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Biomedical subjects

G Wulf

Publications and source records attributed to G Wulf.

At least 37 records · Page 2Linked to original sources
PubMed1999

The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein.

One of the neuropathological hallmarks of Alzheimer's disease is the neurofibrillary tangle, which contains paired helical filaments (PHFs) composed of the microtubule-associated protein tau. Tau is hyperphosphorylated in PHFs, and phosphorylation of tau abolishes its ability to bind microtubules and promote microtubule assembly. Restoring the function of phosphorylated tau might prevent or reverse PHF formation in Alzheimer's disease. Phosphorylation on a serine or threonine that precedes proline (pS/T-P) alters the rate of prolyl isomerization and creates a binding site for the WW domain of the prolyl isomerase Pin1. Pin1 specifically isomerizes pS/T-P bonds and regulates the function of mitotic phosphoproteins. Here we show that Pin1 binds to only one pT-P motif in tau and copurifies with PHFs, resulting in depletion of soluble Pin1 in the brains of Alzheimer's disease patients. Pin1 can restore the ability of phosphorylated tau to bind microtubules and promote microtubule assembly in vitro. As depletion of Pin1 induces mitotic arrest and apoptotic cell death, sequestration of Pin1 into PHFs may contribute to neuronal death. These findings provide a new insight into the pathogenesis of Alzheimer's disease.

Alzheimer Disease↗
PubMed1999

The learning advantages of an external focus of attention in golf.

This study examined whether the learning advantages of an external focus of attention relative to an internal focus, as demonstrated by Wulf, Höss, and Prinz (1998), would also be found for a sport skill under field-like conditions. Participants (9 women, 13 men; age range: 21-29 years) without experience in golf were required to practice pitch shots. The practice phase consisted of 80 practice trials. One group was instructed to focus on the arm swing (internal focus), whereas another group was instructed to focus on the club swing (external focus). One day after practice, a retention test of 30 trials without instructions was performed. The external-focus condition was more effective for performance during both practice and retention.

Adult↗
PubMed1999

Physical assistance devices in complex motor skill learning: benefits of a self-controlled practice schedule.

This study examines the effects of a self-controlled use of physical assistance devices on learning a complex motor skill (i.e., producing slalom-type movements on a ski simulator). Physical assistance was provided by ski poles. One group of learners (self-control) was provided with the poles whenever they requested them, whereas another (yoked) group had no influence on the pole/no-pole schedule. While there were no group differences during the practice phase (Days 1 and 2), clear group differences emerged in the retention test without poles (Day 3). The self-control group produced significantly larger amplitudes than the yoked group. These results extend previous findings by showing learning advantages of the self-controlled use of physical assistance devices in complex motor skill learning.

Humans↗
PubMed1999

Complete heart block as a rare complication of treatment with chloroquine.

Antimalarials are well established disease modifying antirheumatic drugs. A rare and underappreciated treatment difficulty is cardiac complication, in particular conduction disturbances. We describe 2 more patients that developed complete heart block after high dose, longterm treatment. Patient 1, a 73-year-old woman with longstanding rheumatoid arthritis, had taken chloroquine (250 mg/day) for 12 years when she developed complete heart block requiring a permanent pacemaker. Patient 2, a 40-year-old woman with discoid lupus erythematosus, was taking chloroquine from 1979 until 1996. Depending on the clinical disease activity, she intermittently increased the dose from 250 to 750 mg/day. In 1994, she developed complete heart block and a permanent pacemaker had to be implanted. Intensive investigations in both cases did not reveal another underlying cause for conduction disturbances; the atrioventricular block was probably due in both cases to chloroquine related cardiac toxicity. This toxicity seems to be restricted to longterm, high dose treatment; however, it should be kept in mind in patients with preexisting conduction disturbances during longterm treatment.

Adult↗
PubMed1998

Moderate dose escalation for advanced stage Hodgkin's disease using the bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone scheme and adjuvant radiotherapy: a study of the German Hodgkin's Lymphoma Study Group.

The BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen, a rearranged and accelerated version of the standard COPP/adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy, has been shown to be effective and safe in a previous pilot study for advanced stage Hodgkin's disease (HD). The present study aimed to determine a maximum practicable dose of three drugs, ie, etoposide, adriamycin, and cyclophosphamide, for which acute toxicities were acceptable and to assess the feasibility of the escalated scheme. Sixty untreated patients with advanced stage HD were enrolled in this study. Radiotherapy was given in 44 patients (73%) after chemotherapy to initial bulk lesions and residual disease. Granulocyte-colony stimulating factor (G-CSF) was given from day 8 to prevent prolonged neutrocytopenia and severe infections. The intended doses of adriamycin, etoposide, and cyclophosphamide in the BEACOPP schedule could be substantially escalated: adriamycin from 25 to 35, cyclophosphamide from 650 to 1,200, and etoposide from 100 to 200 mg/m2. The major toxicities were leukocytopenia and thrombocytopenia with considerable heterogeneity between individual patients. Of 60 patients, 56 (93%) achieved a complete remission (CR). At a median observation of 32 months, the rates of survival and freedom from treatment failure (FFTF) were estimated to be 91% (95% confidence interval 83% to 99%) and 90% (82% to 98%). These results show that a moderate dose escalation of adriamycin, cyclophosphamide, and etoposide of the baseline BEACOPP regimen is feasible. The escalated BEACOPP regimen shows very encouraging results in advanced stage HD and is now being compared in a randomized phase III study with BEACOPP at baseline dose level.

Adolescent↗
PubMed1998

[Clinical studies in oncology. Relevance, design, ethical considerations].

BACKGROUND: Clinical research in oncology includes the evaluation of diagnostic, prognostic and therapeutic parameters in order to establish standards for the different tumor entities. Prerequisite is the retrospective and prospective analysis of large patient groups with established statistical methods. New potentially better strategies have to be compared in randomised studies with the respective "gold standard". The central role of clinical studies for evaluation and optimisation of therapy can be considered as moral obligation to included the maximal possible number of patients in clinical studies. However, only a small number of tumor patients in Germany is treated in controlled clinical studies. Reasons are lack of organisational structures, but also ethical considerations. STUDY DESIGNS: In this article several models for clinical studies are discussed with respect to their statistical significance, indication, and potential ethical objections. CONCLUSION: Aim of the discussion is to increase the acceptance of the necessity of clinical studies for evaluation and optimisation of therapeutic options in oncology.

Clinical Trials as Topic↗
PubMed1998

BEACOPP: a new regimen for advanced Hodgkin's disease. German Hodgkin's Lymphoma Study Group.

The BEACOPP chemotherapy regimen for advanced Hodgkin's disease employs a rearranged schedule permitting a shortened three-week cycle. With haematological growth factor support, the dosages of cyclophosphamide, etoposide and adriamycin could be moderately escalated. The 3-armed multicentre HD9 trial (recruitment 1993-1998; 1300 patients randomised) aimed to compare BEACOPP with the standard COPP/ABVD chemotherapy and to detect and measure the gain in efficacy, if any, due to moderate dose escalation of BEACOPP. Eight cycles were given, followed by local irradiation. The most recent interim analysis, with 689 evaluable patients, circa 40% of all expected events and a median observation time of 27 months, showed significant differences in progression rate (P) and in two-year freedom from treatment failure (F) between the treatment arms, with escalated BEACOPP (P = 2%, F = 89%) better than baseline BEACOPP (P = 9%, F = 81%) better than COPP/ABVD (P = 13%, F = 72%). Survival was not significantly different. Acute toxicity was more severe due to dose escalation, but remained manageable. These preliminary results suggest that BEACOPP improves efficacy. Moderate dose escalation is feasible with G-CSF support and appears likely to make a worthwhile improvement in the cure rate. The results must await confirmation (or otherwise) by the final analysis including all randomised patients and sufficiently mature data.

Adolescent↗
PubMed1998

BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group.

PURPOSE: The HD9 trial aims to evaluate whether moderate dose escalation and/or acceleration of standard polychemotherapy is beneficial for advanced-stage Hodgkin's disease (HD). Two variants of a novel bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) scheme (standard and escalated dose) are compared with cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). PATIENTS AND METHODS: The randomized, three-arm trial recruited patients in stages IIB and IIIA with risk factors and stages IIIB and IV. BEACOPP in baseline dose contains all drug dosages of COPP/ABVD (except vincristine and procarbazine) rearranged in a shorter, 3-week cycle. Escalated BEACOPP uses higher doses of cyclophosphamide, doxorubicin, and etoposide with granulocyte colony-stimulating factor (G-CSF) support. After eight chemotherapy cycles, initial bulky and residual disease is irradiated. The trial is monitored and analyzed by means of a sequential strategy. RESULTS: An interim analysis with 505 assessable patients and a median follow-up of 23 months showed a significant inferiority (according to sequential monitoring strategy) of the COPP/ABVD regimen in progression rate and freedom from treatment failure (FFTF) compared with the pooled results of both BEACOPP variants. The 24-month FFTF rate was 75% for COPP/ABVD and 84% for BEACOPP pooled (P = .034). There was 12% progressive disease with COPP/ABVD and 6% with BEACOPP pooled. Differences in survival were not significant in sequential analysis. The acute toxicity of baseline BEACOPP resembled that of COPP/ABVD; escalated BEACOPP showed increased but manageable hematologic toxicity. CONCLUSION: Combined with local irradiation, BEACOPP in one or both variants shows superior disease control compared with COPP/ABVD, with acceptable acute toxicity. Further follow-up is required to assess the effect of dosage and the effect on survival and late toxicities.

Adolescent↗
PubMed1997

TGF-beta inhibits growth and induces apoptosis in leukemic B cell precursors.

The uncontrolled proliferation of malignant lymphoblasts is the pathobiological hallmark in B cell precursor-ALL (BCP-ALL). Identification of inhibitory growth factors is of great importance for the understanding of growth control of leukemic B cell precursors and the development of novel therapeutic approaches in BCP-ALL. The aim of our study was the analysis of the effect of TGF-beta on cell survival and apoptosis of B cell precursors (BCP) from patients with acute lymphoblastic leukemia in vitro. Experiments were performed in a coculture system with cloned murine fibroblasts, which efficiently block spontaneous ex vivo apoptosis of BCP and thus allows the assessment of cytokine-induced growth inhibition. TGF-beta significantly reduced cell viability of highly purified, FACS isolated CD10+/CD19+ leukemic BCP by a mean of 53% (P = 0.0001). The loss of cell viability was accompanied by a significant increase of apoptosis with a mean of 70% (P = 0.0028). The TGF-beta effect was blocked specifically by a monoclonal anti-TGF-beta antibody. Induction of apoptotic cell death by TGF-beta was not accompanied by reduction of bcl-2 protein expression. TGF-beta transcription was not detected in the leukemic pre-B cell line BLIN-1, but in the murine fibroblasts. The growth inhibitory effect of TGF-beta was not restricted to leukemic BCP. The cytokine also increased apoptosis of normal, highly purified BCP by a mean of 58%. The data identify TGF-beta as a potent growth inhibitory cytokine for leukemic BCP.

Animals↗
PubMed1997

Continuous concurrent feedback degrades skill learning: implications for training and simulation.

In two experiments we investigated the role of continuous concurrent visual feedback in the learning of discrete movement tasks. During practice the learner's actions either were or were not displayed on-line during the action; in both conditions the participant received kinematic feedback about errors afterward. Learning was evaluated in retention tests on the following day. We separated (a) errors in the fundamental spatial-temporal pattern controlled by the generalized motor program from (b) errors in scaling controlled by parameterization processes. During practice concurrent feedback improved parameterization but tended to decrease program stability. Based on retention tests, earlier practice with continuous feedback generally interfered with the learning of an accurate motor program and reduced the stability of time parameterization. Continuous feedback during acquisition degrades the learning of not only closed-loop processes in slower movements (as has been found in earlier studies) but also motor programs and their parameterization in more rapid tasks. Implications for feedback in training and simulation are discussed.

Analysis of Variance↗
PubMed1996

Average KR degrades parameter learning.

In the present study, the effects of average knowledge of results (KR) about a set of trials on the learning of a spatiotemporal movement pattern were examined. Participants (N = 85) practiced 3 movement patterns with the same relative and absolute timing and the same relative amplitudes but with varied absolute amplitudes. Five groups of participants practiced under 1 of the following 5 conditions: KR after every trial (100% KR); average KR after every 3rd trial (average); average KR after every trial about the last 3 trials (running-average); KR after every 3rd trial (33% KR); and KR after every trial; plus average KR after every 3rd trial (both). Although there were no differences between groups in the learning of the fundamental movement pattern (or generalized motor program), average feedback (average, running-average) clearly degraded subjects' ability to learn to properly parameterize the actions in amplitude.

Journal Article↗
PubMed1994

Inhibition of hematopoiesis by competitive binding of transcription factor PU.1.

Transcription factors have been shown to play a role as "master switch" factors in the programming of hematopoietic cell commitment and differentiation. PU.1 is a hematopoietic-specific member of the Ets family of transcription factors. In human bone marrow CD34-enriched progenitor cells, PU.1 expression was upregulated during the early phases of granulocytic/monocytic differentiation, preceding expression of its target genes encoding CD11b and the macrophage-colony-stimulating factor receptor, whereas PU.1 was expressed at stable levels throughout erythroid differentiation. To study PU.1 function, we synthesized double-stranded phosphorothioate oligonucleotides containing a characterized PU.1 site and demonstrated their ability to specifically compete for PU.1 DNA binding. When added to CD34+ cells in vitro, wild-type PU.1-binding oligonucleotides significantly blocked hematopoietic colony formation, whereas mutated PU.1 oligonucleotides which no longer bind PU.1 had no specific inhibitory effect. These results demonstrate that PU.1 is developmentally upregulated during normal human myelopoiesis and that the function of PU.1 is critical for the development of in vitro hematopoiesis.

Antigens, CD↗
PubMed1994

Multidrug resistance phenotype in patients with chronic lymphocytic leukemia as detected by immunofluorescence (FACS) and northern blot analysis.

The multidrug resistance (MDR) phenotype has been demonstrated to be related to the overexpression of P-glycoprotein, a 170 kDa transmembrane efflux pump. We studied P-glycoprotein expression in 40 patients with chronic B-cell leukemias by FACS analysis using MoAb c219, which recognizes both the MDR1 and the MDR3 gene product. We found significantly elevated P-glycoprotein expression in these patients as compared with normal controls. Patients who had received previous chemotherapy regimens containing MDR-related drugs showed significantly higher P-glycoprotein expression with MoAb c219 than those patients who had been untreated. Northern blot analysis of MDR1 and MDR3 gene expression in 32 of the patients gave a similar result: in the analysis of total RNA four of six patients (66%) pretreated with either vinca alkaloids or anthracyclines were MDR1 positive as opposed to 6 of 26 (23%) who had no treatment or treatment without these agents. In contrast, MDR3 expression was found more frequently (63%), but was randomly distributed in the differently treated groups. Increasing the sensitivity level by analysis of enriched mRNA (polyA+RNA) led to the detection of MDR1 and MDR3 expression all B-CLL patients. We conclude that a basic elevated P-glycoprotein expression is intrinsic in CLL cells, which is possibly upregulated under chemotherapy. This might be responsible for initial and acquired chemotherapy resistance in CLL patients. Follow-up of the B-CLL patients over 46 months showed that the median survival time for MDR1+ patients was 19 months as opposed to 46 months for MDR1- patients (p < 0.01). There was no statistical difference in survival between MDR3+ and MDR3- patients. In the MDR1+ group, eight of nine patients had developed resistance to the therapy with MDR-related drugs. The expression of MDR1 might, therefore, predict treatment failure with MDR-related drugs and be a negative prognostic factor.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Reduced feedback frequency enhances generalized motor program learning but not parameterization learning.

The purpose of the study was to examine the effects of a reduced feedback frequency on the learning of generalized motor programs and movement parameterization. Subjects practiced three movement patterns with the same relative timing and the same relative amplitude, but with varied movement time (Experiment 1) or varied movement amplitude (Experiment 2). KR was given either on 100% or 63% of the trials, with learning being assessed by retention and transfer tests. In both experiments, reduced KR frequency enhanced GMP learning but generally degraded parameter learning. These data provide converging evidence for the dissociation of the program and parameterization processes postulated in GMP theory.

Adult↗
PubMed1993

Contextual interference in movements of the same class: differential effects on program and parameter learning.

Contextual interference effects in motor learning usually were not found when the tasks to be learned presumably required the same generalized motor program (GMP) and differed only with regard to the movement parameters (see Lee, Wulf, & Schmidt, 1992; Magill & Hall, 1990). Thus, tasks requiring different motor programs (e.g., different relative timings) seemed to be a prerequisite for random practice to be more effective than blocked practice. However, the previous studies (that did not find random/blocked differences) used global error measures that confounded errors in relative timing and errors in absolute timing. In the present study, subjects practiced three movement patterns that had the same relative timing (requiring the same GMP) but different overall durations (requiring different parameters). Errors in relative timing and in absolute timing were assessed separately. The results indicate that random practice is more effective for the learning of relative timing (GMP learning) and less effective for the learning of absolute timing (parameter learning) than blocked practice. Preliminary ideas as to the reasons for this effect are discussed.

Journal Article↗