Biomedical subjects

Stefan Schmidt

Publications and source records attributed to Stefan Schmidt.

At least 19 recordsLinked to original sources

PubMed2006

Glucocorticoid resistance in two key models of acute lymphoblastic leukemia occurs at the level of the glucocorticoid receptor.

Glucocorticoids (GCs) specifically induce apoptosis in malignant lymphoblasts and are thus pivotal in the treatment of acute lymphoblastic leukemia (ALL). However, GC-resistance is a therapeutic problem with an unclear molecular mechanism. We generated approximately 70 GC-resistant sublines from a GC-sensitive B- and a T-ALL cell line and investigated their mechanisms of resistance. In response to GCs, all GC-resistant subclones analyzed by real-time polymerase chain reaction (PCR) showed a deficient up-regulation of the GC-receptor (GR) and its downstream target, GC-induced leucine zipper. This deficiency in GR up-regulation was confirmed by Western blotting and on retroviral overexpression of GR in resistant subclones GC-sensitivity was restored. All GC-resistant subclones were screened for GR mutations using denaturing high-pressure liquid chromatography (DHPLC), DNA-fingerprinting, and fluorescence in situ hybridization (FISH). Among the identified mutations were some previously not associated with GC resistance: A484D, P515H, L756N, Y663H, L680P, and R714W. This approach revealed three genotypes, complete loss of functional GR in the mismatch repair deficient T-ALL model, apparently normal GR genes in B-ALLs, and heterozygosity in both. In the first genotype, deficiency in GR up-regulation was fully explained by mutational events, in the second by a putative regulatory defect, and in the third by a combination thereof. In all instances, GC-resistance occurred at the level of the GR in both models.

Cell Line, Tumor↗

PubMed2006

Effect of heavy metals on the biodegradation of dibenzofuran in liquid medium.

The effect of heavy metals on the degradation of dibenzofuran by Sphingomonas wittichii RW1 was determined in liquid cultures. The results showed that 10mg/L cadmium, mercury and copper not only affected the growth of RW1 with dibenzofuran but also the ability of resting cells to degrade this compound. Growth and degradation were strongly inhibited by mercury, even at 1mg/L, while the inhibitory effect of cadmium and copper at the same concentration or at 5mg/L were negligible. In contrast, arsenic and lead did not affect degradation or growth, even at very high concentrations of 100mg/L. Subsequent analyses additionally revealed that concentrations of arsenic and lead remained unchanged following incubation, while those of cadmium, mercury and copper decreased significantly.

Benzofurans↗

PubMed2006

A management approach that drives actions strategically: balanced scorecard in a mental health trust case study.

PURPOSE: Achieving excellence is a current preoccupation in U.K. public health organisations. This article aims to use a case study to explain how a mental health trust delivers excellent performance using a balanced scorecard (BSC) management approach. DESIGN/METHODOLOGY/APPROACH: Reports a project to implement a BSC approach in the South West Yorkshire Mental Health NHS Trust to achieve its "excellence" objectives. The authors were participants in the project. The design of the pilot project was informed theoretically by the work of Kaplan and Norton and practically by in-house discussions on a strategy to achieve excellence. FINDINGS: Explains the process of building a BSC strategy step-by-step. Discusses how the vision and strategies of a mental health trust can be translated into tangible measures, which are the basis for actions that are driven strategically. RESEARCH LIMITATIONS/IMPLICATIONS: There are many possibilities for a BSC management approach and this case study is specific to mental health trusts in the UK, although it is believed that the case has a universally applicable modus operandi. PRACTICAL IMPLICATIONS: This article will help healthcare managers to evaluate the benefits of a BSC management approach. ORIGINALITY/VALUE: This article explains how actions can be structured in connection with a BSC management approach.

Efficiency, Organizational↗

PubMed2006

Biotransformation of 1,2,3-tri- and 1,2,3,4,7,8-hexachlorodibenzo-p- dioxin by Sphingomonas wittichii strain RW1.

Sphingomonas wittichii RW1 is able to catabolize 1,2,3,4-tetrachlorodibenzo-p-dioxin (H. B. Hong, Y. S. Chang, I. H. Nam, P. Fortnagel, and S. Schmidt, Appl. Environ. Microbiol. 68:2584-2588, 2002). Here we demonstrate the aerobic bacterial catabolism of the ubiquitous toxic diaryl ether pollutant 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin by this strain. The products of this biotransformation were identified as tetrachlorocatechol and 2-methoxy-3,4,5,6-tetrachlorophenol by comparing mass spectra recorded before and after n-butylboronate and N,O-bis(trimethylsilyl)-trifluoroacetamide derivatization with those of authentic compounds. Additional experiments showed that the less-chlorinated 1,2,3,7,8-pentachlorodibenzo-p-dioxin was not transformed by the strain RW1. The importance of substitution patterns for the degradability of individual congeners was illustrated by the fact that the 1,2,3-trichlorodibenzo-p-dioxin was catabolized to yield 3,4,5-trichlorocatechol, whereas the 2,3,7-trichlorodibenzo-p-dioxin was not attacked.

Biotransformation↗

PubMed2006

Effects of expectation and caffeine on arousal, well-being, and reaction time.

The objective of this study is to determine the impact of expectation associated with placebo and caffeine ingestion. We used a three-armed, randomized, double-blind design. Two three-armed experiments varying instruction (true, false, control) investigated the role of expectations of changes in arousal (blood pressure, heart rate), subjective well-being, and reaction time (RT). In Experiment 1 (N = 45), decaffeinated coffee was administered, and expectations were produced in one group by making them believe they had ingested caffeinated coffee. In Experiment 2 (N = 45), caffeinated orange juice was given in both experimental groups, but only one was informed about the true content. In Experiment 1, a significant effect for subjective alertness was found in the placebo treatment compared to the control group. However, for RT and well-being no significant effects were found. In Experiment 2, no significant expectancy effects were found. Caffeine produced large effects for blood pressure in both treatments compared to the control group, but the effects were larger for the false information group. For subjective well-being (alertness, calmness), considerable but nonsignificant changes were found for correctly informed participants, indicating possible additivity of pharmacologic effect and expectations. The results tentatively indicate that placebo and expectancy effects primarily show through introspection.

Adolescent↗

PubMed2005

Inadequacy of manual measurements compared to automated CT volumetry in assessment of treatment response of pulmonary metastases using RECIST criteria.

The purpose of this study was to compare relative values of manual unidimensional measurements (MD) and automated volumetry (AV) for longitudinal treatment response assessment in patients with pulmonary metastases. Fifty consecutive patients with pulmonary metastases and repeat chest multidetector-row CT (median interval=2 months) were independently assessed by two radiologists for treatment response using Response Evaluation Criteria In Solid Tumours (RECIST). Statistics included relative measurement errors (RME), intra-/interobserver correlations, limits of agreement (95% LoA), and kappa. A total of 202 metastases (median volume=182.22 mm(3); range=3.16-5,195.13 mm(3)) were evaluated. RMEs were significantly higher for MD than for AV (intraobserver RME=2.34-3.73% and 0.15-0.22% for MD and AV respectively; P<0.05. Interobserver RME=3.53-3.76% and 0.22-0.29% for MD and AV respectively; P<0.05). Overall correlation was significantly better for AV than for MD (P<0.05). Intraobserver 95% LoAs were -1.85 to 1.75 mm for MD and -11.28 to 9.84 mm(3) for AV. The interobserver 95% LoA were -1.46 to 1.92 mm for MD and -11.17 to 9.33 mm(3) for AV. There was total intra-/interobserver agreement on response using AV (kappa=1). MD intra- and interobserver agreements were 0.73-0.84 and 0.77-0.80 respectively. Of the 200 MD response ratings, 28 (14/50 patients) were discordant. Agreement using MD dropped significantly from total remission to progressive disease (P<0.05). We therefore conclude that AV allows for better reproducibility of response evaluation in pulmonary metastases and should be preferred to MD in these patients.

Adult↗

PubMed2005

Identification of glucocorticoid-response genes in children with acute lymphoblastic leukemia.

The ability of glucocorticoids (GCs) to kill lymphoid cells led to their inclusion in essentially all chemotherapy protocols for lymphoid malignancies, particularly childhood acute lymphoblastic leukemia (ALL). GCs mediate apoptosis via their cognate receptor and subsequent alterations in gene expression. Previous investigations, including expression profiling studies with subgenome microarrays in model systems, have led to a number of attractive, but conflicting, hypotheses that have never been tested in a clinical setting. Here, we present a comparative whole-genome expression profiling approach using lymphoblasts (purified at 3 time points) from 13 GC-sensitive children undergoing therapy for ALL. For comparisons, expression profiles were generated from an adult patient with ALL, peripheral blood lymphocytes from GC-exposed healthy donors, GC-sensitive and -resistant ALL cell lines, and mouse thymocytes treated with GCs in vivo and in vitro. This generated an essentially complete list of GC-regulated candidate genes in clinical settings and experimental systems, allowing immediate analysis of any gene for its potential significance to GC-induced apoptosis. Our analysis argued against most of the model-based hypotheses and instead identified a small number of novel candidate genes, including PFKFB2, a key regulator of glucose metabolism; ZBTB16, a putative transcription factor; and SNF1LK, a protein kinase implicated in cell-cycle regulation.

Adolescent↗

PubMed2005

Catabolism of Mesamoll, a technical formulation of alkylsulfonic acid phenyl esters, by two strains of Rhodococcus rhodochrous.

The bacterial catabolism of a technical formulation of alkylsulfonic acid phenyl esters employed as a general purpose plasticizer, Mesamoll, was elucidated. Two strains of the genus Rhodococcus were found able to utilize this substrate mixture as sole source of carbon and energy. Growth experiments along with enzymatic measurements indicated that both strains utilized the phenol that was released from the corresponding alkylsulfonic acid phenyl ester-probably by enzymatic hydrolysis catalyzed by esterases-via the ortho-pathway. By GC/MS analysis it was demonstrated that those alkyl chain homologues with substituents present at or close to the end of the aliphatic backbone (i.e., 2-tetradecylsulfonic acid phenyl ester) are degraded, while those with substituents close to the center of the alkyl chain (i.e., 7-tetradecylsulfonic acid phenyl ester) are rather persistent.

Bacterial Proteins↗

PubMed2005

Glucocorticoid-induced apoptosis and glucocorticoid resistance in acute lymphoblastic leukemia.

Glucocorticoids (GC) induce cell cycle arrest and apoptosis in lymphoid cells, and therefore constitute a central component in the treatment of lymphoid malignancies, particularly childhood acute lymphoblastic leukemia (ALL). In spite of its clinical significance and considerable efforts in many laboratories, however, the molecular basis of GC-induced apoptosis and the clinically important resistance phenomenon remains poorly defined. The anti-leukemic GC effects are critically dependent upon sufficient expression of the GC receptor (GR) throughout the response. In ALL cell lines, this is associated with, and may depend upon, GR autoinduction. In corresponding in vitro models, GC resistance frequently results from mutations in the GR gene and/or deficient regulation of its expression. The downstream components of the pathway, i.e., the GC-regulated genes responsible for cell death induction, have been studied by microarray-based comparative expression profiling, resulting in identification of a considerable number of GC-regulated candidate genes. Their possible function in the death response is, however, still undefined. One model predicts direct regulation of the apoptotic machinery, e.g., components of the "Bcl-2 rheostat", while a complementary hypothesis suggests deleterious GC effects on essential cellular functions, such as metabolism, production of and/or response to oxygen radicals, general transcription/translation, pH and volume control, etc. These regulatory effects may entail cell death, particularly if maintained for sufficient time through GR autoinduction. The latter form of cell death may occur even in the absence of functional apoptotic machinery (e.g., when caspases are blocked), but in this case appears to entail a more necrotic morphology. Taken together, GC may induce different types of cell death through distinct molecular pathways, depending on the cellular context. GC resistance might frequently result from defective GR expression, perhaps the most efficient means to target multiple antileukemic pathways.

Animals↗

PubMed2005

Cancer cell line identification by short tandem repeat profiling: power and limitations.

Cancer cell lines are used worldwide in biological research, and data interpretation depends on unambiguous attribution of the respective cell line to its original source. Short-tandem-repeat (STR) profiling (DNA fingerprinting) is the method of choice for this purpose; however, the genetic stability of cell lines under various experimental conditions is not well defined. We tested the effect of long-term culture, subcloning, and generation of drug-resistant subclones on fingerprinting profiles in four widely used leukemia cell lines. The DNA fingerprinting profile remained unaltered in two of them (U937 and K562) throughout 12 months in culture, and the vast majority of subclones derived therefrom by limiting dilution after long-term culture revealed the same profile, indicating a high degree of stability and clonotypic homogeneity. In contrast, two other cell lines (CCRF-CEM and Jurkat) showed marked alterations in DNA fingerprinting profiles during long-term culture. Limiting dilution subcloning revealed extensive clonotypic heterogeneity with subclones differing in up to eight STR loci from the parental culture. Similar heterogeneity was observed in subclones generated by selection culture for drug resistance where DNA fingerprinting proved useful in identifying possible resistance mechanisms. Thus, common tissue culture procedures may dramatically affect the fingerprinting profile of certain cell lines and thus render definition of their origin difficult.

Apoptosis↗

PubMed2004

The androgen receptor co-activator CBP is up-regulated following androgen withdrawal and is highly expressed in advanced prostate cancer.

The androgen receptor co-activator CREB (cAMP-response element binding protein)-binding protein (CBP) enhances androgen receptor activity after stimulation by androgenic hormones and androgen receptor antagonists. The aim of the present study was to investigate the regulation of CBP expression by steroid and peptide hormones in prostate cancer. For this purpose, LNCaP cells were treated with the synthetic androgen methyltrienolone (R1881), epidermal growth factor, insulin-like growth factor-I or interleukin-6 (IL-6). CBP protein and mRNA expression were studied by western blotting and real-time PCR, respectively. CBP expression was also investigated in tissue specimens obtained from 26 patients with therapy-resistant carcinoma of the prostate. In LNCaP cells, CBP protein was down-regulated by R1881 or IL-6. The non-steroidal anti-androgen bicalutamide antagonized the effects of R1881 and the Janus kinase inhibitor AG 490 reversed the effects of IL-6. In contrast, neither R1881 nor IL-6 caused any effect on CBP expression in the PC-3 cell line. In LNCaP cells, the inhibition of CBP expression by R1881 or IL-6 was also observed at the mRNA level. CBP protein was detected in all 26 specimens by immunohistochemistry. The results suggest that up-regulation of CBP during androgen ablation may be relevant to the failure of endocrine therapy in patients with prostate carcinoma.

Aged↗

PubMed2004

Mindfulness-based stress reduction and health benefits. A meta-analysis.

OBJECTIVE: Mindfulness-based stress reduction (MBSR) is a structured group program that employs mindfulness meditation to alleviate suffering associated with physical, psychosomatic and psychiatric disorders. The program, nonreligious and nonesoteric, is based upon a systematic procedure to develop enhanced awareness of moment-to-moment experience of perceptible mental processes. The approach assumes that greater awareness will provide more veridical perception, reduce negative affect and improve vitality and coping. In the last two decades, a number of research reports appeared that seem to support many of these claims. We performed a comprehensive review and meta-analysis of published and unpublished studies of health-related studies related to MBSR. METHODS: Sixty-four empirical studies were found, but only 20 reports met criteria of acceptable quality or relevance to be included in the meta-analysis. Reports were excluded due to (1) insufficient information about interventions, (2) poor quantitative health evaluation, (3) inadequate statistical analysis, (4) mindfulness not being the central component of intervention, or (5) the setting of intervention or sample composition deviating too widely from the health-related MBSR program. Acceptable studies covered a wide spectrum of clinical populations (e.g., pain, cancer, heart disease, depression, and anxiety), as well as stressed nonclinical groups. Both controlled and observational investigations were included. Standardized measures of physical and mental well-being constituted the dependent variables of the analysis. RESULTS: Overall, both controlled and uncontrolled studies showed similar effect sizes of approximately 0.5 (P<.0001) with homogeneity of distribution. CONCLUSION: Although derived from a relatively small number of studies, these results suggest that MBSR may help a broad range of individuals to cope with their clinical and nonclinical problems.

Adaptation, Psychological↗

PubMed2004

Mindfulness and healing intention: concepts, practice, and research evaluation.

This paper deals with the role of the health care professional in creating an optimal healing environment (OHE), with a special focus on which inner state and way of being in the world can create a healing intention. A core thesis is that every healing effort and every healing intention starts within the health care professional. An accepting, mindful, and warm-hearted relationship with self is primary to any healing intention. Important concepts to develop such an attitude are mindfulness, love, compassion, and awareness. The concept of a healing attitude toward the self is described, as is the mirror principle that states there is symmetry between someone's relationship with the outer world and his or her inner world. The mindfulness concept is outlined through a set of mental and heart qualities. Mindfulness is strongly related to compassion, and it is compassion that serves as a source for all healing intentionality. Compassion connects the suffering of the patient with the healer's own suffering, and this emotional connection instantiates a healing relationship. The power and importance of mindfulness and compassion for healing are explored along the Frank model of nonspecific therapeutic components. This is the approach whereby a health care professional can elicit self-healing powers in patients through his or her inner attitudes. Finally, a research program and some hypotheses on how to implement and research this specific approach toward the creation of an OHE are outlined.

Attitude of Health Personnel↗

PubMed2004

Brain-computer communication and slow cortical potentials.

A thought translation device (TTD) has been designed to enable direct brain-computer communication using self-regulation of slow cortical potentials (SCPs). However, accuracy of SCP control reveals high intersubject variability. To guarantee the highest possible communication speed, some important aspects of training SCPs are discussed. A baseline correction of SCPs can increase performance. Multichannel recordings show that SCPs are of highest amplitude around the vertex electrode used for feedback, but in some subjects more global distributions were observed. A new method for control of eye movement is presented. Sequential effects of trial-to-trial interaction may also cause difficulties for the user. Finally, psychophysiological factors determining SCP communication are discussed.

Adult↗

PubMed2004

Distant intentionality and the feeling of being stared at: two meta-analyses.

Findings in parapsychology suggest an effect of distant intentionality. Two laboratory set-ups explored this topic by measuring the effect of a distant intention on psychophysiological variables. The 'Direct Mental Interaction in Living Systems' experiment investigates the effect of various intentions on the electrodermal activity of a remote subject. The 'Remote Staring' experiment examines whether gazing by an observer covaries with the electrodermal activity of the person being observed. Two meta-analyses were conducted. A small significant effect size (d =.11, p =.001) was found in 36 studies on 'direct mental interaction', while a best-evidence-synthesis of 7 studies yielded d =.05 (p =.50). In 15 remote staring studies a mean effect size of d = 0.13 (p =.01) was obtained. It is concluded that there are hints of an effect, but also a shortage of independent replications and theoretical concepts.

Humans↗

PubMed2003

Semi automated production of a set of different recombinant GST-Streptag fusion proteins.

We describe a high-throughput procedure for the large-scale production of recombinant GST-Streptag fusion proteins. This three-step process, comprising cloning, expression and purification, simultaneously produces up to 96 different proteins in a multi-well format with high yield and purity. Two complementary oligonucleotides, together encoding a specific peptide sequence are annealed and directly ligated into a pre-digested pGEX-2T plasmid carrying an N-terminal GST-tag and a C-terminal Streptag. Following expression, a multichannel pipetting robot purifies the resulting fusion proteins within 2 h by affinity chromatography on Streptactin Macroprep mini-columns.

Automation↗

PubMed2003

Topical treatment of chronic low back pain with a capsicum plaster.

The efficacy and tolerance of a capsicum plaster in non-specific low back pain was investigated in a double-blind, randomised, placebo-controlled multicentre parallel group study. A total of 320 patients were randomly assigned to two groups of n=160 subjects treated by the active or the placebo plaster. The main outcome measures used were a compound pain subscore of the Arhus low back rating scale (continuous variable), and a response criterion of a reduction in pain subscore=30% from baseline to final assessment (secondary, non-continuous variable). In addition, the partial pain scores, disability and mobility restriction subscores, the total score of the Arhus low back rating scale, the global evaluation of efficacy by investigator and patient, adverse events, a patient questionnaire on use of the plaster, and an evaluation of tolerance by investigator and patient were obtained. After 3 weeks treatment with capsicum and placebo plaster respectively, the compound pain subscore was reduced by 42% (capsicum) and 31% (placebo) from values on entry. Responder rate was 67% versus 49% (p=0.002). The investigators rated efficacy as "excellent" or "good" by 74% and 36%; the patient's efficacy rating "symptomfree" or "improved" reached 82% and 50%. Adverse local drug reactions were found in 12 patients (7.5%) on capsicum and 5 (3.1%) on placebo. No systemic side-effects were observed. The superiority of the treatment of chronic non-specific low back pain with capsicum plaster compared to placebo was clinically relevant and highly statistically significant. The capsicum plaster offers a genuine alternative in the treatment of non-specific low back pain.

Administration, Topical↗

PubMed2003

Respiration-related artifacts in EDA recordings: introducing a standardized method to overcome multiple interpretations.

When electrodermal activity (EDA) recordings are controlled for artifacts, i.e., electrodermal reactions [EDRs] elicited by breathing irregularities, several problems arise. For example, respiration is difficult to evaluate because there are no clear-cut criteria for its values, e.g., wave form, depth. Furthermore, respiration and EDA are rather complexly intertwined, and there is no established or standardized method for evaluation. Especially when subjects are not stimulated, i.e., when nonspecific EDRs are taken, EDR recordings elicited by irregular breathing may overestimate the subject's arousal and bias any given research question. Moreover, incidences of concurrent consecutive EDRs and changes in respiratory activity may encourage multicausal interpretation due to both signals' having a common central causation. To circumvent such problems, we developed a method which provides rule-based guidelines to identify potential artifacts. Two experiments (N = 14 and N = 12) were conducted to test the accuracy of the judgments of three independent raters. The reliability coefficients for the number of electrodermal reactions and the sum of their amplitudes yielded satisfactory coefficients of convergence for each individual experiment (.87 and .82 in Exp. 1 vs .94 and .95 in Exp. 2) as well as for the two experiments combined (.92 and .91).

Adolescent↗