Interleukin-2/interferon-alpha2a/13-retinoic acid-based chemoimmunotherapy in advanced renal cell carcinoma: results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN).

We performed a prospectively randomised clinical trial to compare the efficacy of four subcutaneous interleukin-2-(sc-IL-2) and sc interferon-alpha2a (sc-IFN-alpha2a)-based outpatient regimens in 379 patients with progressive metastatic renal cell carcinoma. Patients with lung metastases, an erythrocyte sedimentation rate < or =70 mm h(-1) and neutrophil counts < or =6000 microl(-1) (group I) were randomised to arm A: sc-IL-2, sc-IFN-alpha2a, peroral 13-cis-retinoic acid (po-13cRA) (n=78), or arm B: arm A plus inhaled-IL-2 (n=65). All others (group II) were randomised to arm C: arm A plus intravenous 5-fluorouracil (iv-5-FU) (n=116), or arm D: arm A plus po-Capecitabine (n=120). Median overall survival (OS) was 22 months (arm A; 3-year OS: 29.7%) and 18 months (arm B; 3-year OS: 29.2%) in group I, and 18 months (arm C; 3-year OS: 25.7%) and 16 months (arm D; 3-year OS: 32.6%) in group II. There were no statistically significant differences in OS, progression-free survival, and objective response between arms A and B, and between arms C and D, respectively. Given the known therapeutic efficacy of sc-IL-2/sc-INF-alpha2a/po-13cRA-based outpatient chemoimmunotherapies, our results did not establish survival advantages in favour of po-Capecitabine vs iv-5-FU, and in favour of short-term inhaled-IL-2 in patients with advanced renal cell carcinoma receiving systemic cytokines.

Detection of hematogenous micrometastasis in patients with transitional cell carcinoma.

PURPOSE: Cytokeratin 20 (CK 20) is selectively expressed in urothelium, gastric intestinal epithelium, in Merkel cells and in a variety of malignant neoplasms. CK 20 RT-PCR assay has been extensively used to detect isolated cancer cells in peripheral blood, lymph nodes and bone marrow samples of patients with colorectal carcinoma. Since CK-20 is also actively expressed in transitional cell carcinoma (TCC), we analyzed, whether CK 20 Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) is suitable to detect residual tumor cells in patients with transitional cell carcinoma of the bladder and the upper urinary tract. MATERIALS AND METHODS: Nested Reverse Transcriptase Polymerase Chain Reaction assay was used to analyze CK 20 transcripts in peripheral venous blood samples and tumor biopsies of 49 patients with transitional cell carcinoma. Blood samples of 22 healthy volunteers served as negative controls. RESULTS: CK 20 mRNA was detectable in blood samples of 12 of 49 patients with TCC. All blood samples of the control group tested negative. The detection rate for CK 20 mRNA significantly correlated (p = 0.0019, Cochran-Armitage Trend Test) to the stage of disease and increased from 0% in stage pTa to 63% in stage pT4. CONCLUSIONS: These results suggest that CK 20 is a suitable marker for the detection of disseminated TCC cells in peripheral venous blood samples and may be helpful in the molecular staging of TCC patients. The prognostic relevance has to be evaluated in further followup.

[Effects and importance of higher nursing education (Part 1). On the further development and work satisfaction of students. Presentation and discussion of qualitative questioning of graduated students]. / Welche Auswirkungen und Bedeutung hat die Höhere Fachausbildung in Krankenpflege, Stufe I, auf die weitere berufliche Entwicklung und Arbeitszufriedenheit der AbsolventInnen? Darstellung und Diskussion einer qualitativen Befragung von KursabsolventInnen.

This article shows the outcome of a quality questionnaire from students who have completed a post-diploma course in advanced nursing at the Cantonal Hospital Basle. The results show particularly the relevance of this education/course for the practical work. The final discussion and interpretation refers to the whole outcome.

Function of stem cell factor as a survival factor of spermatogonia and localization of messenger ribonucleic acid in the rat seminiferous epithelium.

To address the possibility that stem cell factor (SCF) is a paracrine regulator of germ cell development in the adult rat testis, stage-specific distribution of SCF messenger RNA (mRNA) was investigated with Northern blot and in situ hybridization analyses. The highest levels of SCF mRNA were found in stages II-VI of the rat seminiferous epithelial cycle, whereas the lowest levels were in stages VII-VIII. Intermediate levels of SCF mRNA were detected in stages IX-XIV-I of the cycle. The expression of the SCF gene was found to be developmentally regulated, and the expression pattern followed the process of Sertoli cell proliferation and differentiation during postnatal life. The effect of mouse recombinant SCF on spermatogonial DNA synthesis was studied using an in vitro tissue culture system for stage-defined seminiferous tubules. A significant increase in DNA synthesis in spermatogonia could be detected when tubule segments from stage XII were cultured in the presence of 100 ng/ml SCF for 48 h (P < 0.05) and 72 h (P < 0.01). This observation was further confirmed with autoradiographic analyses; almost a 100-fold increase in thymidine incorporation in the SCF-treated (100 ng/ml) tubule segments was observed compared with that in untreated samples. The results of the present study suggest that SCF is a Sertoli cell-produced paracrine regulator and acts as a survival factor for spermatogonia in the adult rat seminiferous epithelium in a stage-specific manner.

Semi-continuous versus injectate cardiac output measurement in intensive care patients after cardiac surgery.

OBJECTIVE: Commercially available semi-continuous cardiac output (SCCO) monitoring systems are based on the pulsed warm thermodilution technique. There is evidence that SCCO fails to correlate with standard intermittent bolus cardiac output (ICO) in clinical situations with thermal instability in the pulmonary artery. Furthermore, ventilation may potentially influence thermodilution measurements by enhanced respiratory variations in pulmonary artery blood temperature and by cyclic changes in venous return. Therefore, we evaluated the correlation, accuracy and precision of SCCO versus ICO measurements before and after extubation. DESIGN: Prospective cohort study. SETTING: Intensive care unit (ICU) of a university hospital. PATIENTS AND PARTICIPANTS: 22 cardiac surgical ICU patients. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: SCCO and ICO data were obtained at nine postoperative time points while the patients were on controlled mechanical ventilation. Further sets of measurements were taken during the weaning phase 20 min before extubation, and 5 min, 20 min and 1 h after extubation. SCCO and ICO measurements yielded 286 data pairs with a range of 1.8-9.9 l/min for SCCO and 1.9-9.8 l/min for ICO. The correlation between SCCO and ICO was highly significant (r = 0.92; p < 0.01), accompanied by a bias of -0.052 l/min and a precision of 0.56 l/min. Correlation, accuracy and precision were not influenced by the mode of respiration. CONCLUSIONS: Our results demonstrate excellent correlation, accuracy and precision between SCCO and ICO measurements in postoperative cardiac surgical ICU patients. We conclude that SCCO monitoring offers a reliable clinical method of cardiac output monitoring in ICU patients following cardiac surgery.

Continuous versus intermittent cardiac output measurement in cardiac surgical patients undergoing hypothermic cardiopulmonary bypass.

OBJECTIVE: Continuous thermodilution cardiac output (CCO) measurement was clinically evaluated in patients who underwent coronary revascularization using hypothermic low-flow, low-pressure cardiopulmonary bypass (CPB). DESIGN: Prospective study. SETTING: University hospital setting. PARTICIPANTS: 30 cardiac surgical patients. INTERVENTIONS: CCO was correlated to standard bolus thermodilution cardiac output (ICO) obtained at end-expiration. MEASUREMENTS AND MAIN RESULTS: Measurements were taken at selected time points (n = 18) before anesthesia induction, before CPB, and 5 minutes to 12 hours after CPB. A total of 540 data pairs were thus obtained. ICO ranged from 1.9 to 9.9 L/min, CCO from 1.5 to 9.9 L/min. Correlation between ICO and CCO was highly significant (r = 0.872; p < 0.01), accompanied by an excellent accuracy (bias -0.0213 L) and precision (0.59 L) before CPB and more than 45 minutes after CPB. However, during the first 45 minutes after CPB, there was no correlation (r = 0.273) between ICO and CCO, and ICO tended to be relatively high, whereas CCO measurements showed relatively low values. During the first 45 minutes after hypothermic CPB, but not during the ensuing time period, central blood temperature decreased, which may be interpreted as a lack of thermal equilibration between central and peripheral compartments. It is hypothesized that thermal instability in combination with increased respiratory variations in pulmonary artery blood temperature caused inhomogenous rewarming of different body sites and might be the main reason for the lack of correlation between ICO and CCO. CONCLUSIONS: Despite an excellent correlation, accuracy, and precision between CCO and ICO before CPB and more than 45 minutes after hypothermic CPB, a lack of correlation in the early phase after CPB has been found. Further investigation is needed to elucidate the underlying cause of these findings and to clarify whether ICO or CCO or both fail to represent the real cardiac output up to 45 minutes after weaning from hypothermic CPB.

Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands.

We characterized the pharmacological profiles of the human mineralocorticoid and glucocorticoid receptor for 11 natural and synthetic steroids regarding binding pharmacology, intracellular localization of hormone-receptor complexes, and agonistic or antagonistic properties at the gene expression level. The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. These results are supported by immunofluorescence studies, in which both unliganded human mineralocorticoid and glucocorticoid receptors were distributed throughout the cytoplasm and nucleus, whereas agonist- as well as antagonist-receptor complexes showed an exclusively nuclear localization. These results contribute to the understanding of antihormone pharmacology and increase our understanding of the role of human mineralocorticoid and glucocorticoid receptors in physiological processes during different endocrine states.

Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system.

The effects of the tricyclic antidepressant amitriptyline on the rat hypothalamic-pituitary-adrenocortical (HPA) system were studied. The time-course experiments showed that amitriptyline, given via the drinking water (4.5 mg/kg.day), produces significant decreases (P < 0.05) in adrenal weight after 5 (-20%) and 7 weeks (-21%) of treatment. Hippocampal mineralocorticoid receptor (MR) levels were down-regulated at days 3 (-27%) and 7 (-20%), and transiently up-regulated at 2 (+40%), 5 (+74%), and 7 (+18%) weeks of treatment. Hippocampal glucocorticoid receptor (GR) levels were slightly down-regulated at days 3 (-8%) and 7 (-17%), transiently up-regulated by 26% at 5 weeks, and indistinguishable from controls after 7 weeks of treatment. MR levels were unchanged in the hypothalamus and neocortex, whereas hypothalamic GR concentrations were elevated and neocortical receptor levels were not altered. Dose-response experiments showed significant decreases in adrenal weight when rats were treated with 4.5 (-14%), 8.8 (-16%) and 14.5 (-13%) mg/kg.day antidepressant, but this applied only for the 4.5- (-14%) and 8.8- (-12%) mg/kg.day doses when the ratio of adrenal weight to body weight was considered. The dose-response relationship regarding hippocampal GR content displayed an inverted U-shaped curve, whereas this was less marked for MR levels. A dose of 4.5 mg/kg.day appeared to be optimal for the rise in MR as well as GR. Concerning the neuroendocrine implications of chronic antidepressant treatment, amitriptyline (5 weeks, 4.5 mg/kg.day) produced significant decreases in basal (ACTH, -47%; corticosterone, -31%) as well as stress (30 min novel environment)-induced plasma ACTH (-38%) and corticosterone (-57%) levels. Previous experiments have forwarded a role of limbic MR in the tonic control of basal HPA activity. Based on the present data, we hypothesize that during amitriptyline treatment a rise in limbic MR may be the initial phenomenon in a successively adjusting HPA system, as evidenced by the decreasing plasma hormone concentrations, declining adrenal size, and up-regulation of GR in particular brain regions.

Relative definition of handicap: implications for research.

According to a relative definition handicap arises in the relation between an individual (with a weakness, an impairment or a disability) and his/her environment. To identify handicap it is therefore necessary to use environmental criteria as well as individual ones. Several attempts have been made to take a relative definition as a basis for classification and research. These attempts, however, often end up using a traditional clinical perspective by reducing the highly complex environmental circumstances to the ability of the individual to handle those circumstances. This is the case with the terminology and classification schemes proposed by WHO (International Classification of Impairments, Disabilities and Handicaps: ICIDH). This is also what seems to have happened with the relative notion of mental retardation, presented 15 years ago in terms of "a social system perspective". One of the reasons might be the methodological problems involved in handling the complexity of social environmental factors. To transcend the clinical perspective and take the full consequences of the relative definition social and behavioral research need to focus on the social meaning of handicap as it manifests itself in daily life. This calls for an anthropological approach in studying the everyday lives of mentally retarded persons as well as studies of the role of the professional in labelling those persons.