[Lutetium-177-PSMA radioligand therapy : Consensus within the framework of GKV-funded care between the university hospitals in Aachen, Bonn, Düsseldorf, Essen, and Cologne and the MDK Nordrhein]. / Lutetium-177-PSMA-Radioligandentherapie : Konsensus im Rahmen der GKV-finanzierten Versorgung zwischen den Hochschulkliniken in Aachen, Bonn, Düsseldorf, Essen und Köln und dem MDK Nordrhein.

In the last 3 years, Lutetium-177 prostate-specific membrane antigen radioligand therapy (Lu-177-PSMA-RLT) has received increasing attention in nuclear medicine as a new form of treatment for castration-resistant metastatic prostate cancer. This therapy combines the radionuclide Lutetium-177, which has been therapeutically used in nuclear medicine for many years, with a molecular target of the transmembrane prostate-specific membrane antigen expressed by prostate cancer cells. Since there are no prospective randomized studies on Lu-177-PSMA-RLT and the question of reimbursement has repeatedly been the subject of review by the MDK Nordrhein (Medischenische Dienst der Krankenversicherung), there was a desire because of the increasing number of patients being treated to clarify under which circumstances Lu-177-PSMA-RLT can be reimbursed by German statutory health insurance. The goals of this article are to help treating physicians understand how this new therapy option works, to integrate it in the overall therapy concept for castration-resistant metastatic prostate cancer, and, above all, to use Lu-177-PSMA-RLT-based on the current data-at the right place in the therapy sequence of castration-resistant metastatic prostate cancer.

How to Reach a Thousand-Second in-Plane Polarization Lifetime with 0.97-GeV/c Deuterons in a Storage Ring.

We observe a deuteron beam polarization lifetime near 1000 s in the horizontal plane of a magnetic storage ring (COSY). This long spin coherence time is maintained through a combination of beam bunching, electron cooling, sextupole field corrections, and the suppression of collective effects through beam current limits. This record lifetime is required for a storage ring search for an intrinsic electric dipole moment on the deuteron at a statistical sensitivity level approaching 10^{-29} e cm.

[More Health in Urban Districts: The Integration of Health Promotion in Urban Development]. / Mehr Gesundheit im Quartier: Wie Gesundheitsförderung in die Stadtteilentwicklung integriert werden kann.

Poverty represents a considerable health risk. As social- and health-related disadvantages are spatially concentrated, municipalities must take up the task of forging a stronger link between urban district development and health promotion than has thus far been the case. Moreover, they must put health promotion as part of urban district development as an item on the agenda. The present contribution illustrates in which ways health promotion in disadvantaged urban districts and its scientific monitoring and evaluation can be successful.

[The social city and the elderly]. / Soziale Stadt und ältere Menschen.

Despite the importance of the idea of accommodation and the elderly, this group is currently not the main focus of the "Socially Integrative City" (Soziale Stadt) program. From the perspective of this important target group, housing and the living environment, local supply, mobility, health promotion, and the integration of immigrants are important fields of action that should be further considered. This requires, above all, involving the elderly in planning and implementation of projects and measures for integrated neighborhood development by intense activation and participation. In addition, local partnerships between government, social and health services, housing associations, business and local initiatives (clubs, self-help organizations) are prerequisite for successful development neighborhood.

Endocrine symptom assessment in women with breast cancer: what a simple "yes" means.

GOALS OF WORK: To investigate the self-reported symptoms related to endocrine therapy in women with early or advanced breast cancer and the impact of these symptoms on quality of life (QL) indicators. MATERIALS AND METHODS: Symptom occurrence was assessed by the Checklist for Patients on Endocrine Therapy (C-PET) and symptom intensity was assessed by linear analogue self-assessment (LASA) indicators. Patients also responded to global LASA indicators for physical well-being, mood, coping effort and treatment burden. Associations between symptoms and these indicators were analysed by linear regression models. MAIN RESULTS: Among 373 women, the distribution of symptom intensity showed considerable variation in patients reporting a symptom as present. Even though patients recorded a symptom as absent, some patients reported having experienced that symptom when responding to symptom intensity, as seen for decreased sex drive, tiredness and vaginal dryness. Six of 13 symptoms and lower age had a detrimental impact on the global indicators, particularly tiredness and irritability. CONCLUSIONS: Patients' experience of endocrine symptoms needs to be considered both in patient care and research, when interpreting the association between symptoms and QL.

[Tsutusgamushi fever after travel to Southeast Asia]. / Tsutsugamushi-Fieber nach Südostasienreise.

HISTORY AND CLINICAL FINDINGS: A 49-year-old travel guide fell ill during his return from a 6-week-stay in Vietnam, Myanmar and Thailand. He developed high fever and severe headache. On admission, the body temperature was at 39.5 degrees C with relative bradycardia. A black, crusted skin lesion of approximately 5 mm diameter was noted on the chest wall and was interpreted as an insect bite. INVESTIGATIONS: CRP and liver enzymes were elevated. Total leucocyte count was normal but the differential count showed a left shift and aneosinophilia. Imaging procedures revealed splenomegaly and small pleural effusions on both sides. TREATMENT AND COURSE: The patient was treated with a parenteral quinolone based on the initial suspicion of typhoid fever. Failure of this treatment and negative blood cultures raised concerns about the possibility of Tsutsugamushi fever, based on travel history and a re-evaluation of the skin lesion as an eschar. Tsutsugamushi fever was suspected on epidemiological and clinical grounds and was confirmed by the detection of specific IgM to Orienta tsutsugamushi and by seroconversion of IgG antibodies during follow-up. Even before immunodiagnostic confirmation was available, a course of doxycycline was started. This led to rapid improvement of the patient's condition. CONCLUSION: In febrile travellers returning from Southeast Asia, Tsutsugamushi fever has to be considered in the differential diagnosis. The causative agent, Orienta tsutsugamushi is transmitted by larvae of trombiculid mites (chiggers). Leading symptoms are fever continua, cephalgia, and a primary lesion (eschar) at the site of cutaneous inoculation. The Eschar is easily overlooked and has to be searched carefully. Diagnosis is confirmed by the detection of specific antibodies. However, serology may be negative in the beginning. Therefore, treatment with doxycycline should be initiated on clinical grounds.

[Plasma levels of ropivacaine and bupivacaine during postoperative patient controlled thoracic epidural analgesia]. / Plasmakonzentrationen von Ropivacain und Bupivacain während postoperativer Patienten-kontrollierter thorakaler Epiduralanalgesie.

BACKGROUND: The postoperative continuous epidural application of local anesthetics can cause side effects like motor blockade and systemic intoxication. The study was performed to evaluate the plasma levels of two local anesthetics and their analgesic and side effects in continuous postoperative epidural analgesia. METHODS: In a prospective, randomized and double-blind study we have compared side effects of ropivacaine 0.375% (group R) vs. bupivacaine 0.125% in combination with sufentanil 0.5 microg ml(-1) (group B/S) via thoracic epidural catheters for a duration of 96 hours after major abdominal surgery in 30 gynaecological tumor patients. Analgesic effects, side effects and plasma levels of the respective local anesthetic were measured 24, 48, 72 and 96 h after start of epidural infusion. RESULTS: No differences were seen in demographics, perioperative data and analgesic effects. The following cumulative doses of local anesthetics were applied (Group R vs. B/S (median/minimum-maximum ml)): 24 h: 151/121-225 vs. 141/83-171; 48 h: 311/237-424 vs. 299/184-497; 72 h: 454/366-566 vs. 440/256-598; 96 h: 572/399-859 vs. 568/284-711. Plasma levels of local anesthetics remained far below the toxic threshold of 0.6 micro g/ml (Group R vs. B/S (median/minimum-maximum micro g/ml): 24 h: 0.05/0.03-0.24 vs. 0.0/0.0-0.02; 48 h: 0.06/0.02-0.15 vs. 0.006/0.0-0.02; 72 h: 0.05/0.0-0.11 vs. 0.0/0.0-0.02; 96 h: 0.02/0.01-0.32 vs. 0.0/0.0-0.01). The incidence and intensity of motor block (Bromage scale) and other side effects did also not differ between groups. CONCLUSION: The present study shows that thoracic epidural infusion with bupivacaine 0.125% and with a higher concentration of ropivacaine 0.375% during 96 h provides plasma levels of unbound local anesthetic far below the toxic threshold.

Precise determination of the 2s(1/2)-2p(1/2) splitting in very heavy lithiumlike ions utilizing dielectronic recombination.

The 2s(1/2)-2p(1/2) energy splittings DeltaE(L) of the lithiumlike ions 19779Au76+, 20882Pb79+, and 23892U89+ have been measured at the Experimental Storage Ring, utilizing low energy dielectronic recombination. The resonance energies in total 41 different 1s(2) 2p(1/2)nl(j(')) (n > or =20) autoionizing Rydberg states populated in the dielectronic capture process have been determined. The 2s(1/2)-->2p(1/2) excitation energies have been obtained by extrapolation of these resonance energies to the associated series limits n--> infinity. The combined analysis of the experimental data for all three ions yields DeltaE(L)=216.134(96) eV for Au76+, 230.650(81) eV for Pb79+, and 280.516(99) eV for U89+.

Flow-induced pressure differentially regulates endothelin-1, urotensin II, adrenomedullin, and relaxin in pulmonary vascular endothelium.

We hypothesized that increased pulmonary vascular pressure--one of the characteristics of congestive heart failure--directly regulates pulmonary endothelial vasoconstrictors (endothelin-1, urotensin II) and vasodilators (adrenomedullin, relaxin). To this end, we subjected pulmonary artery endothelial cells in a novel flow-chamber model to different shear stresses (17, 29, and 46 dyn/cm(2)) at low and elevated levels of downstream pressure (10 and 30 mm Hg). Application of elevated pressure over 16 h increased gene expression and peptide secretion of endothelin-1 at all shear levels, whereas secretion of adrenomedullin rose via decreased expression of its clearance receptor. In contrast, preprourotensin II mRNA and urotensin II peptide decreased in response to elevated pressure, and relaxin remained unaffected. This is the first study to identify pressure as key regulator of mediator synthesis by pulmonary vascular endothelium. Pressure-induced mediator regulation may represent an early event in the development of secondary pulmonary hypertension.

Antioxidant status and nitric oxide in the malnutrition syndrome kwashiorkor.

The pathophysiology of kwashiorkor, a severe edematous manifestation of malnutrition, is still poorly understood. The syndrome is, however, known to be associated with alterations in redox metabolism. To further elucidate the role of oxidative stress in kwashiorkor, we carried out a longitudinal study on the major blood antioxidants at the St. Joseph's Hospital, Jirapa, Ghana. All kwashiorkor patients (K) were followed up for 20 d. In comparison with local healthy controls (C), the plasma total antioxidant status was reduced to less than 50% in the patients (C, 0.87 +/- 0.21 mM; K, 0.40 +/- 0.20 mM; p<0.001). Similarly, the major plasma antioxidant albumin (C, 40.9 +/- 2.5 g/L; K, 19.1 +/- 7.4 g/L; p < 0.001) and erythrocyte glutathione (C, 2.39 +/- 0.28 mM; K, 1.01 +/- 0.33; p < 0.001) were decreased, whereas the levels of bilirubin and uric acid were not significantly altered. Nitrite and nitrate were found to be increased by a factor of 2 in kwashiorkor (C, 120 +/- 46 microM; K, 235 +/- 107 microM; p < 0.001). Over the observation period, the trends of albumin and glutathione levels were related to clinical outcome. These concentrations rose in patients who recovered and fell in patients who did not. Our study strongly supports the hypothesis that oxidative and nitrosative stress play a role in the pathophysiology of edematous malnutrition. Prophylactic and therapeutic strategies should aim at the careful correction of the reduced antioxidant status of the patients.

Kinetic characterization of glutathione reductase from the malarial parasite Plasmodium falciparum. Comparison with the human enzyme.

The homodimeric flavoenzyme glutathione reductase (GR) maintains high intracellular concentrations of the antioxidant glutathione (GSSG + NADPH + H(+) <--> 2 GSH + NADP(+)). Due to its central function in cellular redox metabolism, inhibition of GR from the malarial parasite Plasmodium falciparum represents an important approach to antimalarial drug development; therefore, the catalytic mechanism of GR from P. falciparum has been analyzed and compared with the human host enzyme. The reductive half-reaction is similar to the analogous reaction with GR from other species. The oxidative half-reaction is biphasic, reflecting formation and breakdown of a mixed disulfide between the interchange thiol and GSH. The equilibrium between the E(ox)-EH(2) and GSSG-GSH couples has been modeled showing that the Michaelis complex, mixed disulfide-GSH, is the predominant enzyme form as the oxidative half-reaction progresses; rate constants used in modeling allow calculation of an K(eq) from the Haldane relationship, 0.075, very similar to the K(eq) of the same reaction for the yeast enzyme (0.085) (Arscott, L. D., Veine, D. M., and Williams, C. H., Jr. (2000) Biochemistry 39, 4711-4721). Enzyme-monitored turnover indicates that E(FADH(-))(S-S). NADP(+) and E(FAD)(SH)(2).NADPH are dominant enzyme species in turnover. Since the individual forms of the enzyme differ in their susceptibility to inhibitors, the prevailing states of GR in the cell are of practical relevance.

Anti-HER2 therapy: how to use Herceptin in clinical practice.

The recombinant, humanized monoclonal antibody Herceptin is administered as an initial 4 mg/kg i.v. infusion over 90 min, followed by weekly 2 mg/kg i.v. infusions over 30 min. In pivotal clinical trials Herceptin, both as a single agent and in combination with chemotherapy, was found to produce a significant survival benefit in HER2-positive metastatic breast cancer patients. Importantly, Herceptin was well tolerated and was not associated with a poor side-effect profile, producing mainly mild to moderate side-effects. These were generally associated with the initial infusion. The incidence of adverse events was low with Herceptin therapy and severe vomiting and alopecia, typical of many chemotherapy treatment regimens, were not experienced by patients in the trials. Cardiac dysfunction was the most significant Herceptin-related adverse event but could, in most cases, be managed using standard therapy. The favourable adverse event profile seen with Herceptin is reflected in the quality of life (QoL) data. The health-related QoL of patients receiving Herceptin therapy alone or in combination with chemotherapy was found to be maintained. Previous studies have noted a deterioration of health-related QoL in patients treated with chemotherapy only. Thus, as well as providing significant survival benefit, Herceptin therapy improves patient well being.

Monotherapy with piperacillin/tazobactam versus combination therapy with ceftazidime plus amikacin as an empiric therapy for fever in neutropenic cancer patients.

Between July 1993 and September 1996, 107 consecutive febrile episodes in 83 neutropenic cancer patients with a median age of 41 years were randomized to treatment either with piperacillin/tazobactam 4.5 g every 8 h i.v. or ceftazidime 2 g every 8 h plus amikacin 15 mg/kg i.v. per day. In the case of fever > 38 degrees C 48 h after initiation of the antibiotic therapy, vancomycin 500 mg every 6 h i.v. was added. The study population was at serious risk of a poor outcome, since 67% of the patients had leukemia or lymphoma, 19% of the febrile events occurred after autologous bone marrow or blood stem cell transplantation, the median total duration of neutropenia was 16 days, and the median neutrophil count at study inclusion was 0.09 x 10(9)/1. The two patient groups were comparable in terms of risk factors. Bacteremia was found in 37%, other microscopically documented infections in 16%, and clinically documented infections in 26% of the febrile episodes. Most (96) febrile episodes were evaluable for response. No significant difference was found between piperacillin/ tazobactam and ceftazidime plus amikacin in terms of success rate (81% versus 83%), empirical addition of vancomycin (42% versus 38%), median time to fever defervescence (3.3 versus 2.9 days) or median duration of antibiotic therapy (7.2 versus 7.4 days). No patient died from the infection. Both antibiotic regimens were well tolerated, the study treatment being stopped only in 1 patient because of toxicity (cutaneous allergy to piperacillin/tazobactam). On the basis of the 107 febrile events encountered, we conclude that piperacillin/tazobactam is a safe and effective monotherapy. To define the definitive value of piperacillin/ tazobactam as a monotherapy for febrile neutropenic patients a large randomized trial is warranted.

Morphology of locust neurosecretory cells projecting into the Nervus corporis allati II of the suboesophageal ganglion.

The morphology of neurosecretory cells that project from the suboesophageal ganglion into the retrocerebral complex via the Nervus corporis allati II (NCA II) was studied in the migratory locust, Locusta migratoria, using backfilling techniques and intracellular staining. There are two populations of cells located ventrally in the ganglion: an anterior group of four larger cells, and a posterior group of up to 22 smaller cells. Apart from cell body size and position, members of both cell groups have almost all features in common. They show long-lasting soma spikes with large amplitudes typical for arthropod neurosecretory cells. Their dendritic arborisations are found in the same regions of the neuropile. Both types project into the corpora cardiaca and an additional putative neurohaemal region associated with posterior pharyngeal dilator muscles. The axons of the cells bypass the corpora allata, but frequently form putative release sites on the surface of nerve branches in the vicinity of these glands. Finally, using double-labelling techniques, both anterior and posterior cells are shown to be identical with immunoreactive suboesophageal ganglion cells detected in previous studies using antisera directed against either bovine pancreatic polypeptide (BPP) or locustamyotropin II (Lom-MT-II).

Evaluation of membranes for use in on-line cell separation during mammalian cell perfusion processes.

In this study two microporous hollow fibre membranes were evaluated for their use as cell retention device in continuous perfusion systems. A chemically modified permanent hydrophillic PTFE membrane and a hydrophilized PP membrane were tested. To investigate the filtration characteristic under process conditions each membrane was tested during a long term perfusion cultivation of a hybridoma cell line. In both cultivations the conditions influencing membrane filtration (e.g. transmembrane flux) were kept constant. Filtration behaviour was investigated by monitoring transmembrane pressure and protein permeability. Transmembrane pressure was measured on-line with an autoclavable piezo-resistive pressure sensor. Protein permeability was determined by quantitative evaluation of unreduced, Coomassie stained SDS-PAGE. The membrane fouling process influences the filtration characteristic of both membranes in a different way. After fermentation the PP membrane was blocked by a thick gel layer located in the big outer pores of the asymmetric membrane structure. The hydraulic resistance was higher but the protein permeability was slightly better than of the PTFE membrane. For this reason the PP membrane should be preferred. On the other hand, transmembrane pressure decreases slower when the PTFE membrane is used, which favours this membrane for long term cultivations, especially when low molecular weight proteins (< 30 KD) are produced.

Passive and active immunization against hepatitis B virus infection: optimal scheduling in healthy young adults.

Recent in vitro data suggest that an enhanced humoral response to hepatitis B surface antigen (HBsAg) may be achieved when HBsAg is administered to monocyte/lymphocyte mixtures in the presence of antibody to HBsAg (Anti-HBs). In order to determine whether the same response can be achieved in vivo and whether this phenomenon can be used to augment an individual's response to hepatitis B virus (HBV) vaccination, serum antibody levels to hepatitis B surface antigen (anti-HBs) were determined in five groups of healthy young volunteers receiving passive hepatitis B immunoglobulin (HBIG) at various time intervals around a fixed HBV vaccination schedule. Thus HBIG (0.06 ml/kg) was administered to individuals in group I at -4 weeks; group II: -2 weeks; group III: simultaneously with vaccination; group IV; +2 weeks; and group V: +4 weeks following the onset of active immunization. A sixth group of volunteers received HBIG alone. The results of the study indicated that following the initial vaccination, individuals receiving HBIG prior to vaccination responded more often and with slightly higher anti-HBs levels than those receiving HBIG simultaneously or following the onset of vaccination. These differences, however, became less prominent and ultimately non-existent with subsequent boosts of the vaccine. The study also demonstrated that males and individuals over thirty do not respond to HBV vaccination as well as females or those under thirty.

Pilot study of cyclosporin A in patients with symptomatic primary biliary cirrhosis.

The purpose of this pilot study was to determine whether daily administration of cyclosporin A to symptomatic patients with primary biliary cirrhosis for 1 yr would lead to a significant and sustained improvement in liver enzyme abnormalities. Twelve adult patients (11 female, 1 male; aged 52.6 +/- 8.9 yr, mean +/- SD) with serologic and histologically defined primary biliary cirrhosis were randomized to receive either oral cyclosporin A or vehicle placebo. Cyclosporin A was administered at sufficient dosages to maintain serum radioimmunoassay trough levels between 100 and 200 ng/ml (starting dosage, 2.5 mg/kg.day). After 1 yr of therapy, significant changes from pretreatment values were seen only in recipients of cyclosporin A. These included a 37% decrease in mean serum alkaline phosphatase and a 43% decrease in gamma-glutamyltransferase (controls +3% and -14%, respectively). Mean serum bilirubin and albumin levels and prothrombin times remained unaltered in the two groups, as did the extent of inflammation and fibrosis and the histologic staging of liver biopsy specimens. Although mean serum creatinine levels increased by 51% in recipients of cyclosporin A (+2% in controls), there were no associated changes in diastolic blood pressure or creatinine clearance values. Other side effects including thrombocytopenia, hirsutism, headaches, tremor, and parasthesiae were common in the treated group but not of sufficient severity to warrant adjustment in the dosage or discontinuation of therapy. The observed changes in hepatic, renal, and hematologic tests tended to return to baseline after discontinuation of therapy. Two patients, both placebo recipients, died of liver failure during the study period. The results of this study indicate that in symptomatic primary biliary cirrhosis, cyclosporin A administration is associated with a significant improvement in cholestatic liver enzyme abnormalities that persists for the duration of therapy. A progressive rise in serum creatinine levels and a high incidence of side effects raise concerns regarding the long-term safety of this agent in primary biliary cirrhosis.

Efficacy of commercial condoms in the prevention of hepatitis B virus infection.

Tips of synthetic and natural condoms were filled with serum samples containing either hepatitis B virus, herpes simplex virus, or cytomegalovirus, then fit over an 8-in. mechanical vibrator and inserted vibrating into sterile bath solutions for 30 min. Phosphorus 32-labeled hepatitis B and cytomegalovirus molecular probes and viral culture techniques for herpes simplex and cytomegalovirus were used to determine whether leakage of virus had occurred into the surrounding bath solutions. Natural condoms allowed leakage of hepatitis B virus but not herpes simplex virus or cytomegalovirus, whereas synthetic condoms prevented leakage of all viruses. These results suggest that natural condoms might not be effective in preventing sexually transmitted hepatitis B virus infection.