Role of aripiprazole in treatment-resistant schizophrenia

About one third of patients with schizophrenia respond unsatisfactorily to antipsychotic treatment and are termed “treatment-resistant”. Clozapine is still the gold standard in these cases. However, 40%–70% of patients do not improve sufficiently on clozapine either. In the search for more efficacious strategies for treatment-resistant schizophrenia, drugs with different pharmacological profiles seem to raise new hopes, but are they valid? The aim of this review was to evaluate the evidence for aripiprazole as a potential strategy in monotherapy or combination therapy for patients with treatment-resistant schizophrenia. The evidence for aripiprazole monotherapy and for the combination of aripiprazole with psychotropics other than clozapine is scant, and no recommendation can be made on the basis of the currently available data. More effort has been made in describing combinations of aripiprazole and clozapine. Most of the open-label and case studies as well as case reports have shown positive effects of this combination on overall psychopathology and to some extent on negative symptoms. Several reports describe the possibility of dose reduction for clozapine in combination with aripiprazole, a strategy that might help so-called “treatment-intolerant” patients. The findings of four randomized controlled trials with respect to changes in psychopathology seem less conclusive. The most commonly found beneficial effects are better metabolic outcomes and indicators of the possibility of reducing the clozapine dose. However, other side effects, such as akathisia, are repeatedly reported. Further, none of the studies report longer-term outcomes. In the absence of alternatives, polypharmacy is a common strategy in clinical practice. Combining aripiprazole with clozapine in clozapine-resistant or clozapine-intolerant patients seems to be worthy of further investigation from the pharmacological and clinical points of view

Entwicklung quantitativer Analysemethoden in der Lokalisationsmikroskopie

Um biologische Systeme auf dem Niveau einzelner Proteine und kleiner Proteinkomplexe besser untersuchen und verstehen zu können, ist eine Auflösung weit unterhalb der Grenze der konventionellen Fluoreszenzmikroskopie erforderlich. In den letzten Jahren wurden verschiedene Methoden entwickelt, um die Beugungsgrenze zu überwinden. Eine dieser Methoden stellt die Lokalisationsmikroskopie dar, welche eine Strukturauflösung in Zellen bis in den Bereich von 20 nm ermöglicht. Die vorliegende Arbeit beschreibt neue Methoden für quantitative Analysen basierend auf der Lokalisationsmikroskopie. Neben der erhöhten Strukturauflösung wird hierbei die zusätzliche Information der einzeln detektierten Moleküle genutzt. Die Kombination der Visualisierung von Strukturen im Bereich <100 nm mit statistischen Analysen der Proteinverteilung auf diesen Strukturen eröffnet neue Möglichkeiten biologische und biophysikalische Fragestellungen zu untersuchen. Die im Rahmen der vorliegenden Arbeit entwickelten Algorithmen werden vorgestellt und auf verschiedene aktuelle biologische Fragestellungen angewandt. Hierzu zählen die Analyse der Verteilung von Her2/neu-Proteinen in Brustkrebszellen, eine quantitative Untersuchung von Tight Junction-Netzwerken sowie Distanzanalysen von Splicing-Faktoren im Bezug auf den transkribierten DNA-Strang, um einen tieferen Einblick in die Faltung der mRNA zu erhalten. Außerdem wurde eine detaillierte Untersuchung des Einflusses des Einbettmediums auf die Lokalisationsmessungen mit unterschiedlichen konventionellen Farbstoffen durchgeführt

New Bainitic Steel for Cyclic Loaded Safety Parts with Improved Cyclic Material Behaviour

AbstractA bainitic forging steel, which enables the TRIP-effect, has been developed and can be used for lightweight-construction for forged components under cyclic loading. The high potential under cyclic loading conditions of the new generation of TRIP forging steels is shown and also the improved results under service loads, especially under overloads and misuse. A comparison of linear damage accumulations by Palmgren-Miner will depict the differences in characteristic damage sums between quenched and tempered and the new bainitic steel.For TRIP steels properties the process parameters are very important. Hence, the influence of the cooling conditions of TRIP will be discussed

Validity and responsiveness of the EQ-5D in assessing and valuing health status in patients with somatoform disorders

Background: The EQ-5D is a generic questionnaire providing a preference-based index score applicable to cost-utility analysis. This is the first study to validate the EQ-5D in patients with somatoform disorders. Methods: Data of the EQ-5D descriptive system, the British and the German EQ-5D index and the EQ Visual Analogue Scale, the Patient Health Questionnaire 15, the Patient Health Questionnaire 9, the Whiteley Index 7 and the Short Form 36 were collected from 294 patients at baseline, 244 at 6 months and 256 at 12 months after baseline. The discriminative ability of the EQ-5D was evaluated by comparison with a general population sample and by the ability to distinguish between different symptom severities. Convergent validity was analysed by assessing associations between the EQ-5D and the other instruments. Responsiveness was evaluated by analysing the effects on scores between two measurements in groups of patients reporting worse, same or better health. The Bonferroni correction was employed. Results: For all items of the EQ-5D except ‘self-care’, patients with somatoform disorders reported more problems than the general population. The EQ-5D showed discriminative ability in patients with different symptom severities. For nearly all reference instruments there were significant differences in mean scores between respondents with and without problems in the various EQ-5D items and strong correlations with the EQ Visual Analogue Scale and the EQ-5D index scores. Evidence for the responsiveness of the EQ-5D could only be found for patients with better health; effects were medium at the utmost. Conclusions: The EQ-5D showed a considerable validity and a limited responsiveness in patients with somatoform disorders. Trial registration: Current Controlled Trials ISRCTN5528079

Economics of medically unexplained symptoms: a systematic review of the literature

Objective: To review cost-of-illness studies (COI) and economic evaluations (EE) conducted for medically unexplained symptoms and to analyze their methods and results. Methods: We searched the databases PubMed, PsycINFO and National Health Service Economic Evaluations Database of the University of York. Cost data were inflated to 2006 using country-specific gross domestic product inflators and converted to 2006 USD purchasing power parities. Results: We identified 5 COI and 8 EE, of which 6 were cost-minimization analyses and 2 were cost-effectiveness analyses. All studies used patient level data collected between 1980 and 2004 and were predominantly conducted in the USA (n = 10). COI found annual excess health care costs of somatizing patients between 432 and 5,353 USD in 2006 values. Indirect costs were estimated by only one EE and added up to about 18,000 USD per year. In EE, educational interventions for physicians as well as cognitive-behavioral therapy approaches for patients were evaluated. For both types of interventions, effectiveness was either shown within EE or by previous studies

Launch of solar coronal mass ejections and submillimeter pulse bursts

The rapid solar spikes (100-500 ms) recently discovered at submillimeter waves bring new possibilities to investigate energetic processes near the solar surface that might have an important role in the launch and propelling of ionized mass away from the Sun. We present a study on the association between the launch time of coronal mass ejections (CMEs) observed by the LASCO instruments on the SOHO spacecraft and the onset of the new kind of rapid solar spikes (100-500 ms) observed at submillimetric waves (212 and 405 GHz) by the new Solar Submm-wave Telescope (SST). We investigated six submm-wave events, all found associated to CMEs. Seven related CME were identified. Five of them were associated with flares with large GOES class soft X-rays, presenting distinct time histories and associations at other energy ranges, and two of them were related to flares behind the solar limb, with simultaneous related activity observed in the visible solar disk. Ultraviolet images from EIT on SOHO show some kind of small or large-scale magnetic activity or brightening for all events. The extrapolation of apparent CME positions to the solar surface show that they occurred nearly coincident in time with the onset of submm-wave pulses for all six events. These results suggest that pulse bursts might be representative of an important early signature of CMEs, especially for events beginning near the center of the solar disk, sometimes identified as "halo" CMEs. They lead to several challenging questions relative to the physical nature of the pulses and its association to the launch and acceleration of coronal mass ejections. Although these evidences may favor multiple rapid energy releases at the origin near the solar surface, they require further research in order to better understand both diagnostics and model descriptions.Fil: Kaufmann, Pierre. Universidade Estadual de Campinas; Brasil. Universidade Presbiteriana Mackenzie; BrasilFil: De Castro, C. Guillermo Giménez. Universidade Presbiteriana Mackenzie; BrasilFil: Makhmutov, Vladimir S.. Universidade Presbiteriana Mackenzie; Brasil. The Russian Academy Of Sciences; RusiaFil: Raulin, Jean Pierre. Universidade Presbiteriana Mackenzie; BrasilFil: Schwenn, Rainer. Max Planck Institute For Solar System Research; AlemaniaFil: Levato, Orlando Hugo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico "El Leoncito". Universidad Nacional de Córdoba. Complejo Astronómico "El Leoncito". Universidad Nacional de la Plata. Complejo Astronómico "El Leoncito". Universidad Nacional de San Juan. Complejo Astronómico "El Leoncito"; ArgentinaFil: Rovira, M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; Argentin

CD4+ T Cell Count Recovery in HIV Type 1-Infected Patients Is Independent of Class of Antiretroviral Therapy

Background. In recent years, treatment options for human immunodeficiency virus type 1 (HIV-1) infection have changed from nonboosted protease inhibitors (PIs) to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and boosted PI-based antiretroviral drug regimens, but the impact on immunological recovery remains uncertain. Methods. During January 1996 through May 2007, all patients in the Swiss HIV Cohort were included if they received the first combination antiretroviral therapy (cART) and had known baseline CD4+ T cell counts and HIV-1 RNA values (n=3293). The mean (±SD) duration of follow-up was 26.8±20.5 months. The follow-up time was limited to the duration of the first cART. CD4+ T cell recovery was analyzed in 3 different treatment groups: nonboosted PI, NNRTI, or boosted PI. The end point was the absolute increase of CD4+ T cell count in the 3 treatment groups after the initiation of cART. Results. Two thousand five hundred ninety individuals (78.7%) initiated a nonboosted-PI regimen, 452 (13.7%) initiated an NNRTI regimen, and 251 (7.6%) initiated a boosted-PI regimen. Absolute CD4+ T cell count increases at 48 months were as follows: in the nonboosted-PI group, from 210 to 520 cells/µL; in the NNRTI group, from 220 to 475 cells/µL; and in the boosted-PI group, from 168 to 511 cells/µL. In a multivariate analysis, the treatment group did not affect the response of CD4+ T cells; however, increased age, pretreatment with nucleoside reverse-transcriptase inhibitors, serological tests positive for hepatitis C virus, Centers for Disease Control and Prevention stage C infection, lower baseline CD4+ T cell count, and lower baseline HIV-1 RNA level were risk factors for smaller increases in CD4+ T cell count. Conclusion. CD4+ T cell recovery was similar in patients receiving nonboosted PI-, NNRTI-, and boosted PI-based cAR

COMBO-FISH Enables High Precision Localization Microscopy as a Prerequisite for Nanostructure Analysis of Genome Loci

With the completeness of genome databases, it has become possible to develop a novel FISH (Fluorescence in Situ Hybridization) technique called COMBO-FISH (COMBinatorial Oligo FISH). In contrast to other FISH techniques, COMBO-FISH makes use of a bioinformatics approach for probe set design. By means of computer genome database searching, several oligonucleotide stretches of typical lengths of 15–30 nucleotides are selected in such a way that all uniquely colocalize at the given genome target. The probes applied here were Peptide Nucleic Acids (PNAs)—synthetic DNA analogues with a neutral backbone—which were synthesized under high purity conditions. For a probe repetitively highlighted in centromere 9, PNAs labeled with different dyes were tested, among which Alexa 488® showed reversible photobleaching (blinking between dark and bright state) a prerequisite for the application of SPDM (Spectral Precision Distance/Position Determination Microscopy) a novel technique of high resolution fluorescence localization microscopy. Although COMBO-FISH labeled cell nuclei under SPDM conditions sometimes revealed fluorescent background, the specific locus was clearly discriminated by the signal intensity and the resulting localization accuracy in the range of 10–20 nm for a detected oligonucleotide stretch. The results indicate that COMBO-FISH probes with blinking dyes are well suited for SPDM, which will open new perspectives on molecular nanostructural analysis of the genome

Whole-heart dynamic three-dimensional magnetic resonance perfusion imaging for the detection of coronary artery disease defined by fractional flow reserve: determination of volumetric myocardial ischaemic burden and coronary lesion location

Aims Dynamic three-dimensional-cardiac magnetic resonance (3D-CMR) perfusion proved highly diagnostic for the detection of angiographically defined coronary artery disease (CAD) and has been used to assess the efficacy of coronary stenting procedures. The present study aimed to relate significant coronary lesions as assessed by fractional flow reserve (FFR) to the volume of myocardial hypoenhancement on 3D-CMR adenosine stress perfusion imaging and to define the inter-study reproducibility of stress inducible 3D-CMR hypoperfusion. Methods and results A total of 120 patients with known or suspected CAD were examined in two CMR centres using 1.5 T systems. The protocol included cine imaging, 3D-CMR perfusion during adenosine infusion, and at rest followed by delayed enhancement (DE) imaging. Fractional flow reserve was recorded in epicardial coronary arteries and side branches with ≥2 mm luminal diameter and >40% severity stenosis (pathologic FFR < 0.75). Twenty-five patients underwent an identical repeat CMR examination for the determination of inter-study reproducibility of 3D-CMR perfusion deficits induced by adenosine. Three-dimensional CMR perfusion scans were visually classified as pathologic if one or more segments showed an inducible perfusion deficit in the absence of DE. Myocardial ischaemic burden (MIB) was measured by segmentation of the area of inducible hypoenhancement and normalized to left ventricular myocardial volume (MIB, %). Three-dimensional CMR perfusion resulted in a sensitivity, specificity, and diagnostic accuracy of 90, 82, and 87%, respectively. Substantial concordance was found for inter-study reproducibility [Lin's correlation coefficient: 0.98 (95% confidence interval: 0.96-0.99)]. Conclusion Three-dimensional CMR stress perfusion provided high diagnostic accuracy for the detection of functionally significant CAD. Myocardial ischaemic burden measurements were highly reproducible and allowed the assessment of CAD severit

Impacts of Scaling up Agroecology on the Sustainability of European Agriculture in 2050

The European Commission recently embraced the concept of agroecology as a pathway to reduce negative impacts from agri-food systems on the environment. So far, it remains unclear whether agroecology can deliver on these high hopes if implemented on a large scale. We here assess socio-economic and environmental implications of multiple agroecological futures in the European Union in 2050, based on a novel diagnostic scenario approach, i.e. the biomass balancing model BioBaM-GHG 2.0. We find that agroecological measures from the plot to the food systems level can indeed reduce environmental pressures while maintaining domestic food availability within the EU. Such measures are, for example, more hedgerows on croplands or reduced biomass harvest on high natural value – HNV grasslands. However, a key prerequisite is an overall reduction of the food system's size (based on the reduction of animal production, food wastes, and export production) and an optimised crop-livestock integration. Only then does the transformation towards an agroecological agri-food system in the EU not risk overstretching domestic land availability or produce insufficient agricultural commodities. Mitigating the accompanied trade-off of reduced farm income is a central mandate for policy development aimed at re-designing agriculture in Europe to align with the Green Deal goals