Medizin - Open Access LMU - Teil 13/22 Archiv

Reboxetine is a selective noradrenaline reuptake inhibitor, whereas mirtazapine acts as an antagonist at noradrenergic alpha(2), serotonin (5-HT2), 5-HT3 and histamine H-1 receptors. In a former study we could demonstrate an inhibitory impact of mirtazapine on cortisol secretion. In the present investigation, the influence of combined administration of 15 mg mirtazapine and 4 mg reboxetine on the cortisol ( COR), adrenocorticotropin ( ACTH), growth hormone (GH), and prolactin (PRL) secretion was examined in 12 healthy male subjects, compared to reboxetine alone ( 4 mg). In a randomized order, the subjects received reboxetine ( 4 mg) alone or the combination of reboxetine ( 4 mg) and mirtazapine ( 15 mg) at 8: 00 a. m. on two different days. After insertion of an intravenous catheter, blood samples were drawn 1 h prior to the administration of single reboxetine or the combination ( reboxetine and mirtazapine), at time of administration, and during the time of 5 h thereafter in periods of 30 min. Serum concentrations of COR, GH, and PRL as well as plasma levels of ACTH were determined in each blood sample by means of double antibody RIA, fluoroimmunoassay and chemiluminescence immunometric assay methods. The area under the curve (AUC) was used as parameter for the COR, ACTH, GH, and PRL response. For statistical evaluation, the Wilcoxon signed-ranks test was performed. There was a pronounced stimulation of COR, ACTH, GH, and PRL concentrations after single administration of reboxetine. When reboxetine was given in combination with mirtazapine, a significant reduction of the COR, ACTH, and PRL stimulation was observed whereas GH secretion patterns remained unchanged, compared to single administration of reboxetine. Apparently, the stimulatory effects of reboxetine on pituitary hormone secretion via noradrenergic mechanisms are counteracted in part by the alpha(2)-blocking properties of mirtazapine and its inhibitory influence on cortisol secretion. Copyright (C) 2004 S. Karger AG, Basel.

Objective: This comparative in vitro study examined the effects of all known gp130 cytokines on murine corticotroph AtT-20 cell function. Methods: Cytokines were tested at equimolar concentrations from 0.078 to 10 nM. Tyrosine phosphorylation of the signal transducer and activator of transcription ( STAT) 3 and STAT1, the STAT-dependent suppressor of cytokine signaling (SOCS)-3 promoter activity, SOCS-3 gene expression, STAT-dependent POMC promoter activity and adrenocorticotropic hormone ( ACTH) secretion were determined. Results: Leukemia inhibitory factor (LIF), human oncostatin M (OSM) and cardiotrophin (CT)-1 (LIFR/gp130 ligands), as well as ciliary neurotrophic factor ( CNTF) and novel neurotrophin1/B-cell stimulating factor-3 (CNTFRalpha/LIFR/gp130 ligands) are potent stimuli of corticotroph cells in vitro. In comparison, interleukin (IL)-6 (IL-6R/gp130 ligand) and IL-11 (IL-11R/gp130 ligand) exhibited only modest direct effects on corticotrophs, while murine OSM (OSMR/gp130 ligand) showed no effect. Conclusion: (i) CNTFR complex ligands are potent stimuli of corticotroph function, comparable to LIFR complex ligands; (ii) IL-6 and IL-11 are relatively weak direct stimuli of corticotroph function; (iii) differential effects of human and murine OSM suggest that LIFR/gp130 (OSMR type I) but not OSMR/gp130 (OSMR type II) are involved in corticotroph signaling. (iv) CT-1 has the hitherto unknown ability to stimulate corticotroph function, and (v) despite redundant immuno-neuroendocrine effects of different gp130 cytokines, corticotroph cells are preferably activated through the LIFR and CNTFR complexes. Copyright (C) 2004 S. Karger AG, Basel.

In this single-blind study, the effects of acute oral administration of high-dose Hypericum perforatum extract WS 5570 on the cortisol ( COR), adrenocorticotropic hormone ( ACTH), growth hormone (GH), and prolactin (PRL) secretions were examined in 12 healthy male volunteers. In a randomized order, the subjects received placebo or WS 5570 at several dosages (600, 900, and 1,200 mg) at 08.00 h on 4 different days. After insertion of an intravenous catheter, blood samples were drawn 1 h prior to administration of placebo or WS 5570 ( 600, 900, or 1,200 mg), at the time of administration, and during 5 h thereafter at intervals of 30 min. The serum concentrations of COR, GH, and PRL as well as the plasma levels of ACTH were determined in each blood sample by means of double antibody radioimmunoassay, fluoroimmunoassay, and chemiluminescence immunometric assay methods. The area under the curve value was used as parameter for COR, ACTH, GH, and PRL responses. Repeated-measures Anova revealed a significant stimulatory effect of WS 5570 on the ACTH secretion, whereas COR and PRL secretions were not significantly influenced. Moreover, there was a stimulatory peak of GH release 240 min after challenge with WS 5570 in some but not all volunteers, without reaching statistical significance in comparison with placebo. Mean arterial blood pressure and heart rate remained unchanged after administration of WS 5570. Apparently, WS 5570 at the dosages given in this study inconsistently causes endocrinological effects in healthy subjects by influencing central neurotransmitters. Copyright (C) 2004 S. Karger AG, Basel.

A total of 935 patients with extranodal non-Hodgkin lymphoma (NHL) diagnosed in the period between January 1985 and December 2000 in Kuwait Cancer Center, serving the whole population of Kuwait, were used to describe the clinicopathological and epidemiological features of extranodal lymphomas in Kuwait. Extranodal lymphomas accounted for 45% of all NHL observed during this time. All NHL cases from Kuwait Cancer registry were analyzed and pathologically reclassified using the latest WHO ( 2000) classification. The most common lymphoma observed was diffuse large B-cell lymphoma (58.60%) followed by Burkitt's lymphoma (BL) (3.80%). In the pediatric group, BL comprises more than two thirds of all patients (77.20%). The most common extranodal sites were stomach (19.70%) and skin (17.80%) in the adult group, large intestine (29.80%) and small intestine (19.30%) in the pediatric age group. The majority (73.40%) of adult extranodal lymphomas was in stage IE - IIE and had a very good prognosis. On the contrary, the majority of pediatric extranodal lymphomas were found to be in stage III and IV. Variations in treatment policies ( single agent or combined chemotherapy, radiotherapy, combined modality treatment) adopted and changed during the time period of 16 years of this retrospective study were documented. Copyright (C) 2004 S. Karger AG, Basel.

Background: Clinical outcome of patients with head and neck squamous cell carcinoma (SCCHN) depends on several risk factors like the presence of locoregional lymph node or distant metastases, stage, localisation and histologic differentiation of the tumour. Circulating tumour cells in the bone marrow indicate a poor prognosis for patients with various kinds of malignoma. The present study examines the clinical relevance of occult tumour cells in patients suffering from SCCHN. Patients and Methods: Bone marrow aspirates of 176 patients suffering from SCCHN were obtained prior to surgery and stained for the presence of disseminated tumour cells. Antibodies for cytokeratin 19 were used for immunohistochemical detection with APAAP on cytospin slides. Within a clinical follow-up protocol over a period of 60 months, the prognostic relevance of several clinicopathological parameters and occult tumour cells was evaluated. Results: Single CK19-expressing tumour cells could be detected in the bone marrow of 30.7% of the patients. There is a significant correlation between occult tumour cells in the bone marrow and relapse. Uni- and multivariate analysis of all clinical data showed the metastases in the locoregional lymph system and detection of disseminated tumour cells in the bone marrow to be statistically highly significant for clinical prognosis. Conclusion: The detection of minimal residual disease underlines the understanding of SCCHN as a systemic disease. Further examination of such cells will lead to a better understanding of the tumour biology, as well as to improvement of diagnostic and therapeutic strategies.

In about two thirds of cases, patients with paraneoplastic neurological disorders present to the neurologist without a known tumor. Due to the ongoing immune response, this tumor tends to stay biologically relatively benign, and therefore difficult to diagnose. In patients with a known tumor, the neurological symptoms often precede a tumor recurrence. In both scenarios, anti-neuronal antibodies are an invaluable diagnostic help to the clinician, and may be supplemented by other diagnostic tests such as MRI, CSF, and electrophysiology. Tumor therapy remains the mainstay of therapeutic options, although early immune therapy must be started in parallel. It is hoped that the recent fundamental advances in understanding the autoimmune pathology of these disorders, especially the role of cytotoxic T cells, will eventually lead to more effective treatment options.

Purpose: Optimal screening for ocular toxicity caused by chloroquine and hydroxychloroquine is still controversial. With the multifocal pattern electroretinogram (mfPERG), a new electrophysiological technique has recently become available to detect early changes of ganglion cells. In this study this new technique is applied to a series of 10 patients seen consecutively receiving long-term chloroquine medication. Methods: In 10 patients receiving chloroquine medication, clinical examination, Amsler visual field testing and computerized color vision testing were performed. If toxicity was suspected, automated perimetry was carried out. In addition, in all patients conventional pattern electroretinogram (PERG) and mfPERG testing were performed. Results: On clinical examination 8 patients showed no chloroquine-associated maculopathy, while 2 patients did. Of these 2, only 1 reported abnormalities when viewing the Amsler chart, while automated perimetry showed typical, ring-like paracentral scotomas in both affected patients and color vision was significantly abnormal. In the normal patients, 4 of 8 had a mild color vision disturbance, which correlated to age-related macular changes. The amplitudes of the PERG and the central (approximately 10degrees) responses of the mfPERG were markedly reduced in chloroquine maculopathy, while the latencies were unchanged. The peripheral rings of mfPERG (ranging to 48degrees) were not affected by chloroquine toxicity. Both PERG and mfPERG were less affected by age-related macular changes. Conclusions: The reduction of PERG and central mfPERG responses in chloroquine maculopathy may help with the early detection of toxicity. Copyright (C) 2004 S. Karger AG, Basel.

Background: The aim was to examine the agreement and differences between ICD-10 and DSM-IV in the classification of functional psychoses. Sampling and Methods: In a sample of 218 first-hospitalised patients, ICD-10 diagnoses were compared with DSM-IV diagnoses. Functional psychoses of both diagnostic systems were classified into the four diagnostic groups schizophrenia, transient/episodic psychoses, delusional disorders and affective disorders. Based on information from a 15-year follow-up, it was examined which course is associated with each diagnostic group. Results: Although in ICD-10 there was a higher frequency of schizophrenia and a lower one of affective disorders, a high agreement between ICD-10 and DSM-IV (kappa value of 0.82) was found. In both diagnostic systems, transient/episodic psychoses and affective disorders were mainly associated with a non-chronic course and schizophrenia was mainly associated with a chronic one. Nevertheless, several patients with transient/episodic psychoses showed a chronic course (ICD-10: 10%, DSM-IV: 15%) and more than one third of patients with schizophrenia a non-chronic one (ICD-10: 40%, DSM-IV: 33%). Conclusions: In the cross-sectional assessment, there is a high diagnostic agreement between ICD-10 and DSM-IV. With respect to the long-term course, the delimitation of transient/episodic psychoses from schizophrenia was neither completely achieved by ICD-10 nor by DSM-IV. Copyright (C) 2004 S. Karger AG, Basel.

The new DIN (' Deutsche Industrie- Norm') 6875- 1, which is currently being finalised, deals with quality assurance ( QA) criteria and tests methods for linear accelerator and Gamma Knife stereotactic radiosurgery/ radiotherapy including treatment planning, stereotactic frame and stereotactic imaging and a system test to check the whole chain of uncertainties. Our existing QA program, based on dedicated phantoms and test procedures, has been refined to fulfill the demands of this new DIN. The radiological and mechanical isocentre corresponded within 0.2 mm and the measured 50% isodose lines were in agreement with the calculated ones within less than 0.5 mm. The measured absorbed dose was within 3%. The resultant output factors measured for the 14-, 8- and 4- mm collimator helmet were 0.9870 +/- 0.0086, 0.9578 +/- 0.0057 and 0.8741 +/- 0.0202, respectively. For 170 consecutive tests, the mean geometrical accuracy was 0.48 +/- 0.23 mm. Besides QA phantoms and analysis software developed in- house, the use of commercially available tools facilitated the QA according to the DIN 6875- 1 with which our results complied. Copyright (C) 2004 S. Karger AG, Basel.

Clinical and electrographic data were reviewed on 2 of our patients with orbitofrontal epilepsy who were seizure free at 5-year follow-up, and on 2 similar patients from the literature. One of our patients was lesional, and the other was nonlesional. Interictal EEG discharges were lateralized to the side of invasively recorded orbitofrontal seizures in the nonlesional case. In this case, no clinical manifestations occurred until the orbitofrontal discharge had spread to the opposite orbitofrontal and both mesial temporal areas. Unresponsiveness or arrest of activity were the initial manifestations of complex partial seizures in both cases. The 2 cases from the literature with long-term seizure-free follow-up had little impairment of awareness and displayed vigorous motor automatisms. Interictal epileptiform activity was bifrontally synchronous in 1 case. Ipsilateral frontotemporal discharges were seen in both. Invasive ictal epileptiform activity appeared maximal in the ipsilateral orbitofrontal region in both patients. No consistent electrographic or clinical pattern characterized these 4 cases. Seizures of orbitofrontal origin may be characterized by either unresponsiveness associated with oroalimentary automatisms or limited alteration of awareness and associated with vigorous motor automatisms. Invasive monitoring of the orbitofrontal cortex should be considered in nonlesional cases with complex partial seizures that show nonlocalizing ictal patterns and interictal frontal or frontotemporal epileptiform discharges. Copyright (C) 2004 S. Karger AG, Basel.

Nucleosomes, which are typical cell death products, are elevated in the serum of cancer patients and are known to rapidly increase during radiotherapy. As both normal and malignant cells are damaged by irradiation, we investigated to which extent both cell types contribute to the release of nucleosomes. We cultured monolayers of normal bronchoepithelial lung cells (BEAS-2B, n = 18) and epithelial lung cancer cells (EPLC, n = 18), exposed them to various radiation doses (0, 10 and 30 Gy) and observed them for 5 days. Culture medium was changed every 24 h. Subsequently, nucleosomes were determined in the supernatant by the Cell Death Detection-ELISA(plus) ( Roche Diagnostics). Additionally, the cell number was estimated after harvesting the cells in a second preparation. After 5 days, the cell number of BEAS-2B cultures in the irradiated groups (10 Gy: median 0.03 x 10(6) cells/culture, range 0.02-0.08 x 10(6) cells/culture; 30 Gy: median 0.08 x 10(6) cells/culture, range 0.02-0.14 x 10(6) cells/culture) decreased significantly (10 Gy: p = 0.005; 30 Gy p = 0.005; Wilcoxon test) compared to the non-irradiated control group (median 4.81 x 10(6) cells/culture, range 1.50-9.54 x 10(6) cells/culture). Consistently, nucleosomes remained low in the supernatant of nonirradiated BEAS-2B. However, at 10 Gy, BEAS-2B showed a considerably increasing release of nucleosomes, with a maximum at 72 h ( before irradiation: 0.24 x 10(3) arbitrary units, AU, range 0.13-4.09 x 10(3) AU, and after 72 h: 1.94 x 10(3) AU, range 0.11-5.70 x 10(3) AU). At 30 Gy, the release was even stronger, reaching the maximum earlier (at 48 h, 11.09 x 10(3) AU, range 6.89-18.28 x 10(3) AU). In non-irradiated EPLC, nucleosomes constantly increased slightly. At 10 Gy, we observed a considerably higher release of nucleosomes in EPLC, with a maximum at 72 h (before irradiation: 2.79 x 10(3) AU, range 2.42-3.80 x 10(3) AU, and after 72 h: 7.16 x 10(3) AU, range 4.30-16.20 x 10(3) AU), which was more than 3.5 times higher than in BEAS-2B. At 30 Gy, the maximum (6.22 x 10(3) AU, range 5.13-9.71 x 10(3) AU) was observed already after 24 h. These results indicate that normal bronchoepithelial and malignant lung cancer cells contribute to the release of nucleosomes during irradiation in a dose-and time-dependent manner with cancer cells having a stronger impact at low doses. Copyright (C) 2004 S. Karger AG, Basel.

Objective: In order to expand the use of photodynamic therapy (PDT) in the treatment of prostate carcinoma (PCA), the aim of this study was to evaluate PDT by means of 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX ( PPIX) in an in vivo tumor model. Methods: The model used was the Dunning R3327 tumor. First of all, the pharmacokinetics and the localization of PPIX were obtained using fluorescence measurement techniques. Thereafter, PDT using 150 mg 5-ALA/kg b.w.i.v. was performed by homogenous irradiation of the photosensitized tumor (diode laser lambda = 633 nm). The tumors necrosis was determined histopathologically. Results: The kinetics of PPIX fluorescence revealed a maximum intensity in the tumor tissue within 3 and 4.5 h post-application of 5-ALA. At this time, specific PPIX fluorescence could be localized selectively in the tumor cells. The PDT-induced necrosis (n = 18) was determined to be 94 B 12% (range 60-100%), while the necrosis of the controls ( n = 12) differs significantly (p < 0.01), being less than 10%. Conclusion: These first in vivo results demonstrate the effective potential of 5-ALA-mediated PDT on PCA in an animal model. Copyright (C) 2004 S. Karger AG, Basel.

Introduction: Intraoperative bleeding, one of the major complications of conventional transurethral resection of the prostate ( TURP), has led to a search for various alternative methods of tissue ablation in patients with benign prostatic hyperplasia. In 1996, we introduced the newly designed Band Electrode, which combines a high degree of resection efficiency with a better hemostasis. Material and Methods: 265 consecutive patients with prostatism underwent TURP with the Band Electrode. This modified loop electrode does not consist of a thin wire but is rather a flat metal band with a width of 1.2 mm. International prostate symptom score (IPSS), Life Quality Index ( L), peak urine flow and postvoid residual urine were evaluated pre- and postoperatively. Additionally, electrical parameters have been recorded with a specially designed high-frequency generator. Results: Median IPSS decreased from 23 preoperatively to 8 and 9 at 12 (n = 194) and 24 months ( n = 172), respectively (p < 0.001). Life Quality Index ( L) dropped from 4 to 2 and 2, respectively (p < 0.001). Peak urine flow increased from 8.2 ml/s to 18.2 (at postoperative day 3), 17.8 and 17.4 ml/s, respectively (p < 0.001). Median postvoid residual urine decreased from 77 to 15, 22 and 21 ml, respectively (p < 0.001). Resected tissue mass averaged 25 (8 - 102) g, resection time was 36.5 ( 18 - 82) min. Indwelling catheters were removed 32 ( 24 - 72) h postoperatively. None of the patients required blood transfusions or showed signs of a TUR syndrome. Despite a 1.3 times higher power need, the total energy application in vivo was comparable to conventional TURP. Conclusions: This simple exchange of active electrodes leads to a superior hemostasis and thus safety in TURP. Resection speed, tissue ablation and total energy need remain identical. Copyright (C) 2004 S. Karger AG, Basel.