriomeningitis virus (LCMV) infection. Mice homozygous for the lpr mutation and carrying T cell receptor (TCR) alphabeta transgenes specific for the LCMV glycoprotein peptide aa 33-41 in the context of H-2Db were used. Five main results emerged: first, development of lymphadenopathy and of CD4- CD8- double-negative B220+ T cells in lpr mice was not inhibited by the alphabeta TCR transgenes; second, tolerance induction and peripheral deletion of CD8+ T cells induced by LCMV glycoprotein peptide injection was independent of Fas expression; third, clonal down-regulation of Fas-deficient TCR-transgenic CD8+ T cells after acute LCM virus infection was identical to the decline of transgenic T cells expressing Fas; fourth, in vivo activated CD8+ effector T cells from TCR transgenic and TCR-lpr/lpr mice were equally susceptible to activation-induced cell death in vitro; and fifth, transgenic effector T cells from lpr/lpr mice were cleared in the declining phase of the immune response in vivo without giving rise to CD4- CD8- double-negative T cells. Taken together, these data suggest that the homeostatic regulation of CD8+ T cells after antigen challenge in vivo is regulated by mechanisms that do not require Fas.

Animals↗