[Psychotherapeutic interventions in bipolar disorders--treatment programmes, their contents and effectiveness]. / Psychotherapie bei bipolaren Störungen--Therapiekonzepte, ihre Inhalte und Wirksamkeit.

Cognitive-behavioural interventions combined with pharmacotherapy have gained importance in the treatment of bipolar disorders. Based on the vulnerability-stress instability model psychoeducational, cognitive-behavioural, interpersonal and family interventions are provided. This paper gives an overview of treatment programmes and their foci. They include providing knowledge about the illness and its treatment, modifying dysfunctional cognitions and symptom management as well as relapse prevention by promoting a stable life style. There are several English- and German-based randomised controlled follow-up studies in English-speaking countries which provide support for the efficacy of combined treatment. Since 2004 German-based manualised treatment programmes have become available and have been shown to be clinically feasible and promising.

[Cognitive-psychoeducational group programme for bipolar disorder: pilot study with two-year follow-up]. / Kognitiv-psychoedukative Gruppenintervention bei bipolar erkrankten Patienten: Pilotstudie mit Zwei-Jahres-Katamnese.

52 patients with bipolar disorder were treated with psychopharmacotherapy and a cognitive psychoeducational group programme that was established at the Department of Psychiatry and Psychotherapy of the Ludwig Maximilian University, Munich, Germany. The programme covers psychoeducation, identifying and coping with depressive and manic symptoms, relapse prevention and establishing a stable life style. 96 % rated the group to be helpful and felt well informed about their illness. There were significant gains in knowledge (F = 25,714, p < 0.001) and improvements in the severity of the illness (CGI; F = 68,255, p < 0.001) post-treatment. With regard to sociodemographic and clinical variables, only the level of work qualification showed a differential treatment response: patients with higher qualifications had a more favourable course of the illness (F = 4,125, p = 0.048). At one and two year follow-up 25 % and, respectively, 30 % of the sample had to be readmitted. A higher number of previous hospitalisations (p = 0.010) and male sex (p = 0.031) turned out to be significant predictors of relapse (R² = 0.358, p = 0.004) at two year follow-up. This disorder-specific group programme represents a key component of treatment offering emotional support for patients and their relatives. Patients are to be involved in the treatment process and need information about the illness, its psychosocial and pharmacological treatment as well as help in learning practical skills to improve their living with the disease. Being integrated and committed to a supporting network may increase their quality of life.

[The challenge of treating bipolar outpatients]. / Herausforderungen der ambulanten Behandlung von Patienten mit bipolar-affektiven Störungen.

The course of bipolar illness comprises a wide range, which may vary between one single episode once every five years and a severe ultra rapid cycling course with mood changes within days. Even with optimal pharmacological treatment the functional outcome in bipolar patients is still poor. Underlying pathomechanisms are not fully understood yet. This article addresses three possible illness specific-aspects: cognitive defects, high relapse frequency and poor adherence. Causes as well as therapeutic interventions for these therapeutic pitfalls are summarised.

Dimeric IVIG contains natural anti-Siglec-9 autoantibodies and their anti-idiotypes.

BACKGROUND: Intravenous immunoglobulin (IVIG) preparations are increasingly used for the treatment of autoimmune and chronic inflammatory diseases. Naturally occurring autoantibodies against Siglec-9 and Fas are thought to contribute to the anti-inflammatory effects of IVIG via cell death regulation of leukocytes and tissue cells. Dimeric IVIG fractions are suspected to contain idiotypic (Id)-anti-idiotypic complexes of antibodies, which might also include anti-Siglec-9 and anti-Fas autoantibodies. METHODS: Dimeric IVIG fractions were separated from monomeric IVIG by size-exclusion chromatography and remonomerized by low pH treatment. Binding studies of total, monomeric, and dimeric IVIG were performed using surface plasmon resonance and flow cytometry on primary human neutrophils. RESULTS: Anti-Siglec-9 and anti-Fas autoantibodies were contained in both monomeric and dimeric IVIG fractions, but anti-Siglec-9 antibodies were highly enriched in dimeric IVIG. The propensity to engage in dimer formation was paratope dependent. IVIG binding to Siglec-9 was specific and sialylation independent. Interestingly, we detected anti-idiotypic antibodies (anti-Ids) against anti-Siglec-9 autoantibodies in dimeric, but not in monomeric fractions of IVIG. CONCLUSIONS: Our study supports the concept that idiotype-anti-idiotype (Id-anti-Id) interactions contribute to the dimer formation in IVIG preparations. To our knowledge, this is the first description of Id-anti-Id dimers of death receptor-specific antibodies in IVIG. Such Id-anti-Id interactions might determine the activity of immunomodulatory antibodies present both in IVIG and the patient.

Monomeric and dimeric IgG fractions show differential reactivity against pathogen-derived antigens.

Polyvalent Ig preparations, derived from the pooled plasma of thousands of healthy donors, contain a complex mix of both 'acquired' and natural antibodies directed against pathogens as well as foreign and self/auto antigens (Ag). Depending on their formulation, donor pool size, etc., liquid Ig preparations contain monomeric and dimeric IgG. The dimeric IgG fraction is thought to represent mainly idiotype-antiidiotype Ab pairs. Treatment of all IgG fractions at pH 4 effectively monomerizes the IgG dimers resulting in separated idiotype-antiidiotype Ab pairs and thus in a comparable F(ab')(2) binding site availability of the different IgG fractions. Previously, we identified an increased anti-self-reactivity within the monomerized dimer fraction. This study addressed if, among the different IgG fractions, an analogous preferential reactivity was evident in the response against different pathogen-derived protein and carbohydrate antigens. Therefore, we assessed the activity of total unseparated IgG, the monomeric and dimeric IgG fractions against antigenic structures of bacterial and viral antigens/virulence factors. All fractions showed similar reactivity to protein antigens except for exotoxin A of Pseudomonas aeruginosa, where the dimeric fraction, especially when monomerized, showed a marked increase in reactivity. This suggests that the production of antiidiotypic IgG antibodies contributes to controlling the immune response to certain categories of pathogens. In contrast, the monomeric IgG fractions showed increased reactivity towards pathogen-associated polysaccharides, classically regarded as T-independent antigens. Taken together, the differential reactivity of the IgG fractions seems to indicate a preferential segregation of antibody reactivities according to the nature of the antigen.

Proteasome inhibition overcomes the resistance of renal cell carcinoma cells against the PPARgamma ligand troglitazone.

In order to analyze the effects of peroxisome proliferator-activated receptor-gamma (PPARgamma) activation on renal cell carcinomas we utilized several cell lines that were treated with the high affinity PPARgamma agonist, troglitazone. Incubation of RCC cells with troglitazone resulted in reduced secretion of growth factors that was due to the inhibition of MAP kinase signaling and reduced nuclear localized expression of relB and HIF1alpha. Interestingly, the cell lines used showed a different sensitivity towards apoptosis induction that did not correlate with the inhibition of growth factors or expression of pro- and antiapoptotic molecules. To overcome this resistance the cells were treated with a combination of troglitazone and the proteasome inhibitor, bortezomib. The combination of both compounds induced apoptosis even in cells resistant to both agents alone, due to increased induction of ER-stress and caspase-3 mediated cell death.

Effects of testosterone therapy on cardiovascular risk markers in androgen-deficient women with hypopituitarism.

CONTEXT: Low-dose testosterone replacement therapy in women with relative androgen deficiency has been shown to have beneficial effects on body composition, bone mass, and psychosexual function. However, the safety of chronic testosterone administration on cardiovascular risk and insulin resistance is unknown. OBJECTIVE: The aim of the study was to determine the effects of physiological testosterone replacement on cardiovascular risk markers and insulin resistance in women. DESIGN: A 12-month, randomized, placebo-controlled study was conducted. SETTING: A General Clinical Research Center was the setting for the study. STUDY PARTICIPANTS: A total of 51 women of reproductive age with androgen deficiency due to hypopituitarism participated. INTERVENTION: Study participants were randomized to physiological testosterone administration, 300 mug daily, or placebo, by patch. MAIN OUTCOME MEASURES: We measured fasting glucose, fasting insulin, insulin-resistance homeostasis model of assessment (IRHOMA), quantitative insulin sensitivity check index (QUICKI), high-sensitivity C-reactive protein, vascular cell adhesion molecule (VCAM), leptin, lipoprotein (a), apolipoprotein A1, and homocysteine. RESULTS: At 12 months, fasting insulin and IRHOMA were significantly lower in the testosterone compared with the placebo group, and there was a trend toward a higher QUICKI level at 12 months in the testosterone compared with the placebo group. These differences were no longer significant after controlling for baseline levels. We observed no effect, either positive or negative, of testosterone administration on high-sensitivity C-reactive protein, VCAM leptin, lipoprotein (a), or apolipoprotein A1. CONCLUSIONS: Our data suggest that physiological testosterone replacement in women with hypopituitarism for 12 months does not increase, and may improve, insulin resistance. Chronic low-dose testosterone administration does not increase markers of cardiovascular disease reflecting several different mechanistic pathways. Large, randomized, placebo-controlled, long-term prospective studies are needed to determine whether low-dose testosterone replacement affects cardiovascular risk and event rates in women.

A new mathematical procedure to evaluate peaks in complex chromatograms.

Automatic peak evaluation in chromatograms and subsequent quantification of compound concentrations is still a challenge in the analysis of complex samples containing hundreds or thousands of compounds. Although a number of software packages for peak evaluation exist, baseline definition and overlapping peaks of different shapes are the main reasons which prevent reliable automatic analysis of complex chromatograms. A new mathematical procedure is presented which uses peak shapes extracted from the chromatogram itself and modified by nonlinear (in fact, hyperbolic) stretching of the peak head and tail. With this approach, the peak parameters are position, height, scale of front, scale of tail, and smoothness of transition from front to tail scaling. This approach is found to give a substantially better fit than traditional analytically defined peak shapes. Together with a good peak finding heuristic and nonlinear optimization of parameters this allows a reliable automatic analysis of chromatograms with a large number of peaks, even with large groups of overlapping peaks. The analysis matches the quality of standard interactive methods, but still permits interactive refinement. This approach has been implemented and tested on a large set of data from chromatography of hydrocarbons in ambient air samples.

Description and characterization of an on-line system for long-term measurements of isoprene, methyl vinyl ketone, and methacrolein in ambient air.

In this work we present a detailed technical description of the system that was set up for long-term on-line measurements of isoprene and two of its major degradation products, methyl vinyl ketone and methacrolein in order to provide a better understanding of the role of forest stands as a complex source of reactive trace gases into the troposphere and to elucidate the role of forests as chemical reactors. Volatile organic compounds (VOCs) are preconcentrated on cartridges containing a package of two solid adsorbents (Tenax TA and Carbopack X). Ozone removal is performed prior to sampling by titration with nitrogen monoxide. For the calibration and characterization of the system, a diffusion source was built to produce standard gas mixtures of up to 16 different compounds with mixing ratios at tens ppt (parts per trillion) level mixing ratios and high accuracy. The developed system allows a reliable quantification of these VOCs (detection limit approximately 10 ppt, reproducibility approximately 5%) with a high temporal resolution (approximately 30 min) and has proven to be stable and run automatically without major maintainence.

Echolocation by the barbastelle bat, Barbastella barbastellus.

When searching for insects along edges, Barbastella barbastellus alternated between two signal types. Type-2 signals had durations around 6 ms and were composed of an initial shallowly downward frequency modulated component, starting at about 45 kHz and followed by a shorter more steeply modulated component that ended at about 32 kHz. Type-1 signals were rather stereotyped with durations around 2.5 ms and a very short rise time. They covered an approximately 8 kHz-wide frequency band positioned just below the 12-15 kHz-wide frequency band of type-2 signals, with no or small frequency overlap. In the recordings, type-1 signals almost had always a higher amplitude than type-2 signals, at least partly caused by head movements. Assuming that signal structure reflects function, we hypothesize that type-2 signals have the same adaptive value as the signals with a broadband and narrowband component of other vespertilionids, but with a reverse arrangement of the signal elements. Like the broadband component of the type-2 signals, type-1 signals are well suited to localize background targets. Thus, the localization component may be distributed among two signals separated in time, which has the advantage that both signals can be varied independently in the direction of emission and in amplitude.

PUMA-G, an IFN-gamma-inducible gene in macrophages is a novel member of the seven transmembrane spanning receptor superfamily.

IFN-gamma is a key immunoregulatory cytokine that plays a predominant role in innate immunity. By employing PCR-Select to search for genes differentially expressed in IFN-gamma/TNF-alpha stimulated macrophages, we identified a novel IFN-gamma-induced transcript designated PUMA-G (protein up-regulated in macrophages by IFN-gamma). PUMA-G codes for a protein with seven transmembrane helices, a feature commonly shared with the G protein-coupled receptor superfamily (GPCR). The PUMA-G protein is most similar to the human orphan GPCR HM74 (73 % identity) and GPR31 (30 % identity). PUMA-G mRNA was readily induced in macrophages after stimulation with IFN-gamma, LPS, polyIC and CpG oligonucleotides. In vivo PUMA-G was up-regulated in mice suffering from microbial sepsis or from Listeria monocytogenes infection. Characterization of the genomic locus revealed an intronless PUMA-G open reading frame. Genomic Southern blot analysis indicates that PUMA-G is a single-copy gene. PUMA-G maps to mouse chromosome 5F. Confocal microscopy of transiently transfected 264.7 RAW macrophages and 293T cells with a PUMA-G-EGFP fusion construct showed predominant fluorescence at the cell surface, suggesting a localization at the cell membrane. Taken together, our data indicate that PUMA-G is a new inducible representative of GPCR, with potential importance in macrophage functions.

Assessment of dysfunctional working models of self and others in schizophrenic patients: a summary of data collected in nine nations. International Research Group.

OBJECTIVE: To investigate the cross-cultural feasibility of a new scale for assessing dysfunctional working models of self and others, and to evaluate its discriminative power. METHOD: Schizophrenic patients (N=351), non-psychotic patients (N= 86) and non-clinical subjects (N= 511) collected in 10 centres completed the DWM-S. Current psychopathology was assessed by means of the BPRS. RESULTS: Alpha coefficients were high in all samples. Mean scores on the DWM-S appeared to be comparable in all countries, suggesting cross-national generalizability. No significant correlation was found with sex, age, levels of psychopathology and duration of illness. Discriminant analyses showed that more than 70% of the schizophrenic patients are correctly classified. CONCLUSION: The DWM-S is an easily administered self-report instrument which allows to pinpoint internal dysfunctional working models of self and others in various types of patients. It is a useful tool for case conceptualization, especially when psychotherapeutic interventions are part of the treatment programme.

Shift of aberrant antigen expression at relapse or at treatment failure in acute leukemia.

The flow cytometric detection of aberrant antigen expression is one method proposed for the quantification of minimal residual disease (MRD) in acute leukemias. The present study was designed to investigate the stability of the aberrant antigen expression at relapse or at treatment failure of initial chemotherapy. For this purpose, multiparameter immunophenotyping with a panel of 15 monoclonal antibodies was used at diagnosis as well as at relapse (43 patients with overall 65 aberrations) and at treatment failure (35 patients with overall 66 aberrations). There was a significant decrease in the percentage of the initially described aberrant antigen expression on leukemia blasts at relapse (P = 0.001; n = 65) as well as at treatment failure (P = 0.0001; n = 66) considering all aberrations in the whole leukemia population. Concerning only patients with acute myelogenous leukemia (AML), significant decreases in the aberrant expression could be detected at relapse (P = 0.031; n = 42) and at treatment failure (P = 0.0001; n = 52). The changes in patients with acute lymphoblastic leukemia (ALL) were significant only at relapse (P = 0.006; n = 23). Initially, the most informative aberration was not detectable in four patients at relapse and in seven patients at treatment failure. A decrease of under 50% of the initial value was observed in another 8 patients at relapse and in 10 patients at treatment failure. In further studies assessing the detection of aberrant antigen expression for MRD, quantification of the relapses should be explicitly analyzed regarding the persistence of the initially described aberrant antigen expression.

Differentiation and management of endometrium abnormalities and leiomyomas by hydrosonography.

Transvaginal sonography is an established method for numerous clinical indications in the assessment of endometrium pathology. The investigation of the endometrium consists of the measurement of the thickness, the visualization of the echogenity and echotexture and of the demonstration of focal masses. However, evaluation of the uterine cavity by transvaginal sonography is limited and an abnormal ultrasound of the endometrium may reflect benign or malignant conditions. Furthermore, small structures can be missed or overlooked. If indicated, hydrosonography offers various advantages compared to dilatation and curettage and hysteroscopy in terms of costs, availability and risks. Additional informations obtained after hydrosonography may influence the management before consideration of curettage or hysteroscopy.

[Quality of life. Construct validation and the development of a modular system]. / Das Konstrukt Lebensqualität. Metaanalytische Validierung und die Entwicklung eines modularen Erhebungssystems.

The construct Quality of Life (QoL) is investigated by metaanalysis of eight (inter)nationally validated questionnaires in a multicenter study. Data have been collected in a mentally healthy (n = 479), a depressed (n = 171) and a schizophrenic (n = 139) sample. Conventional psychometric criteria and a facet analytical methodology have been applied. The resulting questionnaire "Modular System for Quality of Life" (MSQoL) consists of a core module with 47 items (one "G-factor" and six subdimensions), which is sufficiently valid for all three samples. Additionally, there are four specific modules (demography, family, partnership, profession). No specific modules can be identified for the psychopathological subgroups. The validated radex structure for subjective QoL offers the opportunity for a cumulative research design and for adaptations to the actual setting.

Two families of GTPases dominate the complex cellular response to IFN-gamma.

IFN-gamma induces a number of cellular programs functional in innate and adaptive resistance to infectious pathogens. It has recently become clear that the complete cellular response to IFN-gamma is extraordinarily complex, with >500 genes (i.e., approximately 0.5% of the genome) activated. We made suppression-subtractive hybridization differential libraries from IFN-gamma-stimulated primary mouse embryonic fibroblasts and from a mouse macrophage cell line, ANA-1, in each case with reference to unstimulated cells. Of approximately 250 clones sequenced at random from the two libraries, >35% were representatives of one or the other of two small unrelated families of GTPases, the 65-kDa and 47-kDa families. These families dominate the IFN-gamma-induced response in both cell types. We report here the full-length sequences of one new 65-kDa and two new 47-kDa family members. The 65-kDa family members are under transcriptional control of IRF-1, whereas the 47-kDa family members are inducible in embryonic fibroblasts from IRF-1(-/-) mice. Members of both GTPase families are strongly up-regulated in livers of wild-type mice infected with the pathogenic bacterium, Listeria monocytogenes, but not in IFN-gammaR(0/0) mice. These GTPases appear to be dedicated to the IFN-gamma response, since resting levels are negligible and since neither family shows any significant relationship to any other described family of GTPases. Understanding the role of these GTPases in IFN-gamma-mediated resistance against pathogens is the task for the future.

Training schizophrenic patients to manage their symptoms: predictors of treatment response to the German version of the Symptom Management Module.

This study examined whether patient demographic and clinical characteristics were predictors of differential treatment response in a sample of 57 schizophrenic patients who received the German version of the Symptom Management Module. Psychopathology, global functioning and knowledge about schizophrenia were assessed as dependent variables. Overall, patients improved over the treatment period on most dimensions of psychopathology as well as knowledge about psychosis. There was little evidence of differential treatment response as a function of either sociodemographic or clinical variables. However, gender was related to changes in psychopathology from pre- to posttreatment, with females improving less than males. Possible implications of these findings were discussed.

Performance of the SE-9000 automated haematology analyser in a laboratory serving a haematological oncology unit.

The performance of the SE-9000 automated haematology analyser in a laboratory receiving a high number of abnormal specimens from haematological oncology patients was assessed according to formal protocols for the evaluation of blood cell counters. Linearity over a useful working range, precision in clinically important ranges and negligible carry-over were demonstrated in this group of patient samples confirming the results of previous investigators. The comparability of instrument derived differential leucocyte counts from both normal and distributionally abnormal samples with those obtained by visual microscopy using the NCCLS H-20 A protocol was very good. The sensitivity of flags for the detection of immature granulocytes and myeloid blast cells was high and this can be attributed to the incorporation of a new measuring channel (Immature Myeloid Information or IMI channel). The number of unrecognized abnormalities was low and when compared with the poor sensitivity of the routine 100-cell visual differential leucocyte count, the analyser was judged suitable for monitoring patients with haematological malignancies. The performance of flags such as 'left shift' and 'atypical lymphocytes' can be improved by taking into consideration distributional abnormalities such as neutrophilia and lymphocytosis. The trigger level for these flags should be adapted to the clinical need particularly in cases of neutropenia following chemotherapy, and in lymphoproliferative disorders and infection.