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Biomedical subjects

K Uberla

Publications and source records attributed to K Uberla.

At least 55 records · Page 3Linked to original sources
PubMed1996

Improved outcome in adult B-cell acute lymphoblastic leukemia.

A total of 68 adult patients with B-cell acute lymphoblastic leukemia (B-ALL) were treated in three consecutive adult multicenter ALL studies. The diagnosis of B-ALL was confirmed by L3 morphology and/or by surface immunoglobulin (Slg) expression with > 25% blast cell infiltration in the bone marrow (BM). They were characterized by male predominance (78%) and a median age of 34 years (15 to 65 y) with only 9% adolescents (15 to 20 y), but 28% elderly patients (50 to 65 y). The patients received either a conventional (N = 9) ALL treatment regimen (ALL study 01/81) or protocols adapted from childhood B-ALL with six short, intensive 5-day cycles, alternately A and B. In study B-NHL83 (N = 24) cycle A consisted of fractionated doses of cyclophosphamide 200 mg/m2 for 5 days, intermediate-dose methotrexate (IdM) 500 mg/m2 (24 hours), in addition to cytarabine (AraC), teniposide (VM26) and prednisone. Cycle B was similar except that AraC and VM26 were replaced by doxorubicin. Major changes in study B-NHL86 (N = 35) were replacement of cyclophosphamide by ifosphamide 800 mg/m2 for 5 days, an increase of IdM to high-dose, 1,500 mg/m2 (HdM) and the addition of vincristine. A cytoreductive pretreatment with cyclophosphamide 200 mg/m2, and prednisone 60 mg/m2, each for 5 days was recommended in study B-NHL83 for patients with high white blood cell (WBC) count (> 2,500/m2) or large tumor burden and was obligatory for all patients in study B-NHL86. Central nervous system (CNS) prophylaxis/treatment consisted of intrathecal methotrexate (MTX) therapy, later extended to the triple combination of MTX, AraC, and dexamethasone, and a CNS irradiation (24 Gy) after the second cycle. Compared with the ALL 01/81 study where all the patients died, results obtained with the pediatric protocols B-NHL83 and B-NHL86 were greatly improved. The complete remission (CR) rates increased from 44% to 63% and 74%, the probability of leukemia free survival (LFS) from 0% to 50% and 71% (P = .04), and the overall survival rates from 0% to 49% and 51% (P = .001). Toxicity, mostly hematotoxicity and mucositis, was severe but manageable. In both studies B-NHL83 and B-NHL86, almost all relapses occurred within 1 year. The time to relapse was different for BM, 92 days, and for isolated CNS and combined BM and CNS relapses, 190 days (P = .08). The overall CNS relapses changed from 50% to 57% and 17%, most probably attributable to the high-dose MTX and the triple intrathecal therapy. LFS in studies B-NHL83 and B-NHL86 was significantly influenced by the initial WBC count < or > 50,000/microL, LFS 71% versus 29% (P = .003) and hemoglobin value > or < 8 g/dL, LFS 67% versus 27% (P = .02). Initial CNS involvement had no adverse impact on the outcome. Elderly B-ALL patients (> 50 years) also benefited from this treatment with a CR rate of 56% and a LFS of 56%. It is concluded that this short intensive therapy with six cycles is effective in adult B-ALL. HdM and fractionated higher doses of cyclophosphamide or ifosphamide seem the two major components of treatment.

Adolescent↗
PubMed1996

Early institution of bromocriptine in Parkinson's disease inhibits the emergence of levodopa-associated motor side effects. Long-term results of the PRADO study.

Long-term levodopa treatment in Parkinson's disease is typically associated with "motor side effects" consisting in dyskinesias and/or fluctuations in motility referred to as the on-off phenomena. The main objective of this prospective, randomized, multi-centre study was to determine to what extent the development of such complications could be prevented by partial substitution of levodopa monotherapy (L-DOPA/benserazide) by bromocriptine in patients with early symptoms of the disease. The basic trial population included 674 newly diagnosed Parkinsonian patients that were randomly allocated to monotherapy with levodopa or a combination therapy based upon a nearly 40% replacement of levodopa by bromocriptine. The two target regimens had to be consistently maintained for 42 months. Parkinsonian symptoms were assessed by means of the Webster rating scale, the Hoehn and Yahr scale, and the Zung Self-Rating Depression scale. Motor side effects and adverse events were recorded at each regular clinic visit. Neurological symptoms improved and stabilized in a similar manner during treatment with both regimens throughout the study period. Motor side effects were observed in more patients on levodopa alone than on combination therapy (28.8 vs 20%; p = 0.008). According to Kaplan-Meier estimates the cumulative probability of experiencing motor side effects was 0.43 on monotherapy, compared to 0.28 on combination therapy, which was equal to a one third reduction of risk (p = 0.025). In regard to motor side effects, the degree of substitution of levodopa proved relevant: patients with > 50% substitution by bromocriptine exhibited half the risk observed in those with < 30% (p = 0.045). The overall burden of motor side effects, as reflected by a sum score based upon the relevance, the severity and the extent of motor dysfunction, was also significantly less on combination therapy (p = 0.046). In conclusion, partial substitution of levodopa by bromocriptine (> 30%) as first-line treatment of Parkinson's disease proves active in the prophylaxis of levodopa associated motor side effects. Early combination therapy therefore extends the period of optimal disease control.

Aged↗
PubMed1995

Animal model for the therapy of acquired immunodeficiency syndrome with reverse transcriptase inhibitors.

The reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1) is the major target for antiretroviral therapy of the acquired immunodeficiency syndrome (AIDS). While some inhibitors exhibit activity against most retroviral RTs, others are specific for the HIV-1 enzyme. To develop an animal model for the therapy of the HIV-1 infection with RT inhibitors, the RT of the simian immunodeficiency virus (SIV) was replaced by the RT of HIV-1. Macaques infected with this SIV/HIV-1 hybrid virus developed AIDS-like symptoms and pathology. The HIV-1-specific RT inhibitor LY300046.HCl, but not zidovudine [3'-azido-3'-deoxythymidine (AZT)] delayed the appearance of plasma antigenemia in macaques infected with a high dose of the chimeric virus. Infection of macaques with the chimeric virus seems to be a valuable model to study the in vivo efficacy of new RT inhibitors, the emergence and reversal of drug resistance, the therapy of infections with drug-resistant viruses, and the efficacy of combination therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Sensitivity/resistance profile of a simian immunodeficiency virus containing the reverse transcriptase gene of human immunodeficiency virus type 1 (HIV-1) toward the HIV-1-specific non-nucleoside reverse transcriptase inhibitors.

To develop an animal model for the therapy of AIDS with human immunodeficiency virus type 1 (HIV-1)-specific reverse transcriptase (RT) inhibitors, we recently constructed a hybrid simian immunodeficiency virus (SIV)/HIV-1 in which the RT gene of SIV was replaced by the RT gene of HIV-1. This chimaeric virus, designated RT-SHIV, was found to be markedly sensitive to the inhibitory effects of both nucleoside (ddN) and non-nucleoside RT inhibitors (NNRTIs). In contrast, SIV was inhibited only by ddNs (i.e., 3TC and AZT), but not NNRTIs. When RT-SHIV was grown in the presence of 3TC, nevirapine, TSAO-m3T or the thiocarboxanilide UC-42 drug-resistant mutant virus strains emerged in cell culture as rapid as for HIV-1(IIIB). The antiviral sensitivity/resistance spectrum of the mutant RT-SHIV strains against NNRTIs and ddNs, and the nature of the mutations that appeared in their RT were similar to those of the mutant HIV-1 strains that were selected under identical experimental conditions. Infection of macaques with RT-SHIV may be a useful tool for studying the mechanism of NNRTI-resistance development and the therapy of NNRTI-resistant viruses in an animal model.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Vaccinations with tumor cells genetically engineered to produce different cytokines: effectivity not superior to a classical adjuvant.

The potential of tumor cells (J558L) engineered to produce one of 5 different cytokines (interleukin 2, interleukin 4, interleukin 7, tumor necrosis factor, or gamma-interferon) to give rise to systemic immunity protective against a contralateral challenge with the parental cells was analyzed. The rejection of all cytokine-producing cells appeared to induce some systemic response capable of mediating the rejection of low numbers of subsequently contralaterally injected cells, but the effect was much less obvious with higher cell numbers. The injection of any possible combination of two of the cytokine producers did not reveal any synergistic effects. The cytokine gene-transfected tumor cells were not superior to the parental cells admixed with the adjuvant Corynebacterium parvum with respect to their potential as immunogens to induce immunity.

Animals↗
PubMed1993

Manifestation of atopy is not related to patient's month of birth.

The first months of life may be an important period for allergic sensitization. Several studies suggest a relationship between the month of birth (MB) and the development of skin sensitivity to aeroallergens or the manifestation of an atopic disease. In 1988 and 1989 we investigated a population of 1066 Bavarian preschool children aged 5-6 years. Skin prick tests were performed with common aeroallergens (grass pollen, birch pollen, house-dust mite, cat epithelia). The personal history of atopic disease (atopic eczema, allergic rhinitis, bronchial asthma) was recorded by a questionnaire, and the presence of overt atopic disease was documented by a personal examination. Positive prick test reactions to the above-mentioned aeroallergens were found in 15.4%, 9.2%, 12.2%, and 10.4% of the subjects, respectively; lifetime prevalence of manifest atopic disease was 22.2% for atopic eczema, 11.7% for allergic rhinitis, and 4.5% for asthma. The MB distributions of children reacting to aeroallergens or of those with atopic diseases were compared with those of subjects with corresponding negative findings. Chi-square tests were performed for each aeroallergen and each of the atopic diseases separately. No significant differences among the MB distributions were found (P > 0.3). Thus, in this coherent group, MB correlated neither to allergic sensitization nor to manifest atopic disease.

Air Pollutants↗
PubMed1992

Analysis of cytokine mRNA levels in interleukin-4-transgenic mice by quantitative polymerase chain reaction.

Interleukin (IL)-4-transgenic mice were used as a model system to study the consequences of low levels of IL-4 expression for the expression of other cytokines examined by quantitative polymerase chain reaction (PCR). For this purpose, a plasmid was constructed which contains, in tandem array, 5' and 3' primer sequences specific for the cytokine genes IL-1 to IL-6, tumor necrosis factor (TNF), lymphotoxin (LT), interferon (IFN)-gamma and beta-actin. During co-amplification, target and control DNA compete for the primers and the amount of PCR product is proportional to the amount of input DNA. Competitive PCR was performed first to adjust the cDNA to be compared to identical concentrations of beta-actin cDNA and subsequently to determine cytokine mRNA levels from spleen cells of normal and IL-4-transgenic animals. The sensitivity of this approach was demonstrated by the capability to detect a twofold difference in IL-4 mRNA levels between IL-4-transgenic heterozygous and homozygous animals. Upon lipopolysaccharide activation, the IL-4 transgene which is expressed essentially in B lymphocytes was induced approximately 50-fold. Several cytokine mRNA such as those coding for IL-5, IL-6, IFN-gamma and also the IL-4 receptor were found to be up-regulated in IL-4-transgenic mice, whereas IL-1, IL-2, IL-3, TNF and LT mRNA levels did not seemed to be influenced by IL-4. A possible functional significance of the elevated IFN-gamma mRNA was demonstrated by showing that (a) CD23 expression was not increased, and (b) Mac-1+ cells were markedly increased in the spleen of transgenic mice.

Animals↗
PubMed1992

Interleukin-4-mediated tumor suppression in nude mice involves interferon-gamma.

The molecular events during the anti-tumor response induced by interleukin (IL)-4 were investigated by quantitative polymerase chain reaction. The growth of Chinese hamster ovary cells transfected to produce IL-4 (CHO.T1) was strongly suppressed when cells were injected intraperitoneally into nude mice and this suppression was accompanied by the rapid accumulation of activated macrophages. Peritoneal cells from such mice were analyzed for mRNA induced by IL-4. Correlating with a high local IL-4 concentration, several transcripts were found to be up-regulated during the early phase of the anti-tumor response [IL-4 receptor, IL-5, tumor necrosis factor (TNF) and interferon (IFN)-gamma]. The functional relevance of the elevated mRNA levels was analyzed by injection of CHO.T1 cells together with anti-cytokine monoclonal antibodies (mAb). In contrast to anti-IL-5 and anti-TNF mAb, an anti-IFN-gamma mAb interfered with the anti-tumor response demonstrating the involvement of IFN-gamma during the IL-4-induced tumor suppression. Tumor growth in anti-IFN-gamma mAb-treated animals was significantly delayed in comparison to anti-IL-4 mAb-treated mice, suggesting that IFN-gamma-independent effector cells may also be involved.

Animals↗
PubMed1991

Tumor suppression after tumor cell-targeted tumor necrosis factor alpha gene transfer.

The tumor necrosis factor alpha (TNF-alpha) gene was introduced by retroviral gene transfer into the TNF-alpha-insensitive tumor cell line J558L. Production of 40 pg/ml TNF-alpha by clone J2T12 consistently did not change the growth rate in vitro, but drastically suppressed tumor growth when injected into syngeneic BALB/c mice. Within 2 wk, 90% of the mice inoculated with J558L cells developed a tumor, but none of the mice injected with J2T12 did so. Within the observation period (greater than 3 mo), 60% of the mice inoculated with J2T12 did not develop a tumor. In the other 40% of the mice, tumor manifestation was significantly delayed. Mice injected simultaneously with J2T12 cells and an anti-TNF-alpha monoclonal antibody developed tumors similar to parental J558L cells. Similarly, the tumor-suppressive effects of TNF-alpha were abolished, e.g., by injection of an anti-type 3 complement receptor (CR3) monoclonal antibody that is known to prevent migration of inflammatory cells. These results and the observation of tumor-infiltrating macrophages suggest that lack of tumorigenicity of J2T12 cells is due to the TNF-alpha secretion by the tumor cells and that TNF-alpha acts indirectly by a mechanism that involves chemotactic recruitment and activation of cells, predominantly of macrophages. In contrast, the tumor growth was not affected when, instead of TNF-alpha, interleukin 6 was expressed by J558L cells. Together, our results support the concept of tumor cell-targeted cytokine gene transfer as a tool for cancer treatment, and particularly demonstrate that extremely low doses of TNF-alpha produced by tumor cells are sufficient to inhibit tumor growth without detectable side effects.

Alkaline Phosphatase↗
PubMed1991

Hospital comparisons using a Euro Health Data Base for resource management and strategic planning.

A European approach for resource management and strategic planning has been implemented in the HOSCOM project of AIM by defining information standards needed across countries, as well as a methodology to measure resources and costs at the institutional and interinstitutional level. A Euro Health Data Base (EHDB) has been obtained in order to test data availability and comparability as well as to validate models through macrocomparisons using case-mix (DRG's, refined grouping, disease staging) and microcomparisons based on three diseases (cardiac valve replacement, diabetes mellitus and hip fracture). The EHDB's presently based on 274 164 medical record summaries sampled from 7 countries allowed us to build prototypes (using Clipper, Prolog and SQL) in order to export uniform aggregates in the different countries, with standard software tools for statistical comparisons. It showed the present feasibility of using case-mix based on the European Minimum Basic Data Set (MBDS) and the difficulty of obtaining uniform data on resources and costs other than length of stay across countries. Medical data confidentiality was assured but not yet population-based representativity. Given the present state of the EHDB, problems have been clearly identified in order to be solved by international research and development projects in the near future.

Abstracting and Indexing↗
PubMed1991

The rat interleukin-5 gene: characterization and expression by retroviral gene transfer and polymerase chain reaction.

The rat interleukin-5 (IL-5) gene was isolated from a genomic lambda phage library and a fragment containing all four exons was inserted into the retroviral vector pXT1, resulting in pXTRIL5. Upon retroviral gene transfer into two IL-5-dependent mouse cell lines, B13 and T88M, autonomously growing cells were established and B-cell growth factor activity was detected in the supernatants of the infected cells. "cDNA" versions of the rat IL-5 gene were rescued by the polymerase chain reaction (PCR) with primers specific for the flanking regions of the cloning site in pXT1. Restriction or DNA sequence analysis of five different clones revealed precise splicing in two cases, while three of the clones had retained the first intron. In addition, in two of these about 400 bp of rat IL-5 5' flanking regions were deleted. The sequence comparison of rat, mouse, and human IL-5 genes revealed a high degree of conservation (e.g., mouse and rat were 92% homologous at the amino acid level). The combination of retroviral gene transfer and PCR may offer an alternative, efficient method for the cloning of cDNAs.

Amino Acid Sequence↗
PubMed1991

Generation of competitor DNA fragments for quantitative PCR.

A convenient and generally applicable method for the generation of competitor DNA fragments for quantitative PCR is described. Using mouse-specific primers, fragments are amplified from DNA of an evolutionarily distantly related species under low-stringency annealing conditions. Because these artificially created fragments contain the mouse primer specific ends, they can be used for the quantification of the mouse DNA amplified by these primers. Competitor DNA fragments that differ in size from the corresponding mouse DNA are selected to distinguish both fragments visually by gel electrophoresis. Competitor DNA fragments were generated for mouse beta-actin, interleukin-1, and tumor necrosis factor (TNF). Co-amplification of beta-actin cDNA for adjustment of equal amounts of input cDNA and subsequently TNF cDNA from lipopolysaccharide (LPS)-activated and nonactivated spleen cells with serial dilutions of the respective competitor DNA fragments allowed a semiquantitative comparison of the ratio of TNF mRNA present in both cDNA samples. Under certain conditions, the competitor DNA fragments can be used to determine the approximate molar concentration of a mRNA.

Animals↗
PubMed1990

Retroviral interleukin 5 gene transfer into interleukin 5-dependent growing cell lines results in autocrine growth and tumorigenicity.

Two interleukin 5 (IL5)-specific retroviral expression vectors have been constructed containing the neomycin gene as selectable marker and either the mouse IL5 cDNA region or the rat genomic IL5 gene under the control of the thymidine kinase promoter. High viral titer supernatants derived from the transfected or infected packaging cell line psi 2 were used to infect the two cell lines B13 and T88M whose growth is dependent on exogenous IL 5. Infection resulted in G418 resistance and IL 5-independent growth with a high frequency. Clones were established which secrete between 2 and greater than 1000 U IL5. The proliferation of the IL5 autocrine growing cells could be inhibited by an antibody directed against the IL5 receptor indicating that they grow as a result of the endogenously produced IL5. Regardless of the amount of IL5 they produced, all of the clones were highly tumorigenic in nucle mice. The phenotype of the tumors was indistinguishable from that of the injected cells. T88M or B13 cells infected with a control virus neither produced IL5, nor became factor independent, nor produced tumors. Together, the IL5 gene transfer and expression into IL5-dependent growing cells are in accordance with the "autocrine growth" hypothesis and contrast analogous experiments with IL4.

Animals↗