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Background The regular arrangement of collecting venules (RAC) and the Kimura-Takemoto classification of atrophic change (KTC) are simple and easy-to-use criteria which have been shown to reliably predict or rule out a Helicobacter pylori infection of the stomach. Although these features have been investigated extensively in Asia, their significance in the West has not been evaluated. Methods In a series of 200 consecutive gastroscopic examinations (single examiner, single center), the presence or absence of RAC and the KTC grade (open type vs closed type) were recorded prospectively. Helicobacter pylori infection was defined as a positive histology or a positive rapid urease test. Furthermore, multivariate analysis of endoscopic predictors of H. pylori infection based on the Kyoto classification of gastritis was performed. Results Two hundred patients were examined of which 57 had a H. pylori infection (28%). Both RAC and KTC had excellent negative predictive values of about 90% and sensitivity values of up to 85%. In multivariate analysis, atrophic change and diffuse redness without RAC were significantly associated with H. pylori infection. Conclusion Regular arrangement of collecting venules and KTC are simple endoscopic features which should be given attention by Western endoscopists and can be easily used to rule out a H. pylori infection of the stomach.

Molecular imaging and therapy as applied in nuclear medicine represent an important contribution to modern medicine. The university curricula of medical schools permit to convey knowledge of nuclear medicine. In this study, the status quo of nuclear medicine teaching at German medical schools shall be surveyed for the first time. In cooperation with the chairs and/or lecturers, the topics organizational conditions, scope of teaching, teaching methods, examinations, evaluations, composition of teaching staff, interest of the students in the field of nuclear medicine, as well as suggestions for improvement of teaching were recorded. All 36 public German medical schools participated in the survey. In these medical schools a median of 12 hours of nuclear medicine is being taught. 52 % of the teaching consists of teacher-centered learning. 18 medical schools teach additional elective courses in nuclear medicine. Nine 9 persons (median) per department are involved in the teaching. The examinations, in all but one school, follow a multiple choice format. The students' interest in nuclear medicine is perceived by the educators to be predominately medium to high. Potential improvement might be achieved with regard to the quantity of teaching lessons, innovative methods of teaching, design of the exams, the establishment of a nationwide e-learning platform, as well as measures to increase the motivation of teachers.ZIEL: Nuklearmedizinische molekulare Bildgebung und Therapie leisten einen wichtigen Beitrag zur modernen Medizin. Die universitären Curricula des Medizinstudiums bieten die Möglichkeit, nachhaltig Kenntnisse der Nuklearmedizin zu vermitteln. In dieser Untersuchung soll erstmalig flächendeckend der Status quo der nuklearmedizinischen Lehre an deutschen Universitätskliniken erhoben werden. In Zusammenarbeit mit den Klinikdirektoren und/oder Lehrbeauftragten wurden mithilfe eines semistrukturierten Interviews die Themenbereiche organisatorische Rahmenbedingungen, Unterrichtsumfang, Unterrichtsmethoden, Prüfungen, Evaluationen, Zusammensetzung der Lehrenden, Interesse der Studierenden am Fach Nuklearmedizin sowie Vorschläge zur Verbesserung der nuklearmedizinischen Lehre erfasst. Alle 36 staatlichen deutschen Universitätskliniken haben an der Erhebung teilgenommen. Es werden im Median 12 Unterrichtsstunden im Pflichtanteil des Medizinstudiums gelehrt. 52 % davon ist Frontalunterricht. An 18 Standorten wird darüber hinaus im Rahmen von Wahlpflichtveranstaltungen unterrichtet. Die Prüfungen erfolgen an 35 Standorten als Multiple-Choice-Fragen. An der Lehre sind im Median 9 Personen pro Abteilung beteiligt. Das studentische Interesse an der Nuklearmedizin wird durch die Lehrenden überwiegend als hoch oder mittel bewertet. Verbesserungspotenzial besteht vor allem in Anzahl und Organisation der Unterrichtsveranstaltungen, der Gestaltung der Prüfungen, der Einrichtung eines bundesweiten E-Learning-Angebots sowie Maßnahmen zur Steigerung der Motivation der Lehrenden.

Standard first-line treatment of aggressive B cell lymphoma comprises six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus eight doses of rituximab (R). Whether adding two doses of rituximab to six cycles of R-CHOP is of therapeutic benefit has not been systematically investigated. The Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial investigated the ability of [18F]-fluorodesoxyglucose PET scanning to guide treatment in aggressive non-Hodgkin lymphomas. Patients with B cell lymphomas and a negative interim scan received six cycles of R-CHOP with or without two extra doses of rituximab. For reasons related to trial design, only about a third underwent randomization between the two options. Combining randomized and non-randomized patients enabled subgroup analyses for diffuse large B cell lymphoma (DLBCL; n = 544), primary mediastinal B cell lymphoma (PMBCL; n = 37), and follicular lymphoma (FL) grade 3 (n = 35). With a median follow-up of 52 months, increasing the number of rituximab administrations failed to improve outcome. A non-significant trend for improved event-free survival was seen in DLBCL high-risk patients, as defined by the International Prognostic Index, while inferior survival was observed in female patients below the age of 60 years. Long-term outcome in PMBCL was excellent. Differences between FL grade 3a and FL grade 3b were not apparent. The results were confirmed in a Cox proportional hazard regression model and a propensity score matching analysis. In conclusion, adding two doses of rituximab to six cycles of R-CHOP did not improve outcome in patients with aggressive B cell lymphomas and a fast metabolic treatment response.

Implementation of the guidelines on the Competency-based Learning Objective Catalogue for Undergraduate Medical Education for a Nuclear Medicine curriculum on behalf of the committee on professional training and continuing education of the German Association of Nuclear Medicine (DGN) METHODS:: In 7 domains 100 learning objectives (LOs) were subject to a prioritization in 3 categories (A, B and C) by means of a questionnaire as part of a Delphi method, in collaboration with all members of the DGN holding a "venia legendi" as experts. Category A defined the essential LOs for each medical practitioner. The prioritization was made by ranking the frequency of the A-classifications. In the 2nd step of the Delphi method, a list of LOs with the ranking positions 1-5 in each domain was presented to the first round's experts as a core curriculum, asking either for acceptance or modifications.The results of the 1st step of the Delphi method deliver a return rate of 29% of the questionnaires (55 out of 184). The 2nd round shows a return rate of 30.9% (57 out of 184) and full approval of the proposed LOs in all LO domains by in median 72 % of the experts consulted (61%-81%). The present final version contains 37 competency-based LOs in the LO domains "legal basis and radiation protection", "basic science", indications and contra-indications for "PET/CT", "scintigraphy and SPECT", "patient preparation", "image interpretation" as well as "therapy".The Competency-based Learning Objective Catalogue for Nuclear Medicine describes the knowledge and competencies, every physician should have at the end of his medical studies. The LO catalogue is a living document, which needs to be adapted continuously to the progress of the medical and technological development.

ZusammenfassungUmsetzung der Vorgaben des Nationalen Kompetenzbasierten Lernzielkatalogs Medizin (NKLM, 2015) für ein Curriculum Nuklearmedizin im Auftrag des Ausschusses Fort- und Weiterbildung der Deutschen Gesellschaft für Nuklearmedizin (DGN). Methoden 100 Lernziele (LZ) in 7 Domänen wurden in einem Delphi-Verfahren unter Einbeziehung aller habilitierten Mitglieder der DGN als Experten durch einen Fragebogen einer Priorisierung in 3 Kategorien (A, B und C) unterzogen. Kategorie A definierte für die jeden Arzt unerlässlichen LZ. Die Priorisierung erfolgte durch Rangbildung nach dem Anteil der A-Klassifikationen. Eine LZ-Liste mit den Rangplätzen 1 – 5 in jeder Domäne wurde in der 2. Stufe des Delphi-Verfahrens den Experten der ersten Runde als Kern-Curriculum mit der Frage nach Akzeptanz bzw. Modifikationen vorgelegt. Ergebnisse Die Ergebnisse der 1. Stufe des Delphi-Verfahrens zeigte einen Rücklauf der Fragebögen von 29 % (55 von 184). Die 2. Runde erbrachte einen Rücklauf von 30,9 % (57 von 184) und eine uneingeschränkte Akzeptanz der vorgeschlagenen LZ in allen LZ-Domänen bei im Median 72 % der befragten Experten (61 %–81 %). Die vorliegende Endfassung enthält 37 kompetenzbasierte LZ in den LZ-Domänen „Gesetzliche Grundlagen und Strahlenschutz“, „naturwissenschaftliche Grundlagen“, Indikationen und Kontraindikationen zu „PET/CT“, „Szintigraphie und SPECT“, „Patientenvorbereitung“, „Befundanalyse und -interpretation“ sowie „Therapie“. Ausblick Der kompetenzbasierte LZ-Katalog Nuklearmedizin beschreibt die Kenntnisse und Kompetenzen, über die jeder Arzt am Ende seines Studiums verfügen sollte. Der LZ-Katalog ist ein lebendes Dokument, das fortlaufend an den Fortschritt der medizinischen und technologischen Entwicklung angepasst werden muss.

Updated presentation of the spectrum of nuclear medicine in-vivo examinations and therapies from officially available statistics on out-patient and in-patient care as well as trends of structural data on nuclear medicine in Germany.Data from the German Federal Health Monitoring, from the frequency statistics of the statutory health insurance for out-patients and from the German Medical Association were used and supplemented by data from selective literature searches.In descending order, thyroid, bone and cardiac scans continue to be the most frequent nuclear medicine procedures. With a marked increase of PET/CT and SPECT/CT, the number of basic scintigraphies is declining. Cardiac, lung and brain scans as well as lymph scintigraphies are increasingly requested, bone and thyroid scan decrease. The consultation of nuclear medicine physicians in private practices is increasing by 4 % per year (2009: 2 164 664; 2015: 2 687 359). The number of nuclear medicine physicians in the out-patient sector rose significantly (2009: 756, 2015: 939, growth 24 %) and has remained constant due to restrictions since 2013. The specialist recognitions of women in nuclear medicine increased (proportion currently 46 %). In hospitals, more PET(/CT) scanners (2009: 97; 2015: 125) and fewer gamma cameras (2009: 594; 2015: 550) are operated. The number of non-thyroid (and also out-patient) radionuclide therapies continued to increase.With increased use of hybrid technologies, the nuclear medicine spectrum shows positive trends especially in nuclear cardiology and extra-thyroid therapy. These developments must be taken into account when amending regulations of specialist training and medical student teaching.

Bayesianische Aufgaben stellen in der Medizin eine besondere kognitive Herausforderung fur Studierende dar. Denn sowohl Patienten als auch Medizinstudierende und Arzte haben Schwierigkeiten, einen positiven oder negativen Vorhersagewert zu berechnen, wenn die Pravalenz der Erkrankung mit der Sensitivitat und Falsch-Positiv-Rate eines diagnostischen Tests kombiniert werden muss.

Cerebral (18)F‐deoxyglucose positron emission tomography (FDG‐PET) has shown altered auditory pathway activity in tinnitus. However, the corresponding studies involved only small samples and analyses were restricted to the auditory cortex in most studies. Evidence is growing that also limbic, frontal, and parietal areas are involved in the pathophysiology of chronic tinnitus. These regions are considered to mediate perceptual, attentional, and emotional processes. Thus, the aim of the present study was the systematic evaluation of metabolic brain activity in a large sample of tinnitus patients. Ninety one patients with chronic tinnitus underwent FDG‐PET. The effects of tinnitus severity (assessed by a tinnitus questionnaire score), duration and laterality were evaluated with statistical parametric mapping (SPM) in whole brain analyses. In addition, region of interest analyses were performed for primary auditory areas. Tinnitus duration correlated positively with brain metabolism in right inferior frontal, right ventro‐medial prefrontal, and right posterior cingulate cortex. Tinnitus distress correlated positively with activation of left and right posterior inferior temporal gyrus as well as left and right posterior parahippocampal–hippocampal interface. Region of interest analysis demonstrated an overactivation of left in contrast to right Heschl's gyrus independently from tinnitus laterality and anatomical hemispheric differences. Tinnitus duration and distress were associated with areas involved in attentional and emotional processing. This is in line with recent findings indicating the relevance of higher order areas in the pathophysiology of tinnitus. Earlier results of asymmetric activation of the auditory cortices in tinnitus were confirmed, i.e., left‐sided overactivation was found independently from tinnitus laterality. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.

Summary It was of interest to determine the impact of FDG-PET/CT on general therapy management and radiotherapy (RT) planning in patients with stage IV head and neck tumours. The study was conducted prospectively between March 2006 and March 2007 in 35 patients with histologically confirmed, locally advanced squamous cell carcinomas of the head and neck. Prior to primary radiochemotherapy, whole-body and head/neck FDG-PET/CT was performed. The FDG-PET information was integrated into RT planning. By comparison with anatomical imaging, the FDG-PET/CT yielded the following additional information: distant metastases in 17.1% (6/35), second primary tumours in 11.4% (4/35), and changes in nodal status based on metabolic activity, i.e. upstaging in 34.3% (12/35) or downstaging in 22.9% (8/35). As a result, treatment strategy was changed from curative to palliative in six patients, and additional curative therapy was implemented following exclusion of distant metastases in two patients with a simultaneous local second primary tumour. The discordant nodal status found with head/neck FDG-PET/CT compared with anatomical imaging led to modification of radiotherapy volume and dose in 20 patients (57.1%). From the radiotherapist’s perspective FDG-PET/CT is therefore useful and justifiable in the management of stage IV head and neck tumours.

Therapeutic options to cure advanced, recurrent, and unresectable thymomas are limited. The most important factor for long-term survival of thymoma patients is complete resection (R0) of the tumor. We therefore evaluated the response to and the induction of resectability of primarily or locally recurrent unresectable thymomas and thymic carcinomas by octreotide Long-Acting Release (LAR) plus prednisone therapy in patients with positive octreotide scans. In this open label, single-arm phase II study, 17 patients with thymomas considered unresectable or locally recurrent thymoma (n = 15) and thymic carcinoma (n = 2) at Masaoka stage III were enrolled. Octreotide LAR (30 mg once every 2 weeks) was administered in combination with prednisone (0.6 mg/kg per day) for a maximum of 24 weeks (study design according to Fleming´s one sample multiple testing procedure for phase II clinical trials). Tumor size was evaluated by volumetric CT measurements, and a decrease in tumor volume of at least 20% at week 12 compared to baseline was considered as a response. We found that octreotide LAR plus prednisone elicited response in 15 of 17 patients (88%). Median reduction of tumor volume after 12 weeks of treatment was 51% (range 20%-86%). Subsequently, complete surgical resection was achieved in five (29%) and four patients (23%) after 12 and 24 weeks, respectively. Octreotide LAR plus prednisone treatment was discontinued in two patients before week 12 due to unsatisfactory therapeutic effects or adverse events. The most frequent adverse events were gastrointestinal (71%), infectious (65%), and hematological (41%) complications. In conclusion, octreotide LAR plus prednisone is efficacious in patients with primary or recurrent unresectable thymoma with respect to tumor regression. Octreotide LAR plus prednisone was well tolerated and adverse events were in line with the known safety profile of both agents. peerReviewed

Untersuchung folgender Fragen: Welche Faktoren beeinflussten die Haufigkeit hamatogener Fernmetastasen bei Patienten mit lokal fortgeschrittenen Kopf-Hals-Tumoren (HNO-Tumoren), wie war die topographische Verteilung der Fernmetastasen, und welche Konsequenzen resultierten daraus fur die pratherapeutische Diagnostik? Retrospektiv wurden 600 Patienten (524 Manner, 76 Frauen, medianes Alter 56 Jahre, Behandlungszeitraum 03/1993–07/2005, Stichtag 01.12.2005, mediane Nachbeobachtungsdauer 25,7 Monate) mit HNO-Tumoren (Plattenepithelkarzinome) untersucht. Die Verteilung der Primartumoren und Stadien stellte sich folgendermasen dar: Oropharynx: n = 161 (26,8%), Hypopharynx: n = 187 (31,2%), Mundhohle: n = 89 (14,8%), Larynx: n = 118 (19,7%), Lymphknoten bei unbekanntem Primartumor: n = 13 (2,2%), sonstige: n = 32 (5,3%). Stadium I: n = 24 (4%), II: n = 49 (8,2%), III: n = 89 (14,8%), IV: n = 438 (73%). 270 Patienten (45%) wurden primar radiochemotherapiert, 330 (55%) operiert und nachbestrahlt. Fur die Analyse der Haufigkeitsverteilung von Fernmetastasen wurden folgende Merkmale untersucht: Primartumorlokalisation, Stadium (AJCC), Tund N-Kategorie, Primartherapie, lokale Tumorkontrolle nach abgeschlossener Primartherapie sowie ein bekannter Zweittumor. 114/600 Patienten (19%) manifestierten Fernmetastasen, 29/600 (4,9%) zum Zeitpunkt der Primartherapie, 50% innerhalb von 9,3 Monaten nach Erstdiagnose. Metastasen waren am haufigsten im Stadium IV (24,2%), bei Hypopharynxkarzinom (25,7%), bekanntem Lokalrezidiv (24,3%) bzw. Zweittumor (31,7%) mit folgender Verteilung: pulmonal 61/114 (53,5%), pleural 15/114 (13,1%), davon 8/114 pleuropulmonal, ossar 45/114 (39,5%), hepatisch 14/114 (12,3%), zerebral 8/114 (7%), kutan 14/114 (12,3%). Bei 34/114 Patienten (29,8%) lag eine monotope, bei 80/114 (70,2%) eine polytope Metastasierung vor. 82 Patienten hatten Zweittumoren, davon 20 synchrone oder metachrone Bronchialkarzinome. Bei lokal fortgeschrittenem HNO-Tumor im Stadium IVa/b, Hypopharynxkarzinom, bekanntem Lokalrezidiv bzw. Zweittumor sollte pratherapeutisch zumindest eine CT des Thorax erfolgen, da jeder siebte Patient (88/600) im Verlauf seiner Erkrankung ein primares oder sekundares Malignom im Thoraxraum manifestierte. In Anbetracht der Nebenwirkungen und Kosten kurativer Therapien bei lokal fortgeschrittenen HNO-Tumoren ware die Definition allgemein akzeptierter Richtlinien zum Ausschluss von Fernmetastasen sinnvoll.

We report the clinical, structural, functional and genetic characterization of a 37-year-old Caucasian female, presenting as a sporadic case of complicated spastic paraplegia with thin corpus callosum (CC), cognitive impairment, amyotrophy of the hand muscles and a sensorimotor neuropathy and review the literature for spastic paraplegia with thin CC. Magnetic resonance imaging (MRI) examination revealed a thin CC with fronto-parietal cortical atrophy. 18Fluordesoxyglucose positron emission tomography (FDG–PET) showed reduced cortical and thalamic metabolism. By transcranial magnetic stimulation, we delineated a severe impairment of transcallosal inhibition. Sequence analysis did not reveal disease causing mutations in the genes SLC12A6 (Andermann), Spastin (SPG 4), BSCL2 (SPG 17) and Spartin (SPG 20). We reviewed the literature for HSP with thin CC and found 113 HSP patients with thin CC previously described (35 with linkage to chromosome 15q13–15). Thin CC and peripheral neuropathy often appear together in spastic paraplegia and might be indicative for combined degeneration mechanism of central and peripheral axons.

In the diagnosis of coronary artery disease (CAD) with Dobutamine Stress Echocardiography (DSE), regional wall motion abnormalities (RWMA) are assumed to indicate a perfusion deficit.For a more particular examination of RWMAs, we compared simultaneous echo-contrast (Optisone)-enhanced DSE (0-40 microg/kg Dobutamine, 16-segment- model) and MiBi-SPECT in a prospective double-blinded study design in 69 non-selected consecutive patients (44 male, 25 female, age 64+/-12 years). Additionally, all patients were examined by coronary-angiography. The prevalence of significant CAD (stenosis50% lumen diameter) was 52%. DSE had a sensitivity of 78% and a specificity of 66% for the detection of significant CAD with a positive and negative predictive value of 72 and 73%, respectively. Among 28 patients with significant CAD and positive DSE study (true positive), 78% displayed a corresponding perfusion deficit in MiBi-SPECT. Among 11 patients with a positive DSE study but no current significant coronary stenosis (false positive), 82% showed stress-induced RWMAs in the inferior/posterior region, 73% displayed left ventricular hypertrophy, 54% resting-ECG abnormalities and 45% resting-RWMA (3 previous MI, 2 previous CABG surgery). Among 8 patients with negative DSE study but significant coronary stenosis (false negative), 75% had a stenosis of the LCX, 63% displayed resting- WMA, 63% displayed left bundle branch block or ST-segment depression, 50% displayed only peripheral coronary stenosis, and DSE visualization was suboptimal in 38%.This prospective study in non-selected patients shows that the majority of RWMAs in DSE are matched to a perfusion deficit detectable by nuclear imaging. Nevertheless, pre-existing cardiac abnormalities may also lead to stress-induced RWMA not associated with a perfusion deficit or mask a perfusion deficit upon DSE. Particularly in patients with LV hypertrophy, resting-RWMA, bundle branch block or ST segment depression, the predictive value of DSE may, therefore, be limited.

Histologisch entspricht die Sekundarkatarakt („posterior capsule opacification“ [PCO]) regenerativem Gewebe aus transformierten Linsenepithelzellen („lens epithelial cells“ [LEC]) und Extrazellularmatrix. In dieser Studie wurde der Einfluss ionisierender Strahlen auf proliferierende LEC in vitro untersucht. Jeweils vier bzw. 14 Linsen aus Schweinebulbi wurden mit Elektronen der Energie 6 MeV mit je 8, 10, 12 und 20 Gy bestrahlt. 1–2 h nach Radiatio wurde der Linsenkern durch Kapsulorrhexis und Hydrodissektion aus der Linsenkapsel extrahiert. Nach Fixation der Linsenkapsel in einer speziellen Halterung wurde taglich die Proliferation residueller LEC bei zwolffacher Vergroserung untersucht und photographisch dokumentiert. Der Versuch galt als beendet, wenn die Linsenkapsel durch konfluierende Zellproliferate vollstandig getrubt war. Eine Radiatio mit Elektronen verzogert signifikant die Entwicklung einer PCO im Dosisbereich von 8–12 Gy in vitro. Ab 20 Gy induziert sie eine vollstandige Inhibition der PCO. Zur Inhibition einer PCO in vitro ist eine Einzeldosis von mindestens 20 Gy erforderlich. Das hier angewandte Modell erlaubt eine optimale Untersuchung der PCO-Genese unter verschiedenen auseren Einflussen und eignet sich gut fur radiobiologische Fragestellungen.

BACKGROUND Doxorubicin exhibits high efficacy in malignant glioma cell cultures. Nonetheless, as a standard formulation, doxorubicin has not been used clinically, due to poor penetration of the blood-brain barrier. Furthermore, doxorubicin is known to induce tumor resistance genes. To address both of these issues, the authors investigated the use of pegylated liposomal doxorubicin (Caelyx™; Essex Pharma, Munich, Germany) alone (Trial 1) and in combination with tamoxifen (Trial 2) in two sequentially performed nonrandomized prospective Phase II trials involving patients with recurrent high-grade glioma. METHODS Twenty patients were included in each trial. Progression-free survival at 6 months (PFS-6) and toxicity were the primary endpoints. Expression of the tumor resistance proteins multidrug resistance protein 1 (MDR-1) and multiple resistance protein (MRP) was evaluated by immunohistochemical methods and by sestamibi–single-photon emission computed tomography (SPECT). RESULTS The overall response rate (including cases of disease stabilization) was 40% in both Trial 1 and Trial 2. PFS-6 was 15%, and the median time to disease progression was 17 weeks. It is noteworthy that 40% of patients with Grade III tumors had long-term responses, which lasted for up to 3 years. There was no significant difference between Trial 1 and Trial 2 in terms of efficacy. Both regimens were well tolerated, with the main side effect being palmoplantar erythrodysesthesia. The authors found no correlation between clinical response and expression of tumor resistance genes or between clinical response and SPECT data. CONCLUSIONS Pegylated liposomal doxorubicin administered alone or in combination with tamoxifen is safe and moderately effective in patients with recurrent high-grade glioma. None of the putative predictors for response that were evaluated proved to be significant in this setting. Cancer 2004. © 2004 American Cancer Society.

OBJECTIVE To report a case of acute central nervous system (CNS) toxicity with multiple hemorrhages restricted to the corpus callosum associated with combination therapy of cisplatin, ifosfamide, and etoposide. CASE SUMMARY A 38-year-old white man with a testicular germ cell tumor received a cisplatin-based chemotherapy consisting of cisplatin 45 mg (20 mg/m 2 ), etoposide 570 mg (250 mg/m 2 ), and ifosfamide 4600 mg (2000 mg/m 2 ) given on 5 consecutive days during each course. After the first course of chemotherapy, the patient appeared to be neuropsychologically impaired with episodes of decreased alertness and features of a depressive syndrome. He became severely diminished in mental function, orientation, and psychomotor activity after a second course of treatment. In addition, he showed transient urinary incontinence. Motor and sensory deficits could not be detected. Magnetic resonance imaging demonstrated multiple hemorrhages restricted to the corpus callosum. An objective causality assessment revealed that an adverse drug reaction was probable. DISCUSSION Neurotoxicity has been associated with the administration of various antineoplastic agents. In particular, cisplatin and ifosfamide can cause both acute and delayed CNS toxicity. While ifosfamide neurotoxicity has been predominantly associated with neuropsychological impairment without evidence of structural abnormalities in neuroimaging studies, cisplatin has been shown to cause cerebrovascular complications. Various pathophysiologic conditions may contribute to these complications including thrombosis secondary to vascular endothelial injury or thromboembolic events. To our knowledge, as of December 2, 2003, vascular lesions restricted to the corpus callosum have not been reported as a complication of cisplatin- or ifosfamide-based chemotherapy. CONCLUSIONS Clinicians should be aware of the potential neurovascular adverse effects of cisplatin-based protocols. This is especially true in patients with subtle neurologic or neuropsychological symptoms. Chemotherapy-induced neurotoxicity should be considered in the differential diagnosis.

Purpose Heat shock protein 70 (Hsp70) was detected on the cell membrane of human tumor cell lines, but not on normal cells. Here we studied Hsp70 membrane expression as a target for natural killer (NK) cells on tumor material and control tissues of head-and-neck cancer patients. Methods and materials Membrane-bound Hsp70 was determined by flow cytometry on single-cell suspensions of tumors and the corresponding normal tissues of head-and-neck cancer patients. The cytolytic activity of NK cells against Hsp70-positive tumor cells was measured in a standard cytotoxicity assay. Results In total, 54 of 74 primary tumors were found to be Hsp70 membrane-positive (73%); tongue/mouth, 21 of 24 (88%); oropharynx, 13 of 20 (65%); hypopharynx, 3 of 6 (50%); larynx, 8 of 11 (73%); trachea 1 of 2 (50%); esophagus, 4 of 5 (80%); lymph node metastases, 4 of 6 (67%). The corresponding control tissue was negative for membrane-bound Hsp70. Biopsies (6 of 6) of patients after in vivo γ-irradiation (fractionated 5 × 2 Gy) were strongly Hsp70 membrane-positive. Irradiated, Hsp70-positive tumor cells are targets for Hsp70-peptide stimulated NK cells. Conclusion An irradiation-inducible, tumor-selective Hsp70 membrane localization provides a target structure for Hsp70-peptide stimulated human NK cells.

Background Clinical as well as neurophysiological and neuroimaging data suggest that chronic tinnitus resembles neuropsychiatric syndromes characterized by focal brain activation. Low-frequency repetitive transcranial magnetic stimulation (rTMS) has been proposed as an efficient method in treating brain hyperexcitability disorders by reducing cortical excitability. Methods In three patients suffering from chronic tinnitus, the effect of magnetic resonance imaging and positron emission tomography guided neuronavigated 1 Hz rTMS on auditory cortex activity was evaluated, using a sham controlled double-blind crossover design. Results Two of three patients revealed clearly increased metabolic activity in circumscript areas of the primary auditory cortex (PAC), allowing a selective stimulation of these cortical areas with low-frequency rTMS. Considerable improvement in tinnitus was achieved in these patients. Conclusions Neuronavigated rTMS of increased PAC activity may help to better understand the neuronal basis of chronic tinnitus and might offer a new option for treating auditory phantom perceptions like chronic tinnitus.

"Psychopathy" describes a type of personality disorder characterized by a dysregulation of emotion processing. Social behaviour, emotion regulation and competency are of particular relevance in forensic psychiatry. Structural-morphological and functional imaging studies prove that emotion regulation, aggressive-impulsive behaviour and learning from negative experiences are greatly influenced by frontal brain regions. These abilities are impaired in severe cases of dissocial personality disorders and in traumatic "pseudopsychopathy". We illustrate the importance functional neurobiological changes in patients personality disorders and "acquired psychopathy" by two case reports on patients who were admitted to a forensic-psychiatric facility for sexual crimes.

As a result of increased interest and public demand, providing patients with adequate information about radiooncology has become more and more difficult for the doctor. Insufficient patient information can not only cause anxiety for the patient, but can also lead to legal action against the physician. In order to gain a deepter insight into our clinical practice of providing patient information, we developed a special questionnaire. We describe our first experiences in using this questionnaire at our institute. Patients and Methods: We examined the amount of information and level of satisfaction, as well as the agreement of assessment between patient and physician after the provision of standard patient information before and at the end of radiotherapy. 51 consecutive patients were interviewed with a newly designed questionnaire. The first questioning with 13 items was carried out before radiotherapy and the second with ten items was done at the end of treatment. Sum scores for information and satisfaction were defined and agreement was measured by the weighted κ coefficient. Results: Global level of information and satisfaction was good, and a significant increase in information level and a significant decline in satisfaction were seen between questionnaire 1 and 2. Agreement between patient and physician was fair, for example intent of treatment resulted in a κ coefficient of 0.34, and poor for the doctor's role with a κ coefficient of −0.002. Only 52% of the patients who received palliative radiotherapy rated correctly the non-curative intent of treatment, whereas 86% of the patients who received curative radiotherapy made a currect statement. Before radiotherapy, emotional state was often both negatively and positively assessed by the patients. Conclusion: Our short questionnaire is simple and easy to understand. It provides insights into patient information with respect to assessment of the information, satisfaction level, and agreement between doctor and patient. Therefore, it is suitable for use in the clinical routine. We found a high information and satisfaction score, but limited agreement between physician and patient. In the future, the questionnaire can be used as an aid to evaluate patient information in everyday practice and to train the communication skills of the physician. Further evaluation of the questionnaire is needed and, in particular, the aspect of patient information with palliative radiotherapy has to be improved.

A detailed mathematical analysis of the diffusion process of neurotransmitter inside the synaptic cleft is presented and the spatio-temporal concentration profile is calculated. Using information about the experimentally observed time course of glutamate in the cleft the effective diffusion coefficient Dnet is estimated as Dnet approximately 20-50 nm(2) microseconds(-1), implying a strong reduction compared with free diffusion in aqueous solution. The tortuosity of the cleft and interactions with transporter molecules are assumed to affect the transmitter motion. We estimate the transporter density to be 5170 to 8900 micrometer(-2) in the synaptic cleft and its vicinity, using the experimentally observed time constant of glutamate. Furthermore a theoretical model of synaptic transmission is presented, taking the spatial distribution of post-synaptic (AMPA-) receptors into account. The transmitter diffusion and receptor dynamics are modeled by Monte Carlo simulations preserving the typically observed noisy character of post-synaptic responses. Distributions of amplitudes, rise and decay times are calculated and shown to agree well with experiments. Average open probabilities are computed from a novel kinetic model and are shown to agree with averages over many Monte Carlo runs. Our results suggest that post-synaptic currents are only weakly potentiated by clustering of post-synaptic receptors, but increase linearly with the total number of receptors. Distributions of amplitudes and rise times are used to discriminate between different morphologies, e.g. simple and perforated synapses. A skew in the miniature amplitude distribution can be caused by multiple release of pre-synaptic vesicles at perforated synapses.

We present a minimal kinetic model for excitatory synaptic transmission to cerebellar Purkinje cells. The main components are a kinetic model for a single glutamate receptor, which is calibrated with the help of patch clamp data, and a mean field approximation for the dynamics of a population of channels, which generate an EPSC. The resulting minimal model of the parallel fiber–Purkinje cell synapse is used to estimate the dynamics of glutamate in the synaptic cleft and to clarify the role of receptor desensitization in synaptic transmission. We also apply the model to different aspects of synaptic modulation, like long-term depression and potentiation by pharmacological application of ampakines. In the framework of the minimal model these effects can be understood as the result of modified receptor kinetics.

OBJECTIVE To describe differences in cerebral glucose metabolism between frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). METHODS 14 patients with FTLD (7 f/7 m, mean age 60.1 years) and 14 patients with AD (7 f/7 m, mean age 59.5 years) were examined. [18F]FDG positron emission tomography (PET) scans were analysed with statistical nonparametric mapping (SnPM) and statistical parametric mapping (SPM99). RESULTS Significant decreases in glucose metabolism in FTLD compared to AD were detected in the left insula/left inferior frontal gyrus (Brodman area [BA]13, 45 and 47) and in the medial frontal gyrus bilaterally (BA10). A significant decrease in AD compared to FTLD was identified in the right middle temporal gyrus (BA39). CONCLUSION Cerebral PET could be a promising tool to discriminate FTLD from AD.

Objective Clinical, neurophysiological and neuroimaging data suggest that chronic tinnitus resembles neuropsychiatric syndromes characterised by focal brain activation. Low frequency repetitive transcranial magnetic stimulation (rTMS) has been proposed as an efficient method in treating brain hyperexcitability disorders. Methods Patients suffering from chronic tinnitus underwent a [ (18)F]deoxyglucose-PET (positron emission tomography). Fusioning of the individual PET scan with the structural MRI-scan (magnetic resonance imaging, T1, MPRAGE) revealed an increased metabolic activation in the primary auditory cortex as target point for rTMS. A neuronavigational system enabled the positioning of the figure of eight coil in relation to the target area. rTMS (110 % motor threshold; 1 Hz; 2000 stimuli/day over 5 days) was performed using a placebo controlled cross-over design. Results Following active rTMS there was a moderate improvement of tinnitus perception. Treatment effects lasted up to six months in some patients. Conclusions Neuronavigated rTMS offers new possibilities in the understanding and treatment of chronic tinnitus.

Idiopathic hypertrophic chronic pachymeningitis (IHCP) is characterised by inflammatory fibrotic thickening of the dura mater. Long term management is controversial. A 28 year old man with craniospinal IHCP and prominent lymphocytic meningitis is reported. Cerebrospinal fluid and histological examination suggested a CD4+ T cell driven process and B cell stimulation. After surgical, tuberculostatic, and immunosuppressive treatment failed to control the progressive meningeal hypertrophy, causing severe headache and neurological disability, the disease process eventually abated with intraventricular cytarabine treatment.

Introduction: The PETAL trial is a multicenter randomized controlled study for patients with aggressive lymphomas of diverse histologies (EudraCT 2006-001641-33, NCT00554164). In the study population as a whole interim PET (iPET) reliably predicted time to treatment failure (TTTF) and overall survival (OS). Interim PET-based treatment changes, however, had no impact on outcome (ASH 2014, abstract 391). Here we report the exploratory analysis for aggressive B cell lymphomas. Methods: Pts. aged 18 to 80 yrs. with newly diagnosed aggressive lymphomas and a positive baseline PET received 2 cycles of rituximab (R), cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) followed by iPET. The conditions of iPET were strictly defined: 3-week interval between the 2nd R-CHOP cycle and iPET to avoid inflammatory reactions (Eur J Nucl Med Mol Imaging 30:682, 2003), no G-CSF after the 2nd cycle to avoid altered glucose biodistribution (J Nucl Med 47:950, 2006), standardized uptake value (SUV)-based PET interpretation to improve reproducibility (favorable iPET response: reduction of maximum SUV by > 66 % compared to baseline; J Nucl Med 48:1626, 2007). Pts. with CD20+ lymphomas and a favorable iPET were randomized to receive 4 more cycles of R-CHOP or the same treatment plus 2 extra doses of R (part A of the trial). Pts. with an unfavorable iPET were randomized to continue R-CHOP for 6 additional cycles or receive 6 blocks of a more complex methotrexate-, cytarabine- and etoposide-based regimen originally designed for Burkitt lymphoma (Blood 124: 3870, 2014; part B). R was omitted in pts. with CD20- lymphomas. Sample size of the entire study population was based on the empirically derived assumption that treatment failure after 2 yrs. (TF: progression, relapse, treatment discontinuation due to toxicity, start of alternative therapy, death of any cause) could be improved from 80 % to 90 % in part A and from 30 % to 45 % in part B (alpha=0.05, power=0.8). Secondary endpoints included OS and toxicity. Results: Fifty-seven oncological centers and 23 nuclear medicine institutions participated in the trial. Between 2007 and 2012 1072 pts. were registered, and 862 (80.4 %) had a positive baseline PET, received 2 cycles R-CHOP, underwent iPET and were allocated to one of the post-iPET treatment arms detailed above. Reference pathology was available in 98 %, and median follow-up is 52 months. All in all, there were 779 patients with CD20+ aggressive B-cell lymphomas (90.4 % of all treated pts.) of whom 606 had diffuse large B-cell lymphoma (DLBCL), 42 primary mediastinal B-cell lymphoma (PMBCL) and 42 follicular lymphoma grade 3 (FL3). Interim PET was favorable in 691 pts. (88.7 %) and unfavorable in 88 pts. with CD20+ lymphomas (11.3 %). It was highly predictive of TTTF for CD20+ lymphomas in general and for each of the DLBCL, PMBCL and FL3 subgroups (Table). In CD20+ lymphomas and DLBCL, the iPET response predicted TF independently of the International Prognostic Index, and it was also predictive of OS. The groups of PMBCL and FL3 were too small for multivariate analyses. In part A, adding 2 extra doses of R failed to improve TTTF and OS in all histological entities. Separate analyses for subgroups defined by sex, age (< vs. > 60 yrs.) or a combination of the two showed no statistically significant benefit of extra doses of R in any of the subgroups. In pts. with an unfavorable iPET response, a switch from R-CHOP to the Burkitt regimen failed to improve TTTF or OS in CD20+ lymphomas in general (Figure) and in the DLBCL, PMBCL and FL3 subgroups. In part B, the Burkitt protocol was associated with more grade 3/4 leukopenia (82 % vs. 57 %, p=0.02), thrombocytopenia (59 % vs. 18 %, p=0.0001), infection (41 % vs. 16 %, p=0.017) and mucositis (39 % vs. 7 %, p=0.0007) than R-CHOP, but treatment-related mortality was similar in both arms (1 death each). Conclusion: In this large multicenter trial iPET proved highly predictive of outcome in pts. with CD20+ aggressive B-cell lymphomas, DLBCL, PMBCL or FL3 treated with R-CHOP. In pts. with a favorable iPET response, addition of 2 extra doses of R to 6 cycles R-CHOP failed to improve outcome in CD20+ lymphomas in general and in subgroups defined by histology, sex or age. In pts. with an unfavorable iPET response, switching to a more aggressive protocol also failed to improve outcome in any of the entities. Novel strategies are required for aggressive B-cell lymphomas failing to respond to the first 2 cycles of R-CHOP. Table Table. Figure Figure. Disclosures Duehrsen: Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding. Giagounidis:Celgene Corporation: Consultancy. Grube:BMS, Sanofi: Consultancy. Klapper:Roche, Novartis, Amgen, Takeda: Research Funding. Hüttmann:Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria; Gilead, Amgen: Other: Travel cost.

Background Patients with encephalitis associated with antibodies against N-methyl-D-aspartate-receptor antibody (NMDAR-ab) encephalitis frequently show psychotic symptoms, amnesia, seizures and movement disorders. While brain MRI in NMDAR-ab encephalitis is often normal, abnormalities of cerebral glucose metabolism have been demonstrated by positron emission tomography (PET) with 18F-fluorodeoxyglucose(FDG) in a few usually isolated case reports. However, a common pattern of FDG-PET abnormalities has not been reported. Methods The authors retrospectively identified six patients with NMDAR-ab encephalitis in two large German centres who underwent at least one whole-body FDG-PET for tumour screening between January 2007 and July 2010. They analysed the pattern of cerebral uptake derived from whole-body PET data for characteristic changes of glucose metabolism compared with controls, and the changes of this pattern during the course of the disease. Results Groupwise analysis revealed that patients with NMDAR-ab encephalitis showed relative frontal and temporal glucose hypermetabolism associated with occipital hypometabolism. Cross-sectional analysis of the group demonstrated that the extent of these changes is positively associated with clinical disease severity. Longitudinal analysis of two cases showed normalisation of the pattern of cerebral glucose metabolism with recovery. Conclusions A characteristic change in cerebral glucose metabolism during NMDAR-ab encephalitis is an increased frontotemporal-to-occipital gradient. This pattern correlates with disease severity. Similar changes have been observed in psychosis induced by NMDAR antagonists. Thus, this pattern might be a consequence of impaired NMDAR function.

On the assumption that maximum R peak time prolongation in the left-sided leads I, V5, or V6 and its time relationship to the S peak time of the maximum S amplitude in leads V1, V2, or V3 (representing dorsally directed forces of ventricular depolarization) could indicate the extent of left ventricular volume overloading and possibly left ventricular systolic function, these variables and the preoperative findings of angiocardiography were compared between patients with chronic mitral incompetence who, late after corrective valve surgery, had either well-preserved radionuclide left ventricular ejection fraction (group 1, n = 36) or radionuclide left ventricular ejection fraction below 50% (group 2, n = 30). Before surgery, group 2 patients had a highly significant lower mean left ventricular ejection fraction, a highly significant greater mean end-systolic volume index, a significantly greater mean end-diastolic volume index, a significantly greater mean maximum R peak time in leads I, V5, or V6, and a significantly greater prolongation of the maximum R peak time above the S peak time in the right precordial leads, as compared with group 1. R peak times greater than 50 ms or the presence of R peak delay (maximum R peak time greater than the S peak time of the maximum right precordial S amplitude) yields less sensitive but highly reliable results in predicting radionuclide left ventricular ejection fraction below 50% with both specificity and positive predictive values of 100%. Thus, in chronic mitral regurgitation surgery should not be delayed if patients present these signs because they are specific markers of irreversibly impaired chamber function.

Accelerated glycolysis is one of the biochemical characteristics of cancer cells. The glucose transporter isoform 1 (GLUT1) gene encodes a key rate-limiting factor in glucose transport into cancer cells. However, its expression level and functional significance in hepatocellular cancer (HCC) are still disputed. Therefore, we aimed to analyze the expression and function of the GLUT1 gene in cases of HCC. We found significantly higher GLUT1 mRNA expression levels in HCC tissues and cell lines compared with primary human hepatocytes and matched nontumor tissue. Immunohistochemical analysis of a tissue microarray of 152 HCC cases revealed a significant correlation between Glut1 protein expression levels and a higher Ki-67 labeling index, advanced tumor stages, and poor differentiation. Accordingly, suppression of GLUT1 expression by siRNA significantly impaired both the growth and migratory potential of HCC cells. Furthermore, inhibition of GLUT1 expression reduced both glucose uptake and lactate secretion. Hypoxic conditions further increased GLUT1 expression levels in HCC cells, and this induction was dependent on the activation of the transcription factor hypoxia-inducible factor-1alpha. In summary, our findings suggest that increased GLUT1 expression levels in HCC cells functionally affect tumorigenicity, and thus, we propose GLUT1 as an innovative therapeutic target for this highly aggressive tumor.

Chairpersons of medical conferences usually allow a central place in the program for poster exhibitions. Moderated poster presentations often take place during lunch breaks on the main conference days. These presentations compete only with the satellite symposia organized by the pharmaceutical industry. In contrast to the prominent positioning of poster exhibitions in conference programs, conference delegates’ interest in and attendance at poster presentations at national (and sometimes international) specialist medical conferences is occasionally rather modest. Who benefits from poster exhibitions? To whom are they useful? How might they be made more attractive? Should they even be organized at all? There are some studies relating to partial aspects of poster exhibitions at non-German specialist conferences, e.g., about the process of abstract selection for diverse conferences (1–11), electronic posters (12, 13), and the publication rate of conference contributions (14–20). Further studies have shed light on the motivation of authors to design a poster (21), redundant poster contributions (22, 23), or the time spent by conference delegates in studying a poster (24). This study aims to present systematically and prospectively the poster exhibition of a German specialist medical conference as a platform for presenting current research findings in terms of its acceptance and perceived value. The selection process for contributions and the poster awards, the scientific and personal benefits of the poster exhibition for its authors, chairpersons, and visitors were studied systematically. The number of participants at the individual poster presentations was documented and compared with the number of poster contributions on offer.

Akathisia is a clinical important symptom, frequently induced by neuroleptic treatment. Despite its clinical importance, less is known about its pathophysiology.Using [18]-FDG-PET, imaging patterns of cortical metabolic activity were obtained in a patient during olanzapine-induced akathisia and after recovery.Akathisia was characterized by a reduced metabolic activity in thalamus and cerebellum. After discontinuing medication akathisia disappeared, reflected by a recovery of metabolic activity in these brain areas.[18]-FDG-PET may be useful to identify cortical regions mediating clinical aspects of drug-induced akathisia, thereby offering a deeper insight into the pathophysiology of this serious side effect.

To address the following questions: which parameters influenced the frequency of distant metastases in patients with locally advanced ear-nose-throat (ENT) tumors, which was the distribution pattern of metastases, and what were the diagnostic consequences for pretherapeutic staging?600 patients (526 men, 76 women, median age 56 years) with ENT tumors (squamous cell carcinoma histology) were studied retrospectively. The distribution of primary tumor site and stage (AJCC) was as follows: oropharynx: n = 161 (26.8%), hypopharynx: n = 187 (31.2%), oral cavity: n = 89 (14.8%), larynx: n = 118 (19.7%), cancer of unknown origin: n = 13 (2.2%), others: n = 32(5.3%), I: n = 24 (4%), II: n = 49 (8.2%), III: n = 89 (14.8%), IV: n = 438 (73%). 270 patients (45%) received radiochemotherapy, 330 (55%) postoperative radiotherapy. The following parameters were analyzed in association with distant metastases: tumor localization, T- and N-category, primary treatment, local tumor control, and second neoplasms.114/600 patients (19%) developed distant metastases, 29/600 (4.9%) at presentation, 50% within 9.3 months after diagnosis of the primary tumor. Distant metastases were most frequent in stage IV (24.2%), carcinoma of the hypopharynx (25.7%), local recurrence (24.3%), and second neoplasm (31.7%) with the following distribution pattern: pulmonary 61/114 (53.5%), pleural 15/114 (13.1%), osseous 45/114 (39.5%), hepatic 14/114 (12.3%), cerebral 8/114 (7%), cutaneous 14/114 (12.3%). 34/114 patients (29.8%) presented monotopic, 80/114 (70.2%) polytopic metastases. 82/600 (13.6%) patients additionally had second neoplasms, 20 corresponding with synchronous or metachronous bronchial tumors.With locally advanced ENT tumor stage IVa/b, carcinoma of the hypopharynx, local recurrence or second neoplasms, at least a pretherapeutic CT of the thorax should be performed because every seventh patient (88/600) developed metastases or second primary tumors within the thoracic space during the course of disease. Regarding the side effects and costs of curative therapy, the definition of generally accepted guidelines for the systemic staging of locally advanced ENT tumors should be undertaken.

The genes for the human ATP-binding cassette (ABC) transporter ABCA7 and the minor histocompatibility antigen HA-1 are juxtaposed in close proximity on chromosome 19p13.3. The multispan transmembrane protein ABCA7 contains an extracellular domain that is recognized by antisera from patients with Sjogren's syndrome (“Sjogren-epitope”). Recent work from our laboratory demonstrating the involvement of ABCA7 in cellular ceramide and phosphatidylserine export suggests a role for this transporter in programmed cell death. In HA-1, a protein of unknown function, a His/Arg polymorphism (His168Arg), which constitutes the immunologic target for HA-1-specific cytotoxic T cells, has been causatively linked to graft-versus-host disease after allogeneic stem cell transplantation. Because these findings suggest a potential implication of ABCA7 and HA-1 in immune processes, we tested the hypothesis that allelic variants in both genes are associated with autoimmune disorders. We identified a total of 31 exonic single-nucleotide polymorphisms (SNP) in the ABCA7/HA-1 gene complex, nine of which represent non-synonymous nucleotide alterations. Genotypes of ABCA7 and HA-1 SNP were determined in three distinct Caucasian populations of patients with primary Sjogren's syndrome and ethnically matched controls. Comparison of allele frequencies between these groups revealed that the incidence of the HA-1 168His allele is significantly lower in Sjogren's syndrome patients than in controls (p

CX+/CX- and Colo+/Colo- tumor sublines with stable heat shock protein 70 (Hsp70) high and low membrane expression were generated by fluorescence activated cell sorting of the parental human colon (CX2) and pancreas (Colo357) carcinoma cell lines, using an Hsp70-specific antibody. Two-parameter flow cytometry revealed that Hsp70 colocalizes with Bag-4, also termed silencer of death domain, not only in the cytosol but also on the plasma membrane. After nonlethal gamma-irradiation, the percentage of membrane-positive cells and the protein density of Hsp70 and Bag-4 were found to be strongly upregulated in carcinoma sublines with initially low expression levels (CX-, Colo-). Membrane expression of Hsp70 was also elevated in Bag-4 overexpressing HeLa cervix carcinoma cells when compared to neo-transfected cells. In response to gamma-irradiation, neo-transfected HeLa cells behaved like Hsp70/Bag-4 low-expressing CX- and Colo-, and Bag-4-transfected HeLa cells like Hsp70/Bag-4 high-expressing carcinoma sublines CX+ and Colo+. Immunoprecipitation studies further confirmed colocalization of Hsp70 and Bag-4 but also point to an association of Hsp70 and Hsp40 on the plasma membrane of CX+ and Colo+ cells; on CX- and Colo- tumor sublines, Hsp40 was detectable in the absence of Hsp70 and Bag-4. Other co-chaperones including Hsp60 and Hsp90 were neither found on the cell surface of CX+/CX-, Colo+/Colo- nor on HeLa neo-/HeLa Bag-4-transfected tumor cells. Functionally, Hsp70/Bag-4 and Hsp70/Hsp40 membrane-positive tumor cells appeared to be better protected against radiation-induced effects, including G2/M arrest and growth inhibition, on the one hand. On the other hand, membrane-bound Hsp70, but neither Bag-4 nor Hsp40, served as a recognition site for the cytolytic attack mediated by natural killer cells.

Clinical, neurophysiological and neuroimaging data suggest that chronic tinnitus resembles neuropsychiatric syndromes characterised by focal brain activation. Low frequency repetitive transcranial magnetic stimulation (rTMS) has been proposed as an efficient method in treating brain hyperexcitability disorders.Patients suffering from chronic tinnitus underwent a [ (18)F]deoxyglucose-PET (positron emission tomography). Fusioning of the individual PET scan with the structural MRI-scan (magnetic resonance imaging, T1, MPRAGE) revealed an increased metabolic activation in the primary auditory cortex as target point for rTMS. A neuronavigational system enabled the positioning of the figure of eight coil in relation to the target area. rTMS (110 % motor threshold; 1 Hz; 2000 stimuli/day over 5 days) was performed using a placebo controlled cross-over design.Following active rTMS there was a moderate improvement of tinnitus perception. Treatment effects lasted up to six months in some patients.Neuronavigated rTMS offers new possibilities in the understanding and treatment of chronic tinnitus.

Histologically, the posterior capsule opacification (PCO) corresponds to regenerative tissue of transformed lens epithelial cells (LECs) with extracellular matrix production. In this study, the influence of ionizing radiation on proliferating LECs and the development of PCO was investigated in vitro.Each four and 14 pork lenses, respectively, were irradiated with 6 MeV electrons with single doses of 8, 10, 12, and 20 Gy. 1-2 h after irradiation the lens was removed by capsulorrhexis and hydrodissection. After fixation of the capsular bag in a special device the proliferation of residual LECs was examined daily. The experiment was considered to be finished when the capsular bag was completely opacified by confluent cell proliferates.Single dose irradiation with electrons in a dose range from 8 to 12 Gy significantly protracted the development of PCO with complete inhibition of PCO after application of 20 Gy.To inhibit PCO in vitro, a single dose of 20 Gy is necessary. The actual in vitro model allows an optimal investigation of PCO formation under different external influences and is therefore very suitable for radiobiological questions.

"Psychopathy" describes a type of personality disorder characterized by a dysregulation of emotion processing. Social behaviour, emotion regulation and competency are of particular relevance in forensic psychiatry. Structural-morphological and functional imaging studies prove that emotion regulation, aggressive-impulsive behaviour and learning from negative experiences are greatly influenced by frontal brain regions. These abilities are impaired in severe cases of dissocial personality disorders and in traumatic "pseudopsychopathy". We illustrate the importance functional neurobiological changes in patients personality disorders and "acquired psychopathy" by two case reports on patients who were admitted to a forensic-psychiatric facility for sexual crimes.

Cardiovascular morbidity and mortality is high in patients following renal transplantation. The present analysis assessed major cardiovascular risk factors and estimated the risk of coronary artery disease in the largest present-day comparative trial of tacrolimus vs. microemulsified cyclosporine A. In this 6-month study, 557 patients were randomly allocated to therapy with tacrolimus (n = 286) or cyclosporine A (n = 271) concomitantly with azathioprine and corticosteroids. The primary endpoint was the incidence of and time to acute rejection. Blood pressure, serum cholesterol, HDL cholesterol, triglycerides, and blood glucose were measured at baseline, and at months 1, 3, and 6. Ten-year risk of coronary heart disease was estimated according to the Framingham risk algorithm. Tacrolimus resulted in significantly lower summary measures (time-weighted average) of serum cholesterol (p = 0.0004) and mean arterial blood pressure (p = 0.0156), but in a higher summary measure of blood glucose (p = 0.0028) than cyclosporine. The summary measure of serum triglycerides was not different between treatment groups (p = 0.368). The mean 10-year coronary artery disease risk estimate was significantly lowered in men (p = 0.0032) treated with tacrolimus, but was unchanged in women. Tacrolimus and cyclosporine A microemulsion exert a compound-specific impact on cardiovascular risk factors and appear to affect the predicted rate of cardiovascular morbidity in different manners.

PURPOSE: An accelerated rate of glucose metabolism mediated by overexpression of key regulatory glycolytic enzymes and glucose transporters is among the most characteristic biochemical marker of malignant transformed cells. In thyroid neoplasms, however, an increased uptake of glucose [measured by 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET)] seems to be restricted to more aggressive and high-grade tumors, whereas tumors with favorable prognosis demonstrate no significant tracer uptake. We therefore studied the expression of glucose transporters in thyroid carcinomas with different grades of malignancy. METHODS: Sections of formalin-fixed and paraffin-embedded tissue obtained from 45 patients with thyroid cancer (5 anaplastic, 20 papillary and 20 follicular tumors) were investigated. Polyclonal rabbit antiglucose transporter antibodies, reactive with glucose transporters 1-5 (GLUT1-5), were used after heat pretreatment of the sections. Staining was performed by the avidin-biotin conjugate immunoperoxidase reaction and evaluated semiquantitatively. RESULTS: Expression of GLUT1 transporter on the cell membrane was closely related to the grade of malignancy in thyroid neoplasms (Fisher exact test p < 0.05). All anaplastic tumors showed a high level of GLUT1 expression in the cytoplasm and on the cell membrane. Positive membranous staining in differentiated tumors was detected predominantly in neoplasms with unfavorable prognosis, e.g., in widely invasive follicular or metastatic tumors, whereas low or no immunoreactivity could be seen in well-differentiated tumors or in normal thyroid epithelium. CONCLUSIONS: These data indicate that overexpression of GLUT1 on the cell membrane of thyroid neoplasms is closely related to tumors demonstrating a more aggressive biological behavior. Therefore, determination of GLUT1 expression in thyroid cancer tissue may be a prognostic marker, and FDG-PET may be a helpful technique in identifying patients at a higher risk.

The regulation of renin secretion is not understood in detail. There is evidence that amiloride (CAS 17440-83-4) has a stimulatory effect on the renin secretion but it is still in question whether this is volume and/or sodium independent. The purpose of this study was to investigate whether a single dose of amiloride has a direct stimulatory effect on the renin secretion in humans independent of its diuretic effect. Blood pressure, plasma renin activities and plasma aldosterone concentrations as well as serum electrolytes and serum creatinine were assessed in 11 healthy male humans over a period of 6 hours after a single dose of 20 mg of amiloride (Midamor ®), or placebo. Furthermore every hour urine was collected for analysis of urinary creatinine and electrolytes. To avoid a possible effect on the renin secretion via augmented diuresis induced by amiloride the urinary volume loss was replaced by 0.9 % NaCl solution. There was a decrease in plasma renin activities and plasma aldosterone concentrations after amiloride and placebo administration, but the plasma renin activity after amiloride was significantly higher compared with placebo. Also the plasma aldosterone concentration was higher after amiloride compared with placebo, but the difference did not reach statistical significance. Serum and urinary concentrations of sodium and potassium clearly confirmed the known potassium-saving and natriuretic effect of amiloride. Serum creatinine concentrations decreased and urinary sodium chloride concentrations increased due to the administered volume load using physiologic sodium chloride solution. The present study provides evidence that amiloride induces renin secretion by direct mechanisms in man, which might go along with augmented aldosterone secretion.

To investigate new methods of diagnostic transcranial sonography for brain parenchymal, vascular and perfusion imaging, we performed 3-D native tissue harmonic transcranial sonography (3D-nthTCS), 3-D transcranial color-coded duplex sonography (3D-TCCS), and "loss-of-correlation" imaging (LOC-TCCS) in four patients following early hemicraniectomy due to space-occupying "malignant" middle cerebral artery infarction (MMCAI). Three-dimensional datasets, utilizing 3D-nthTCS and 3D-TCCS, were created and up to 10 axial 2-D B-mode image planes, similar to CCT, reconstructed in each patient. Three-dimensional reconstructions of the circle of Willis documented one persistent carotid-T occlusion and three recanalizations of the MCA. LOC-TCCS, based on stimulated acoustic emission from an ultrasound (US) contrast agent, demonstrated a perfusion deficit in 2 of 3 patients, with regard to their infarcts. Concluding, 3D-nthTCS, 3D-TCCS and LOC-TCCS are promising tools for bedside monitoring, early prognosis and treatment evaluation for MMCAI in the postoperative period. Further studies should be performed to standardize these new methods and evaluate their applications through the intact calvarina.