[Implementation of the principle of supported employment in Germany : Position paper of a task force of the DGPPN]. / Umsetzung der Prinzipien des Supported Employment in Deutschland : Positionspapier einer Task-Force der DGPPN.

The effects of mental diseases on the employment and working situation can be substantial. They are one of the main reasons for inability to work and reduced earning capacity. Against this background the question arises about suitable occupational reintegration measures for people with severe mental illnesses. In recent years, the principle of supported employment has been internationally shown to be increasingly more successful. In this context mentally ill people are primarily placed at a position of the first employment market and supported on-site by a job coach. This concept is inclusive, individual and evidence based. Despite proven effectiveness, it has so far been insufficiently implemented in German-speaking regions. In the future it will be a matter of considering the individual needs for assistance of mentally ill people more intensively than previously and to respond with functional and in a best-case scenario, multiprofessional and flexible offers.

[DGPPN recommendations on quality indicators for schizophrenia]. / Aktuelle Empfehlungen der DGPPN für Schizophrenie-Qualitätsindikatoren.

BACKGROUND: In Germany, several quality indicators have been proposed for the measurement of quality of mental healthcare. Some of these quality indicators have been tested in feasibility studies. The German Association for Psychiatry and Psychotherapy (DGPPN) established the "Task Force Quality Indicators (QI)" that, based on previous experience in the development and pilot testing of indicators, considered the further development and practical realization of QI for schizophrenia. AIM: The aim was to select a set of QI for schizophrenia that can also be applied to other diagnoses or used in generic measurements. Another goal was to focus on high feasibility of indicators. METHODS: In a multistage selection process, the DGPPN Task Force selected QI that focus on essential quality aspects from an inventory of 161 existing QI developed by national and international research groups. Indicators were adapted in consultation with the "trialogic forum" of the DGPPN. RESULTS: The DGPPN proposes the following ten indicators for quality measurement in mental healthcare for schizophrenia: QI1 Long-term treatment/Monitoring of side effects, QI2 Seclusion and restraint, QI3 Number of suicides, QI4 Psychoeducational-oriented intervention for significant others, QI5 Timely beginning of outpatient treatment after discharge from inpatient treatment, QI6 Aggression management - inpatient treatment, QI7 Diagnostic procedures/Physical examination, QI8 Antipsychotic polypharmacy, QI9 Rehabilitation/Vocational rehabilitation, QI10 Diagnostic procedures/Psychosocial functioning. DISCUSSION: Most of our proposed QI have to be measured by means of additional data documentation. Based on prior experience in the pilot testing of QI, the DGPPN estimates that the additional efforts in data documentation would be manageable, but have to be refinanced. The indicators will be tested in feasibility studies in different mental healthcare hospitals in Germany.

[Standards for treatment in forensic committment according to § 63 and § 64 of the German criminal code : Interdisciplinary task force of the DGPPN]. / Standards für die Behandlung im Maßregelvollzug nach §§ 63 und 64 StGB : Interdisziplinäre Task-Force der DGPPN.

People who have been convicted of a crime due to a severe mental disorder and continue to be dangerous as a result of this disorder may be placed in a forensic psychiatric facility for improvement and safeguarding according to § 63 and § 64 of the German Criminal Code (StGB). In Germany, approximately 9000 patients are treated in clinics for forensic psychiatry and psychotherapy on the basis of § 63 of the StGB and in withdrawal centers on the basis of § 64 StGB. The laws for treatment of patients in forensic commitment are passed by the individual States, with the result that even the basic conditions differ in the individual States. While minimum requirements have already been published for the preparation of expert opinions on liability and legal prognosis, consensus standards for the treatment in forensic psychiatry have not yet been published. Against this background, in 2014 the German Society for Psychiatry and Psychotherapy, Psychosomatics and Neurology (DGPPN) commissioned an interdisciplinary task force to develop professional standards for treatment in forensic psychiatry. Legal, ethical, structural, therapeutic and prognostic standards for forensic psychiatric treatment should be described according to the current state of science. After 3 years of work the results of the interdisciplinary working group were presented in early 2017 and approved by the board of the DGPPN. The standards for the treatment in the forensic psychiatric commitment aim to initiate a discussion in order to standardize the treatment conditions and to establish evidence-based recommendations.

[Innovations in biomarker development: a pathway towards individualized cancer therapy?]. / Moderne Methoden der Biomarkerentwicklung: eine Chance für die individualisierte Tumortherapie?

Despite multiple medical and scientific achievements, cancer remains a leading cause of death worldwide. Next to imaging technologies, molecular methods for early detection and for monitoring of the course of disease are of increasing interest. Thus, over the past years numerous studies have focused on the identification of biomarkers for cancer diagnosis, prognosis and response to therapy. The study of biomarkers seems to pose a high degree of complexity because many different types of molecules may, in principle, serve as potential biomarkers. In addition, these molecules can be produced either by the tumor or by the tumor-host in response to the presence of cancer. In this review the authors will address several major topics encompassed by the field of biomarker research. They will discuss the primary sources from which biomarker candidates can be 'mined' as well as the technological or methodological challenges associated with identification of biomarkers. Furthermore, the review will focus on current biomarker candidates for head and neck squamous cell carcinoma (HNSCC), with particular interest on several molecules yielding potential relevance for detection and prognosis of this type of cancer. Finally, several biomarker candidates with predictive potential for the response to therapy of HNSCC patients will be discussed, since identifying such molecules is crucial for developing individually-tailored and improved therapeutic strategies.

[Diagnostic and prognostic biomarkers in head and neck squamous cell carcinoma]. / Tumormarker und Prognosefaktoren bei Plattenepithelkarzinomen der Kopf-Hals-Region.

Classical prognostic factors for squamous cell carcinoma of the head and neck (HNSCC) are based on general parameters such as tumor stage or histological grading and only allow for a rough estimation of the clinical course. However, predicting individual responses to treatment remains challenging and diverging clinical courses of same-stage HNSCC stage remain obscure. The need for a better understanding of the individual genomic or proteomic signature of HNSCC resulted in a great number of publications on novel biomarkers. Still, in most cancer centres therapy planning and risk appraisal are solely based on the classical factors with only a few exceptions such as HPV status in oropharyngeal carcinoma. Future improvements in biomarker research will probably be achieved with sets of various genomic and proteomic markers as provided by microarray technology. This review highlights the criteria for a successful biomarker candidate, gives an overview on the most important new biomarkers, and introduces the principles of genomic and proteomic biomarker chips.

Adenosine triphosphate-deficient erythrocytes of the egg-laying mammal, echidna (tachyglossus aculeatus).

The erythrocytes of the short-beaked echidna (Tachyglossus aculeatus), an egg-laying mammal, were examined for the presence of phosphorylated compounds. The erythrocytes contained only 0.03 +/- 0.01 micromoles of adenosine 5'-triphosphate per milliliter of cells. This amount is two orders of magnitude less than that in human cells. Although the echidna erythrocytes had an abundance of 2,3-diphosphoglycerate and other glycolytic intermediates, no other energy-rich pyridine and purine compounds were detected.

Evaluation of 177Lu[Lu]-CHX-A″-DTPA-6A10 Fab as a radioimmunotherapy agent targeting carbonic anhydrase XII.

INTRODUCTION: Due to their infiltrative growth behavior, gliomas have, even after surgical resection, a high recurrence tendency. The approach of intracavitary radioimmunotherapy (RIT) is aimed at inhibiting tumor re-growth by directly administering drugs into the resection cavity (RC). Direct application of the radioconjugate into the RC has the advantage of bypassing the blood-brain barrier, which allows the administration of higher radiation doses than systemic application. Carbonic anhydrase XII (CA XII) is highly expressed on glioma cells while being absent from normal brain and thus an attractive target molecule for RIT. We evaluated a CA XII-specific 6A10 Fab (fragment antigen binding) labelled with 177Lu as an agent for RIT. METHODS: 6A10 Fab fragment was modified and radiolabelled with 177Lu and characterized by MALDI-TOF, flow cytometry and radio-TLC. In vitro stability was determined under physiological conditions. Biodistribution studies, autoradiography tumor examinations and planar scintigraphy imaging were performed on SCID-mice bearing human glioma xenografts. RESULTS: The in vitro CA XII binding capacity of the modified Fab was confirmed. Radiochemical purity was determined to be >90% after 72 h of incubation under physiological conditions. Autoradiography experiments proved the specific binding of the Fab to CA XII on tumor cells. Biodistribution studies revealed a tumor uptake of 3.0%ID/g after 6 h and no detectable brain uptake. The tumor-to-contralateral ratio of 10/1 was confirmed by quantitative planar scintigraphy. CONCLUSION: The radiochemical stability in combination with a successful in vivo tumor uptake shows the potential suitability for future RIT applications with the 6A10 Fab.

COX-inhibitors relieve the immunosuppressive effect of tumor cells and improve functions of immune effectors.

A common phenomenon in cancer patients is a suppressed cell-mediated immunity, characterized by the inability of immune effector cells to mount efficient anti-tumor responses. Immunosuppressive factors, released by the tumor, contribute to this phenomenon and thus to tolerance. Prostaglandins, catalyzed by the cyclooxygenases (COX-1 and COX-2) from arachidonic acid, are one class of these factors. Since at least one of the COX enzymes is often expressed at high level in human cancers, the enzymes were ascribed a causal role in tumor etiology and progression. Non-steroidal antiinflammatory drugs (NSAIDs) like aspirin, which block COX activity, have demonstrated their antitumor effects in preclinical and clinical trials. Pro-apoptotic and anti-angiogenic effects in tumor cells may account for this activity. In addition, by inhibiting the release of prostaglandins from the tumor and by blocking COX activity in immune effector cells, NSAIDs may also bias the function of immune cells towards a more tumoricidal phenotype. We show here that tumor cells inhibit the physiological function of immune cells, and that NSAIDs restore this function. These data contribute to an understanding of the antineoplastic effect ascribed to NSAIDs and support the prophylactic use of these drugs in high-risk patients.

Rapid proliferation of B cells from adenoids in response to Epstein-Barr virus infection.

EBV is a human tumor virus that is associated with different types of tumors. A unique feature of EBV is its capability to infect and immortalize human B cells both in vivo and in vitro. In cell culture, this progress is termed immortalization and infected B cells grow out to permanent, so-called lymphoblastoid cell lines. During our experiments, we observed that B lymphocytes derived from adenoids are infected efficiently by EBV and proliferate much more rapidly than any other known type of B cell. High concentrations of adhesion molecules and of CD21, the EBV receptor, present on these cells may account for this phenomenon. Adenoid B cells may therefore represent a particular subpopulation of preactivated B lymphocytes that can greatly simplify and enhance the production of lymphoblastoid cell lines for, e.g., antigen-presenting cells for gene therapeutic approaches and similar applications.

Cultured cells from renal cortex of hibernators and nonhibernators. Regulation of cell K+ at low temperature.

Cells were grown as primary monolayer cultures from kidney cortex of guinea pigs (nonhibernators), hamsters and ground squirrels (both hibernating species). When plates of cells were placed at 5 degrees C, cells of guinea pigs lost 37% of their K+ in 2 h and those of the hibernator lost about 10%. Uptake of 42K into the cells exhibited a simple, single exponential time course at both temperatures. Unidirectional efflux of K+ was equal to K+ influx in all cultures at 37 degrees C and, within limits of error, in hibernator cells at 5 degrees C. Efflux was 3-to 5-fold greater than influx in guinea pig cells at 5 degrees C. After 2 h in the cold the ouabain sensitive K+ influx remaining (7-15% of that at 37 degrees C) was about the same in the cells of the 3 species. Cells from active hamsters and from hibernating ground squirrels, however, exhibited significantly greater pump activity after 45 min in the cold (19 and 14%, respectively). The stimulation of K+ influx by increasing [K+] did not show an increase in Km+ at 5 degrees C in cells of guinea pigs and ground squirrels. Lowering [K+]c and/or raising [Na+]c by treatment in low- and high-K+ media caused only slight stimulation of K+ influx, except in cells of ground squirrels at 5 degrees C in which the stimulation was at least 11-times greater than at 37 degrees C or in cells of guinea pigs at either temperature. This altered kinetic response of K+ transport to cytoplasmic ion stimulation with cooling accounted for about one-third of the improved regulation of K+ at 5 degrees C in ground squirrel cells; the other two-thirds was attributable to a greater decrease in K+ leak with cooling. The inhibition of active transport by cold in all 3 species was much less severe than that previously seen in any (Na++K+)-ATPase of mammalian cells.

The liver is an organ site for the release of inosine metabolized by non-glycolytic pig red cells.

The metabolic energy source used by the pig red cell, which is unable to metabolize blood-borne glucose, was examined. Potential physiological substrates include adenosine, inosine, ribose, deoxyribose, dihydroxyacetone and glyceraldehyde, of which inosine was previously implicated. A net ATP synthesis by red cells occurs during in situ perfusion through the adult miniature pig liver. HPLC analysis of the perfusate revealed the presence primarily of inosine and hypoxanthine. Inosine production by the liver was 0.015 mumol/g per min. Moreover, red cells maintain ATP when suspended in a balanced salt medium during a 6 h incubation at 38 degrees C, in which inosine is continuously infused to give an external concentration of no more than 3 mumol/l, mimicking its plasma level. Inosine consumption under these infusion conditions was 56 nmol/ml cell per h, which is two orders of magnitude lower than when inosine is present in millimolar concentration. The total red cell inosine consumption of 9.63 mumol/h is much less than the total liver inosine production of 212 mumol/h. These findings suggest that the liver is an organ site elaborating inosine, and that maintenance of a 3 mumol/l inosine in plasma is sufficient to meet the energy requirements of the pig red cells.

NMR study of in vivo RIF-1 tumors. Analysis of perchloric acid extracts and identification of 1H, 31P and 13C resonances.

Perchloric acid extracts of radiation-induced fibrosarcoma (RIF-1) tumors grown in mice have been analyzed by multinuclear NMR spectroscopy and by various chromatographic methods. This analysis has permitted the unambiguous assignment of the 31P resonances observed in vivo to specific phosphorus-containing metabolites. The region of the in vivo spectra generally assigned to sugar phosphates has been found in RIF-1 tumors to contain primarily phosphorylethanolamine and phosphorylcholine rather than glycolytic intermediates. Phosphocreatine was observed in extracts of these tumor cells grown in culture as well as in the in vivo spectra, indicating that at least some of the phosphocreatine observed in vivo arises from the tumor itself and not from normal tissues. In the 31P-NMR spectra of the perchloric acid extract, resonances originating from purine and pyrimidine nucleoside di- and triphosphate were resolved. HPLC analyses of the nucleotide pool indicate that adenine derivatives were the most abundant components, but other nucleotides were present in significant amounts. The 1H and 13C resonance assignments of the majority of metabolites present in RIF-1 extracts have also been made. Of particular importance is the ability to observe lactate, the levels of which may provide a noninvasive measure of glycolysis in these cells in both the in vitro states. In addition, the aminosulfonic acid, taurine, was found in high levels in the tumor extracts.

Preferential hemolysis of postnatal calf red cells induced by internal alkalinization.

Red blood cells from neonatal calves, but not from adult cows, rapidly hemolyze in buffered 300 mM solutions of a variety of nonelectrolytes and amino acids. Of these compounds, sucrose is chosen to elucidate the mechanism by which this preferential hemolysis takes place. As in other mammalian red cells, both calf and cow cells are found to be impermeable to sucrose and, in an isosmolar sucrose solution, to undergo volume shrinkage caused by the net loss of chloride ions with concomitant increase in intracellular pH. To test the potential role of intracellular pH change associated with chloride loss in promoting hemolysis, intracellular pH was altered by: (a) a direct addition of fixed acid or base to sucrose solution; (b) the removal of dissolved CO(2) from sucrose solution; and (c) the addition of cells to isotonic NaHCO(3) solution in the absence of sucrose. In all cases, only calf and not cow cells underwent hemolysis. Moreover, 4-acetamido-4'-isothiocyano-2,2'-stilbene disulfonic acid, a potent anion transport inhibitor, completely protected calf cells from hemolysis and caused a nearly total inhibition of both chloride loss and intracellular alkalinization. Furthermore, the hemolytic process is closely related to the integrity of a membrane protein, the band 3 protein, which can be cleaved to varying degrees by the combined treatment of pronase and lipase. Hemolysis is progressively inhibited as the band 3 protein undergoes proteolysis, until a total inhibition of hemolysis takes place when almost all of the band 3 protein is digested into smaller protein components with a mol wt of 65,000 and 35,000 daltons. These results suggest that the intracellular alkalinization process leading to a structural instability of the membrane band 3 protein is responsible for this calf cell hemolysis.

Kinetics of 3-O-methyl glucose transport in red blood cells of newborn pigs.

The glucose-permeable fetal red cells in the pig are entirely replaced by glucose-impermeable adult red cells within a month after birth. This study investigates the kinetic parameters of the glucose transport mechanism in newborn pig red cells in comparison with immature adult red cells (reticulocytes) as well as the fully matured adult erythrocytes. Influx and efflux of the nonmetabolizable 3-O-methyl glucose (3-O-M-G) in red cells of newborn pigs saturate at high substrate concentrations and exhibit typical Michaelis-Menten kinetics. Km values for efflux are 15.2 and 18.2 mM for 15 and 22 degrees C, respectively. Q10 computed between 10 and 26 degrees is 5.0. The energy of activation for the transport process is 34,000 cal mol-1. The effectiveness of hexoses in competing with 3-O-M-G in efflux is in the following order: D-glucose greater than D-mannose greater than D-fructose greater than D-galactose. Efflux of 3-O-M-G does not increase with 3-O-M-G or D-ribose in the medium and is reduced by 2,4-dinitroflurobenzene (DNFB), p-chloromercuriphenyl sufonic acid (PCMBS), and phloridzin. The reticulocytes are shown to possess a carrier-mediated transport but with a considerably lower transport rate. As the reticulocytes mature into normal red cells, the carrier transport mechanism is lost.

IFN-gamma-mediated coordinated transcriptional regulation of the human TAP-1 and LMP-2 genes in human renal cell carcinoma.

Some human tumor cells exhibit deficient expression of the peptide transporters TAP1 and TAP2 and of the proteasome subunits low molecular weight protein (LMP)-2 and LMP-7, which could be partially restored by cytokine treatment. Here, we show that IFN-gamma stimulation of human renal cell carcinoma lines increased the MHC class I, transporter associated with antigen processing (TAP), and LMP transcript and protein levels, but TAP and LMP expression are more rapidly induced by IFN-gamma than MHC class I molecules. No correlation between the level of induction of the MHC class I antigen presentation genes and IFN sensitivity/resistance was detected. The IFN-gamma-mediated increase of MHC class I, TAP-1, and LMP-2 expression was independent of de novo protein synthesis. Analysis of the dual TAP-1/LMP-2 promoter activity revealed that TAP-1 and LMP-2 expression are controlled by IFN-gamma at the transcriptional level. Site-specific mutations in the IFN-gamma-responsive element of the TAP-1/LMP-2 promoter blocked induction by IFN-gamma. Thus, the IFN-gamma-mediated coordinated transcriptional up-regulation of TAP-1 and LMP-2 expression occurs through the use of a common regulatory element, which might result in enhanced recognition of renal cell carcinoma cells by the immune system.

Phagocytosis, chemiluminescence, and cell volume of alveolar macrophages from neonatal and adult pigs.

Broncho-alveolar cells lavaged from the lungs of 1- and 7-day-old piglets and adult pigs were examined to determine their alveolar macrophage content, cell size, and ability to phagocytyze emulsified oil droplets and to chemiluminesce in response to opsonized zymosan particles. Alveolar macrophages were identified by specific cytochemical stains and differential cell counts as being 95%, 97%, and 90% of the cell populations, respectively. The cell volume of macrophages from 1-day-old pigs was 383 +/- 40 microns3; while the cell volumes from 7 day and adult pigs were 1,660 +/- 265 and 1,411 +/- 310 microns3. Alveolar macrophage from 1-day-old piglets possessed little ability to engulf oil droplets; however, macrophages from 7-day-old piglets phagocytized these opsonized droplets at a rate equivalent to alveolar macrophages obtained from adult pigs. The phagocytosis of oil droplets by both 7-day and adult alveolar macrophages manifested similar characteristics. Both rates can be described by saturation kinetics, and while temperatures from 37 degrees to 30 degrees C had little effect, the rate declined rapidly between 30 degrees and 16 degrees C. Alveolar macrophages from 1-day-old piglets displayed a lower magnitude of chemiluminescence than cells from 7-day-old and adult pigs and did not always respond to zymosan exposure. On the other hand, 7-day-old and adult pig alveolar macrophages were quite similar in their ability to chemiluminesce. Increasing extracellular glucose from 1 to 20 mM induced a concomitant increase in chemiluminescence. The findings suggest that functionally competent alveolar macrophages emerge in the pig lung approximately 1 week after birth.

Gene therapy--phase I trial for primary untreated head and neck squamous cell cancer (HNSCC) UICC stage II-IV with a single intratumoral injection of hIL-2 plasmids formulated in DOTMA/Chol.

Recombinant IL-2 protein has shown many immunostimulatory effects in a variety of human tumors. However, the clinical use of rIL-2 is limited by common and serious side effects after systemic administration. IL-2 expression plasmids may circumvent these drawbacks, producing high local IL-2 concentrations that cause limited or no systemic side effects. Due to the superficial growth of squamous cell carcinoma of the head and neck (HNSCC) are readily accessible for direct intratumoral injection and therefore an optimal target for such a gene therapy approach. There has been evidence for local and systemic activation of immune cells by peritumoral injections of IL-2 in patients with advanced HNSCC (Whiteside et al. 1993; Cortesina et al. 1994; De Stefani et al. 1996). We now perform a placebo-controlled, dose-rising study of the safety and tolerability of a single intratumoral injection of hIL-2 plasmid at four dose levels formulated in DOTMA/Chol in patients with primary untreated head and neck squamous cell cancer (HNSCC) TNM stage II-IV. The patients will be monitored for the occurrence of any adverse reactions to the given medication. In addition, we will determine whether the intratumoral administration of the plasmid induces and or enhances tumor-specific host responses at the immunological and or clinical level.

Metabolic properties of low ATP erythrocytes of the monotremes.

The erythrocytes of the monotremes, having a trace amount of ATP, can metabolize glucose to lactate at a rate comparable to human and other mammalian erythrocytes. The echidna energy metabolism is unique in that adenosine can stimulate glycolytic carbon flow, resulting in a nearly 20-fold net synthesis of ATP.

Ep-CAM--a marker for the detection of disseminated tumor cells in patients suffering from SCCHN.

Disseminated tumor cells are considered as the origin of metastases. Since the number of circulating tumor cells in the bone marrow or the peripheral blood of patients correlates well with the tumor stage, their early detection is an important feature for the identification of high risk patients. We therefore investigated the pan-carcinoma antigen Ep-CAM for its suitability to serve as a specific marker for disseminated tumor cells in patient with squamous cell carcinoma of the head and neck (SCCHN). In order to detect small numbers of tumor cells in early tumor stages, we developed and describe here a RT-PCR assay that detects a single tumor cell within 10(5) normal cells. We examined bone marrows from patients and healthy donors and demonstrate that Ep-CAM can be used as a tumor marker for the diagnosis of single tumor cells in patients with SCCHN.

Targeting head and neck cancer by GM-CSF-mediated gene therapy in vitro.

BACKGROUND: The prognosis for patients with squamous cell carcinoma of the head and neck (SCCHN) has remained poor during the last decades, emphasizing the need for new treatment modalities. Consequently, the objective of our study was to evaluate the feasibility and efficacy of cytokine-mediated gene therapy in SCCHN in vitro. MATERIALS AND METHODS/RESULTS: The SCCHN cell line PCI-1 was transduced by lipofection with a plasmid encoding the human granulocytemacrophage colony-stimulating factor (GM-CSF). Transfection of PCI-1 resulted in the production of significant amounts of GM-CSF as tested by ELISA. Enhanced proliferation of a GM-CSF sensitive cell line, TF-1, after incubation with supernatants of GM-CSF-transduced tumor cells demonstrated the release of biological active GM-CSF from these PCI-1 cells. In addition, GM-CSF-secreting PCI-1 cells enhanced antitumor cytotoxicity of allogeneic peripheral blood mononuclear cells, as tested in 24h-MTT-cytotoxicity assays. CONCLUSIONS: Our data demonstrate the feasibility and efficacy of GM-CSF-mediated stimulation of the antitumor immune response against SCCHN in vitro and may help to define new strategies in the treatment of this malignancy.