Four-year follow-up on fatigue and sleep quality of a three-armed partly randomized controlled study in breast cancer survivors with cancer-related fatigue.

Cancer-related fatigue (CRF) is a frequent long-term symptom in non-metastasized breast cancer patients (BC). This 4-year follow-up intended to compare the long-term effects of a 10-week multimodal therapy (MT: sleep education, psychoeducation, eurythmy- and painting therapy) and combination therapy [CT: MT plus aerobic training (AT)] to AT-control. BC-patients were randomized or allocated by preference to three arms in a comprehensive cohort study. Primary outcome was a composite score including Pittsburgh Sleep Quality Index (PSQI) and Cancer Fatigue Scale (CFS-D), captured at baseline, after 10 weeks of intervention (T1), 6 months later (T2), and after 4 years (T3). We exploratively tested for superiority of MT and CT versus AT after 4 years (T3) based on the statistical model of the main analysis. Of 126 (65 randomized) BC-patients included, 105 started treatments and 79 were re-assessed for long-term effects (T3). MT and CT were superior over AT after 4 years regarding PSQI/CFS-D and PSQI sum-score, respectively (all p < 0.05), but not for CFS-D. The multimodal and combination treatment for breast cancer patients with CRF indicates sustainable long-term superiority over aerobic training for the outcomes sleep quality and combined sleep quality/fatigue. A confirmative randomized controlled trial is warranted.

[Spiritual needs of patients in an emergency room]. / Spirituelle Bedürfnisse von Patienten eines Notfallzentrums.

BACKGROUND: Spiritual needs (spN) are important for human beings-independently of religious affiliation. They can be a resource for coping with stressful situations, e.g., those triggered by the acute onset of a disease. Emergency rooms are hospital departments with high medical performance which may cause a particular insecurity among emergency patients. The present study is the first to examine spiritual needs in a sample of patients in the emergency room. METHODS: A total of 383 out of 479 patients were approached and asked to complete the German version of the Spiritual Needs Questionnaire (SpNQ-20). All consented to the collection of demographics and clinical data. The analysis encompassed descriptive statistics, correlations analysis, univariate and multiple variance analysis. RESULTS: The needs for inner peace and generative needs (to pass something on to others, to do something for others) were more important than religious (rN) and existential (eN) needs. We did not find a correlation between spN on the one hand and the reason for consultation, the severity, and the number of comorbidities on the other hand. Age did not play a decisive role, rather, patients' needs, especially rN, were significantly more important among women than among men. CONCLUSION: Even in an emergency situation, people are ready to express their spN. Early assessment of these needs exposes important nonmedical aspects of the sick person and helps to consider the assessed needs. Further studies will show whether this has an impact on the further course of treatment and the well-being of the patients.

Development in Danish medical students' empathy: study protocol of a cross-sectional and longitudinal mixed-methods study.

BACKGROUND: Clinical empathy has been associated with positive outcomes for both physicians and patients such as: more accurate diagnosis and treatment, increased patient satisfaction and compliance, and lower levels of burnout and stress among physicians. International studies show mixed results regarding the development of empathy among future physicians associating medical education with decline, stability or increase in empathy levels. These mixed results are due to several study limitations. In Denmark, no investigation of Danish medical students' empathy trajectory has yet been conducted wherefore such a study is needed that optimizes the study design of earlier studies. METHODS: The aim of the study is to examine and analyze empathy levels and empathy changes among Danish medical students from the four medical faculties in Denmark, employing a cross-sectional and longitudinal mixed-methods design including a control group of non-medical students. By supplementing cross-sectional and longitudinal questionnaire studies with a focus group interview study it is the aim to identify and analyze factors (including educational) that are perceived by medical students to influence the development of empathy and its expression in clinical care. DISCUSSION: The results of the study will provide insight into the trajectory of medical students' empathy and in undergraduate and graduate students' experiences with and perceptions of empathy development. In addition, the study will provide evidence to support further research on how targeted educational programmes can best be designed to educate empathic and patient-centered physicians.

Reliability and first validity of the inner correspondence questionnaire for painting therapy (ICPTh) in a sample of breast cancer patients.

Objectives Art therapy (ArT) such as mindfulness-oriented painting therapy is increasingly used in psychosomatic, oncological integrative and rehabilitative medicine. Though it remains unknown how ArT works, we hypothesize that an engaged participation with painting ('Inner-Correspondence') contributes to improved symptom scores. In the context of a comprehensive cohort study for breast cancer survivors with cancer-related fatigue, we developed a patient-reported outcome measure to assess 'Inner Correspondence' with painting therapy and conducted a first validation study. Design A 24-item questionnaire on 'Inner Correspondence' (ICPTh) was administered after ten weeks of intervention and at six month followup together with concurrent scales (Inner Correspondence and Peaceful Harmony, Cancer Fatigue Scale, Hospital Anxiety and Depression Scale, Internal Coherence Scale). Statistical assessment included reliability- and factor analyses. Results A total of n = 68 BC (mean age, 58.2 years, SD = 8.7) participated in the preliminary validation study. Exploratory factor analysis revealed a robust 22-item scale with an unambiguous four-factor solution explaining 78% of total variance and the following subsales: 1) therapy congruence and relaxation (11 items), 2) inner development and mood (6 items), 3) artistic skill (3 items) and 4) task congruence (2 items). The 22-item ICPTh yielded high reliability (Cronbach's alpha = .966, item-total correlation = .497 - .883, test-retest reliability = .888). Conclusions We present a reliable instrument to measure 'Inner Correspondence' with painting therapy. Due to the small sample size and sample selection further validation studies are indicated.

[Systematic Review of the Application of Complementary and Alternative Medicine and their Potential Therapeutic Benefits in the Treatment of Ophthalmology Patients]. / Ergebnisse eines systematischen Reviews zu Einsatz und berichtetem therapeutischem Nutzen komplementärmedizinischer Methoden in der Augenheilkunde.

Purpose A systematic review was carried out of the reported therapeutic effects of complementary and alternative medicine methods as supplementary or primary treatments for patients suffering from glaucoma, cataract or age-related macular degeneration (AMD). Material and Methods For the years 1990 to 2013, the following databases were screened for reports of the application of complementary and alternative treatments: PubMed, Cochrane Library, EMBASE, CAMbase and AMED. Both randomised and prospective non-randomised patient trials were included in the review; results were evaluated in the following classes: "phytotherapy", "acupuncture/acupressure", "biofeedback" and "other alternative treatments". The studies were evaluated by measures of clinical effect, statistical significance (p value and/or confidence interval) and the underlying trial design. Results 30 clinical trials were included, including 13 on glaucoma, 5 on cataract and 12 on AMD patients. These trials were based on patient numbers of 6 - 332, 27 - 157 and 6 - 328 patients, respectively. Phytotherapy was applied in 14 trials, including 6 on glaucoma patients (all 6 with a controlled design, and 3 of which reporting statistically significant results); 5 trials were on cataract patients (3 with a controlled design and 2 with a significant result) and 3 on AMD patients (only 1 with a controlled design, with a significant result). Acupuncture/acupressure was investigated in 9 trials, 5 on glaucoma patients (3 with a controlled design, 1 with a significant result); no acupuncture/acupressure trial was found in cataract patients, but 4 trials in AMD patients (none with a controlled design). Biofeedback was studied in 4 trials, all on AMD patients (only one with a controlled design, without statistically significant findings). Conclusion Despite its rigorous inclusion criteria, this review identified several clinical trials on complementary and alternative medicine in ophthalmological patients. Phytotherapeutic methods gave significant results in half of the reported controlled trials, whereas there were few significant benefits with acupuncture or acupressure.

Spiritual needs in patients suffering from fibromyalgia.

The objective of this study was to assess spiritual needs of patients with fibromyalgia syndrome (FMS) and to evaluate correlations with disease and health associated variables. Using a set of standardized questionnaires (i.e., Spiritual Needs Questionnaire, Fibromyalgia Impact Questionnaire, SF-36's Quality of Life, Brief Multidimensional Life Satisfaction Scale, etc.), we enrolled 141 patients (95% women, mean age 58 ± 10 years). Here, needs for inner peace and giving/generativity scored the highest, while existential needs and religious needs scored lowest. Particularly inner peace needs and existential needs correlated with different domains of reduced mental health, particularly with anxiety, the intention to escape from illness, and psychosocial restrictions. Thirty-eight percent of the patients stated needs to be forgiven and nearly half to forgive someone from their past life. Therefore, the specific spiritual needs of patients with chronic diseases should be addressed in clinical care in order to identify potential therapeutic avenues to support and stabilize their psychoemotional situation.

Spiritual needs of patients with chronic pain diseases and cancer - validation of the spiritual needs questionnaire.

PURPOSE: For many patients confronted with chronic diseases, spirituality/religiosity is a relevant resource to cope. While most studies on patients' spiritual needs refer to the care of patients at the end of life, our intention was to develop an instrument to measure spiritual, existential and psychosocial need of patients with chronic diseases. METHODS: In an anonymous cross-sectional survey, we applied the Spiritual Needs Questionnaire (SpNQ version 1.2.) to 210 patients (75% women, mean age 54 +/- 12 years) with chronic pain conditions (67%), cancer (28%), other chronic conditions (5%). Patients were recruited at the Community Hospital Herdecke, the Institute for Complementary Medicine (University of Bern), and at a conference of a cancer support group in Herten. RESULTS: Factor analysis of the 19-item instrument (Cronbach's alpha +/- .93) pointed to 4 factors which explain 67% of variance: Religious Needs, Need for Inner Peace, Existentialistic Needs (Reflection / Meaning), and Actively Giving. Within the main sample of patients with chronic pain and cancer, Needs for Inner Peace had the highest scores, followed by Self competent Attention; Existentialistic Needs had low scores, while the Religious Needs scores indicate no interest. Patients with cancer had significantly higher SpNQ scores than patients with chronic pain conditions. There were just some weak associations between Actively Giving and life satisfaction (r +/- .17; p +/- .012), and negatively with the symptom score (r +/- -.29; p < .0001); Need for Inner Peace was weakly associated with satisfaction with treatment efficacy (r +/- .24; p < .0001). Regression analyses reveal that the underlying disease (i.e., cancer) was of outstanding relevance for the patients' spiritual needs. CONCLUSION: The preliminary results indicate that spiritual needs are conceptually different from life satisfaction, and can be interpreted as the patients' longing for spiritual well-being. Methods how health care professionals may meet their patients' spiritual needs remain to be explored.

[Assessment of quality of life in health services research - conceptual, methodological and structural prerequisites]. / Die Erfassung von Lebensqualität in der Versorgungsforschung - konzeptuelle, methodische und strukturelle Voraussetzungen.

On July 1, 2009, the German Network for Health Services Research [Deutsches Netzwerk Versorgungsforschung e. V. (DNVF e. V.)] approved the Memorandum III "Methods for Health Services Research", supported by the member societies mentioned as authors and published in this Journal [Gesundheitswesen 2009; 71: 505-510]. This is an in-depth publication on "quality-of-life assessment in health services research". Within the context of the health sciences, quality of life (QL) encompasses the subjective well-being and functioning in the physical, psychological and social domains. QL informs about the aspects of health care that "actually get to the patient". QL is what patients primarily experience, what they talk about and what to a large degree affects the acceptance of health-care services and processes in the society. Therefore, QL can be considered as a highly important endpoint within health services research. The importance of the construct quality of life is also emphasised in German treaties on social law and utility analyses. This paper is the first account on the relations between health services research and the concept and assessment of QL. Our working group has specified key criteria for QL assessment within studies on health services research. (1) Assessment instruments need to comply with standard quality criteria (reliability, validity, sensitivity, interpretability) and the decision for a particular instrument has to be reasonably justified. (2) Study design and study population have to match with the scientific research question and the sample size has to be biometrically sound. (3) QL assessment including time points over the course of the study has to follow a standardized protocol. (4) Criteria for analysis and interpretation have to be prospectively specified. (5) Studies focusing on diagnostic/therapeutic issues need to specify standards for diagnostic criteria and related therapeutic interventions.

Validation of the brief multidimensional life satisfaction scale in patients with chronic diseases.

OBJECTIVE: We intended to determine the reliability of a brief life satisfaction scale in a sample of patients with chronic diseases, and to analyze its external validity. METHODS: Reliability and factor analysis of the 8-item "Brief Multidimensional Life Satisfaction Scale" (BMLSS) were performed according to standard procedures. The test sample contained 979 individuals (mean age 54+/-11 years). Forty-two percent had cancer, 22% chronic pain conditions, 10% depressive disorders, 6% other chronic diseases, and 20% were healthy. RESULTS: Reliability analysis of the 8-item pool revealed a good internal consistency coefficient (Cronbach's alpha=.869), and a single-factor structure which explains 53% of variance. The BMLSS sum scores significantly differed with respect to the underlying disease, family status, duration of disease, and age. The highest scores were found in healthy individuals, and the lowest in patients with chronic pain conditions and depressive disorders. In cancer patients, the BMLSS correlated negatively with Depression/Anxiety (HADS), Fatigue (CFS-D), and positively with SF-12's mental health and to a weaker content also with physical health. Stepwise regression analyses revealed that life satisfaction can be predicted best by (the absence of) depression, but also by Conscious Living (AKU), which is an active cognitive-behavioral style in terms of adaptive coping. CONCLUSIONS: The evaluation of the BMLSS revealed that the instrument has good psychometric properties and can be regarded as a brief, reliable and valid measure of LS in patients with chronic diseases. The instrument can be an important additive to existing health-related quality of life questionnaires, since it captures dimensions that contribute to quality of life but are not health related.

Adaptation of the Herdecke Quality of Life questionnaire towards quality of life of cancer patients.

Although instruments for the measurement of quality of life (QoL) do exist for cancer patients, factors like sleepiness or digestion are only marginally addressed. We intended to adapt the Herdecke Quality of Life (HLQ) towards these aspects in a multi-centre cross-sectional validation study. A group of 293 subjects [79% female, age: 55.9 +/- 13.4 years; 146 cancer patients, 28 patients with rheumatic diseases and a healthy control group (n = 119)]. Structural relations between the items were detected by factor and reliability analyses. For external validation, correlations with the hospital anxiety and depression scale (HADS), self-regulation score (SRS) and the Marburger short questionnaire on chronotypology (MQC) were performed, and test-retest reliability was calculated. Factor analysis found three sub-scales: physical abilities (PA) (Cronbach's alpha = 0.90), sleep quality (SQ) (Cronbach's alpha = 0.89) and digestive well-being (DWB) (Cronbach's alpha = 0.80). Sleep quality correlated well with HADS-anxiety (r =-0.52), PA with HADS-depression (r =-0.49). We found moderate correlations of PA and SQ with SRS, while the HLQ scales did not correlate with the MQC. Analysis of test-retest reliability resulted in values of r = 0.757 for PA, r = 0.715 for SQ and r = 0.603 for DWB. The HLQ-cancer suits to measure unique features of cancer-related QoL aspects. In future studies it has to be tested in larger samples of cancer patients.

Validation of the German version of the Cancer Fatigue Scale (CFS-D).

Fatigue is a very important factor determining the quality of life in patients with malignancies. Cancer fatigue occurs with anaemia, during and after chemo- or radiotherapy and in patients with advanced tumours. The Cancer Fatigue Scale (CFS) is a three-dimensional inventory with 15 items which was originally developed in Japan. We present the results of a validation study of the German version (CFS-D) of this instrument. The CFS-D was administered to 114 participants in a matched-pair study. In total, 57 (41 women) of the participants had malignant conditions, and 57 (41 women) were healthy volunteers. The Fatigue Numerical Scale was used to test convergence. The physical and performance status of the cancer patients was assessed by the Karnofsky-Index. Criteria for testing multidimensionality were the Hospital Anxiety and Depression Scale, and the questionnaire on autonomic regulation. We generated a three-dimensional inventory of the CFS-D with the subscales physical fatigue/vitality, cognitive and affective fatigue. The reliability results for the complete scale: Cronbach's alpha: r(alpha) = 0.94, retest reliability: r(rt) = 0.82. The convergence criteria correlate between r = 0.44-0.65 (all P < 0.001). The CFS-D is highly reliable and has construct validity in relation to other measures.

Course of mitogen-stimulated T lymphocytes in cancer patients treated with Viscum album extracts.

BACKGROUND: In a prospective observational study, the impact of two different dose regimes of a commercially available fermented Viscum album L. extract (VA-E, Iscador) on the function of T lymphocytes from cancer patients was investigated. PATIENTS AND METHODS: A total of 71 cancer patients were enrolled. These patients attended two different sections of a tumor outpatient clinic which are used to apply different VA-E escalation schemes. Our hypothesis was that a rapid dose escalation of subcutaneously applied VA-E may induce strong local reactions at the injection side (>3 cm diameter) and may have an effect on the functional competence of T lymphocytes (mitogen-activated interleukin-2 receptor alpha chain), which was recorded over an observation period of six month. RESULTS: Within this observation period, a decline of stimulated T cell function was observed, particularly in patients with colorectal or prostate cancer; this decline was not seen in patients with breast cancer (who received lower mean concentrations per month) nor in patients with dose adaptation in response to too strong local reactions. CONCLUSION: With respect to T-cell function, our results indicate that in patients without local reactions, a long lasting mistletoe extract application should be withheld periodically to allow T-cell reactivity to recover.

[Pilot study for the development of a questionnaire for the measuring of the patients' attitude towards spirituality and religiosity and their coping with disease(SpREUK)]. / Pilotstudie zur Entwicklung eines Fragebogens zur Erfassung der spirituellen und religiosen Einstellung und des Umgangs mit Krankheit (SpREUK).

OBJECTIVE: Life-threatening diseases are the standard situations which confront patients with spirituality and religiosity. Although both are wellknown factors in disease coping, their measurability and operationability remains a basic problem due to the variety of different meanings and interpretations of these terms. In this paper we describe the development of a questionnaire for the measuring of the patients' attitudes towards spirituality and religiosity and their disease coping (SpREUK). MATERIAL AND METHODS: For a first evaluation, 129 patients with a mean age of 54 years (SD 14.3) completed the questionnaire. 67% of them were women. 76% had a Christian denomination, 19% no denomination, and only 4% reported other religious traditions. 45% of the patients suffered from cancer, 18% from multiple sclerosis, 22% from other chronic diseases, and 15% from acute diseases. The questionnaire comprises 29 five-stage likert-scaled items. Apart from a descriptive analysis of the single items, reliability (Cronbach's alpha) and validity analysis (factor analysis) of the questionnaire was performed. RESULTS: Factor analysis resulted in four dimensions: (1) 'Search for meaningful support', (2) 'Guidance, control and message of disease', (A) 'Support in relations with the external through spirituality/religiosity', and (B) 'Stabilization of the inner condition through spirituality/religiosity'. The reliability of the four scales of the SpREUK questionnaire is high: Cronbach's alpha 0.82, 0.62, 0.89, resp. 0.74. Women had significantly higher SpREUK scores for scales 1 and 2 than male patients. Non-denominational patients had significantly lower scores in all four scales than those with a Christian denomination. The scores did not correlate with disease or duration of disease; however, there might be a positive correlation between age and the score of scale 2. DISCUSSION: The impact of spirituality and religiosity on the course of disease, coping skills, and health-related quality of life is broadly discussed not only in complementary medicine. With the SpREUK questionnaire we present a reliable and valid instrument to measure the patients' search for meaningful support through spirituality/religiosity in terms of disease coping and health restoration. Further evaluation of this instrument is planned with a focus on hospitals which are affiliated with a specific denomination, as a reasonable extension of quality management and concept development.

Mistletoe in cancer - a systematic review on controlled clinical trials.

BACKGROUND: Mistletoe preparations are among the most widely used unconventional cancer therapies in Central Europe. Their clinical effectiveness, however, is controversial. OBJECTIVE: To investigate whether prospective controlled clinical trials provide evidence for efficacy of mistletoe therapy in cancer. DESIGN: Systematic review. MATERIAL AND METHODS: Search of 11 electronic databases, reference lists and expert consultations. Criteria based analysis was performed to assess methodological quality of the studies. RESULTS: Twenty-three studies were identified: 16 randomized, 2 quasi-randomized and 5 non-randomized. Cancer sites included breast, lung, stomach, colon, rectum, head and neck, kidney, bladder, melanoma, glioma, and genital. Among these studies, statistically significant positive outcomes were reported for survival (n = 8), tumor remission (n = 1), overall quality of life (QOL) (n = 3), and QOL in relation to side effects during cytoreductive therapy (n = 3). Further, positive trends were reported for survival (n = 8), disease-free-survival (n = 1), and tumor remission (n = 2). Several studies reported no effect on survival (n = 4), disease-free-survival (n = 1), recurrence (n = 2), remission (n = 3), and QOL (n = 1). One study showed a negative trend for disease-free-survival. However, methodological quality of the studies was sometimes far below the standard that is today regarded as optimal or necessary. In view of substantial heterogeneity of the studies and potential positive and negative biases, we considered effect size estimation by quantitative synthesis to be unreliable and decided on a non-quantitative synthesis and discussion. Mistletoe therapy was well tolerated, and no major side effects were noted. CONCLUSIONS: Among 23 identified studies evaluated for clinically relevant outcome measures, 12 studies showed one or more statistically significant, positive results, another 7 studies showed at least one positive trend, 3 showed no effect and 1 had a negative trend. All studies, however, suffered from methodological shortcomings to some degree, and many of the studies are not conclusive. As several reasonably well conducted studies indicate beneficial effects, further properly designed trials should be encouraged. Future controlled studies should take into account the methodological limitations and potential biases of these past mistletoe trials.

The care information system PIK--the fit between user and system.

OBJECTIVES: The presented laboratory study explores the relationship between the care information system PIK and its users, focusing on intuitive program usage, occurring errors, the usefulness of the evaluation method, and the role of person related variables. METHODS: Three studies were conducted. While thinking aloud, a sample of 26 participants performed certain tasks, which were recorded in protocols. In addition, the occurring errors were rated in an error taxonomy. RESULTS: While the actual use of the program proved quite easy, conceptual structuring caused the participants difficulties. These difficulties stemmed mainly from problems encountered in generating a clear mental picture of the system, and the consequences of the actions. Over time, the program showed a positive development. CONCLUSIONS: Discussion of the results focuses on implementation processes in the context of usability research. The need to train users in the conceptual structure of the program and to build realistic expectations are the focus of our outline.

The role of tacit knowledge in the work context of nursing.

AIMS OF THE STUDY: Previous research on the role of tacit knowledge is ambiguous. Some studies show the superiority of expertise, while other studies found experts would not be better than laymen. This paper aims at clarifying the contribution of tacit knowledge to expertise in the domain of nursing. BACKGROUND: Two important concepts for dealing with critical situations are outlined - tacit knowledge and experience-guided working. The framework of tacit knowledge and experience-guided working can contribute to an explanation of the ambiguous results. Tacit knowledge is acquired implicitly in the course of working and is therefore not subject to reflection. For this reason it can contain erroneous or problematic contents. METHODS: A method for the explication of tacit knowledge was developed and a laboratory study with 16 experienced nurses conducted. In the laboratory study the nurses had to deal with a critical nursing situation that was developed in co-operation with nursing experts. The explicit knowledge of the nurses was tested before the laboratory study. RESULTS: No systematic differences in explicit knowledge could be observed, i.e. differences in performance could not be attributed to this knowledge mode. Results from multidimensional scaling procedures illustrate differences in the tacit knowledge of nurses who successfully accomplished the critical situation and those who did not. CONCLUSIONS: The findings are in line with the assumption that experience-guided working is of the utmost importance for dealing with critical situations. Consequences of these results for nursing and person-related services in general are discussed and the aim of future research is outlined.

[Team and patient orientation in nursing as a part of quality management--status and needs for research]. / Mitarbeiter- und Patientenorientierung in der Pflege als Teil des Qualitätsmanagements--Stand und Forschungsbedarf.

The paper introduces a holistic concept of quality management in hospitals--the approach of employee and patient orientation ("MPO-Mitarbeiter- und Patientenorientierung"). It is shown that quality in health care does not primarily depend on the regulation of quantitative input and output of the health care system but is largely determined by improvements of processes within the system. TQM models like the European Quality Award are showing the way towards improving processes by focusing on employee and client orientation and satisfaction. Patient satisfaction has become a more and more popular indicator for quality in health care. However, reviews of the vast amount of literature on patient satisfaction reveal that present research suffers from the same problems and shortcomings that have already been criticised about 20 years ago. Only few studies choose innovative approaches by integrating the perspectives of patients and employees and by refraining from the insufficient measurement of satisfaction. Three of these studies are presented and compared. Against this background the MPO-approach is described; the approach integrates results from work psychology as well as from nursing research within the concept of complete activity. In contrast to other models of quality management the MPO-approach provides suitable methods for analysis and assessment of employee and patient orientation. These methods are described and are finally discussed with respect to strategies of total quality management in hospitals.

Intracellular expression of IL-4 and inhibition of IFN-gamma by extracts from European mistletoe is related to induction of apoptosis.

BACKGROUND: Extracts from European mistletoe are used for adjuvant cancer treatment. Their influence on the intracellular expression of cytokines of the T-helper cells type-1 (Th1; IFN-gamma) or type-2 (Th2; IL-4) is still unknown. MATERIALS AND METHODS: Lymphocytes from controls were incubated with mistletoe extracts (ME) and mistletoe lectins (ML) for 24 hours and co-stimulated with PMA/Ca-ionophore/monensin during the last 6 hours. Apoptosis and intracellular cytokine expression were detected by flow cytometry, the cytokine release into the supernatants by ELISA. RESULTS: ME and ML significantly inhibited intracellular expression of IFN-gamma but stimulated IL-4. Thereby, IL-4 was mainly expressed in apoptotic (Apo2.7+) cells. However, IFN-gamma secretion into the supernatants of the cells was dose-dependently inhibited by ME and ML, while IL-4 was not detected at all. CONCLUSION: The intracellular expression of the 'Th2-cytokine' IL-4 in ME- and ML-exposed cells may not be related to a typical Th2-response but rather to cell death. This effect might be of great relevance e.g. after intratumoural injection of the mistletoe extracts and, in general, for the inhibition of an inflammatory response during apoptosis.

Expression of interleukin-4 in apoptotic cells: stimulation of the type-2 cytokine by different toxins in human peripheral blood mononuclear and tumor cells.

BACKGROUND: Immunological reactivity is regulated by T-cell populations (type-1 and type-2 cells) via cytokine secretion, but their influence on apoptosis remains unclear. METHODS: Intracellular expression of type-1 (interferon [IFN]-gamma) and type-2 (interleukin [IL]-4) cytokines and apoptosis-related molecules (Apo2. 7, Bcl-2 protein) was studied by flow cytometry in human peripheral blood mononuclear cells (PBMC), myeloma (U-266), monocytic (THP-1), and T-leukemia cells (MOLT-4) in response to toxins, which act on different intracellular targets (actinomycin D, cycloheximide, the mistletoe lectins [ML]-1 and ML-3, brefeldin A, staurosporine). RESULTS: The apoptosis-inducing toxins stimulated intracellular IL-4 expression mainly in PBMC with high expression of the mitochondrial apoptosis marker, Apo2.7, but with decreased level of the anti-apoptotic Bcl-2 protein. Up-regulation of IL-4 coincided with a significant down-regulation of IFN-gamma in CD4(+) and CD8(+) cells. The inhibitor of oxidative phosphorylation, oligomycin, and the caspase inhibitor, z-VAD-fmk, abolished IL-4 expression and DNA fragmentation in the PBMC. Also in the myeloma, monocytic, and T-leukemia cells, IL-4 was mainly observed in the Apo2.7(+) apoptotic cells in response to the toxins. CONCLUSIONS: We suggest that the different apoptotic toxins activate a common pathway in which IL-4 production plays a yet unknown intracellular role further downstream during apoptosis.

Toxic proteins from European mistletoe (Viscum album L.): increase of intracellular IL-4 but decrease of IFN-gamma in apoptotic cells.

BACKGROUND: Mistletoe lectins (ML), the major biologically active components of mistletoe extracts, which are used for adjuvant cancer therapy, induce apoptosis in lymphocytes and tumor cells. In addition, ML at toxic concentrations induce the release of cytokines, but it remains unclear as to whether dying or activated cells are responsible. MATERIALS AND METHODS: By flow cytometry, expression of IFN-gamma, IL-4, apoptosis marker Apo2.7 and anti-apoptotic Bcl-2 proteins were analyzed in response to ML or viscotoxins (VT) in PBMC from controls and plasmocytoma cells (U-266). RESULTS: While ML inhibited PMA/Ca-ionophore/monensin co-stimulated IFN-gamma production, they increased IL-4 expression in CD8+ and CD4+ T-cells. Thereby, IL-4 was mainly expressed in apoptotic cells with a low level of Bcl-2 proteins. In contrast, the cell membrane permeabilising VT induced complete loss of Bcl-2 proteins but did not stimulate IL-4 production within 24 hours, indicating that IL-4 expression is related to apoptosis but not to necrosis. CONCLUSION: Despite the role of IL-4 during activation of type2 T-helper cells, IL-4 expression may play an important yet undefined role during apoptosis of normal and tumor cells.