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The interaction-based hazard index (HIint) allows a prediction of mixture effects different from linear additivity by including information on binary mixtures between the chemicals. The aim of this study is to make a solid estimate on the possible synergistic potential of combined antibiotics and to quantify the subsequent effect for the case of the receiving river Elbe, Germany. Pieces of information on binary interactions between antibiotic groups were used from literature and from knowledge on human antibiotic combination therapy. Applying a moderate and a worst-case scenario, in terms of the interaction magnitude, resulted in 50 to 200% higher environmental risks, compared to the classical assessment approach applying simple concentration addition. A subsequent sensitivity analysis revealed that the data strength for some binary antibiotic combinations is too low to be considered for a solid estimate of synergistic effects. This led to the definition of certain preconditions in order to decide whether or not to include certain interaction information (e.g. the necessary number of interaction studies). The exclusion of information with low data strength resulted in an attenuated risk increase of 20 to 50%, based on the currently available scientific information on binary antibiotic mixtures. In order to include antibiotics with the highest share in the overall risk (macrolides, quinolones, and cephalosporins) as well as their corresponding metabolites, investigations should focus on binary interactions between them., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Parafoveal preprocessing is an important factor for efficient reading and, in eye-movement studies, is typically investigated by means of parafoveal masking: Valid previews are compared to instances in which masks prevent preprocessing. A long-held assumption was that parafoveal preprocessing, as assessed by this technique, only reflects facilitation (i.e., a preview benefit). Recent studies, however, suggested that the benefit estimate is inflated due to interference of the parafoveal masks, i.e., the masks inflict processing costs. With children from Grades 4 and 6, we administered the novel incremental priming technique. The technique manipulates the salience of the previews by systematically varying its perceptibility (i.e., by visually degrading the previews). This technique does not require a baseline condition, but makes it possible to determine whether a preview induces facilitation or interference. Our salience manipulation of valid previews revealed a preview benefit in the children of both Grades. For two commonly used parafoveal masks, we observed interference corroborating the notion that masks are not a proper baseline. With the novel incremental boundary technique, in contrast, one can achieve an accurate estimate of the preview benefit.

Objective: Increasing numbers of older patients are undergoing surgery. Older surgical patients are at a higher risk of perioperative complications and mortality. Multimorbidity, frailty, and physiological changes of ageing contribute to adverse outcomes. These complications are predominantly medical, rather than directly surgical. Guidelines recommend preoperative assessment of comorbidity, disability, and frailty in older patients undergoing surgery and closer perioperative collaboration between surgeons and geriatricians. We conducted a survey to assess knowledge and beliefs of surgical trainees toward common perioperative problems encountered in older surgical patients., Design: Paper-based survey., Setting: Unselected UK surgical training-grade physicians (CT1-ST8) attending the 2013 Congress of The Association of Surgeons of Great Britain and Ireland, Glasgow, UK, May 1-3, 2013., Participants: A total of 160 eligible UK surgical trainees attending the conference were invited to participate in the survey. Of them, 157 participated., Results: Of the trainees, 68% (n = 107) reported inadequate training and 89.2% (n = 140) supported the inclusion of geriatric medicine issues in surgical curricula. Of the respondents, 77.2% (n = 122) were unable to correctly identify the key features required to demonstrate mental capacity, and only 3 of 157 respondents were familiar with the diagnostic criteria for delirium. Support from geriatric medicine was deemed necessary (84.7%, n = 133) but often inadequate (68.2%, n = 107). Surgical trainees support closer collaboration with geriatric medicine and shared care of complex, older patients (93.6%, n = 147)., Conclusions: UK surgical trainees believe that they receive inadequate training in the perioperative management of complex, older surgical patients and are inadequately supported by geriatric medicine physicians. In this survey sample, trainee knowledge of geriatric issues such as delirium and mental capacity was poor. Surgical trainees support the concept of closer liaison and shared care of complex, older patients with geriatric medicine physicians. Changes to surgical training and service development are needed., (Copyright © 2015 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Demand theory can be applied to analyse how a human or animal consumer changes her selection of commodities within a certain budget in response to changes in price of those commodities. This change in consumption assessed over a range of prices is defined as demand elasticity. Previously, income-compensated and income-uncompensated price changes have been investigated using human and animal consumers, as demand theory predicts different elasticities for both conditions. However, in these studies, demand elasticity was only evaluated over the entirety of choices made from a budget. As compensating budgets changes the number of attainable commodities relative to uncompensated conditions, and thus the number of choices, it remained unclear whether budget compensation has a trivial effect on demand elasticity by simply sampling from a different total number of choices or has a direct effect on consumers' sequential choice structure. If the budget context independently changes choices between commodities over and above price effects, this should become apparent when demand elasticity is assessed over choice sets of any reasonable size that are matched in choice opportunities between budget conditions. To gain more detailed insight in the sequential choice dynamics underlying differences in demand elasticity between budget conditions, we trained N=8 rat consumers to spend a daily budget by making a number of nosepokes to obtain two liquid commodities under different price regimes, in sessions with and without budget compensation. We confirmed that demand elasticity for both commodities differed between compensated and uncompensated budget conditions, also when the number of choices considered was matched, and showed that these elasticity differences emerge early in the sessions. These differences in demand elasticity were driven by a higher choice rate and an increased reselection bias for the preferred commodity in compensated compared to uncompensated budget conditions, suggesting a budget context effect on relative valuation.

Predicting the input loads of antibiotics to wastewater treatment plants (WWTP) using certain input data (e.g. prescriptions) is a reasonable method if no analytical data is available. Besides the spatiotemporal uncertainties of the projection itself, only a few studies exist to confirm the suitability of required excretion data from literature. Prescription data with a comparatively high resolution and a sampling campaign covering 15 months were used to answer the question of applicability of the prediction approach. As a result, macrolides, sulfamethoxazole and trimethoprim were almost fully recovered close to 100% of the expected input loads. Nearly all substances of the beta-lactam family exhibit high elimination rates during the wastewater transport in the sewer system with a low recovery rate at the WWTP. The measured input loads of cefuroxime, ciprofloxacin and levofloxacin fluctuated greatly through the year which was not obvious from relatively constant prescribed amounts. The latter substances are an example that available data are not per se sufficient to monitor the actual release into the environment. Furthermore, the extensive data pool of this study was used to calculate the necessary number of samples to determine a representative annual mean load to the WWTP. For antibiotics with low seasonality and low input scattering a minimum of about 10 samples is required. In the case of antibiotics exhibiting fluctuating input loads 30 to 40 evenly distributed samples are necessary for a representative input determination. As a high level estimate, a minimum number of 20-40 samples per year is proposed to reasonably estimate a representative annual input load of antibiotics and other micropollutants., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Mutant p53 can exert oncogenic activity by inhibitory interaction with p73. The small-molecule RETRA has been described to disrupt this interaction and to suppress carcinoma cells (Kravchenko et al., 2008). RETRA's anticancer activity was restricted to tumour cells bearing mutant p53; it was not active in p53 negative and in p53 wild-type cells. Here, we explored the responsiveness of Ewing's sarcoma (ES) cells with mutant p53 to RETRA. For comparison, we also tested RETRA in p53 null and in p53 wild-type ES cells. We found RETRA to be effective in the three mutant p53 ES cell lines investigated. Strikingly, however, RETRA was similarly effective in the p53-deficient and in the two p53 wild-type ES cell lines examined. RETRA elicited apoptosis, as assessed by flow cytometric analyses of mitochondrial depolarisation and DNA fragmentation, caspase 3/7 activity assay and PARP-1 cleavage immunodetection, and G2/M cell cycle arrest completely independent of the cellular TP53 status. In contrast, various p53-deficient and -proficient carcinoma, osteosarcoma and leukaemia cells were unresponsive to RETRA. RETRA also induced gene expression of p53 target genes PUMA and p21 in ES cells irrespective of their TP53 status. These in vitro findings provide a rationale for an in vivo exploration of RETRA's potential as an effective therapeutic approach for patients with ES., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Mesenchymal stem cells, considered one of the most promising cell types for therapeutic applications due to their capacity to secrete regenerative bioactive molecules, are present in all tissues. Stem cells derived from the adipose tissue have been increasingly used for cell therapy in humans and animals, both as freshly isolated, stromal vascular fraction (SVF) cells, or as cultivated adipose-derived stem cells (ASCs). ASCs have been characterized in different animal species for proliferation, differentiation potential, immunophenotype, gene expression, and potential for tissue engineering. Whereas canine and equine ASCs are well studied, feline cells are still poorly known. Many companies around the world offer ASC therapy for dogs, cats, and horses, although in most countries these activities are not yet controlled by regulatory agencies. This is the first study to review the characterization and clinical use of SVF and ASCs in spontaneously occurring diseases in veterinary patients. Although a relatively large number of studies investigating ASC therapy in induced lesions are available in the literature, a surprisingly small number of reports describe ASC therapy for naturally affected dogs, cats, and horses. A total of seven studies were found with dogs, only two studies in cats, and four in horses. Taken as a whole, the results do not allow a conclusion on the effect of this therapy, due to the generally small number of patients included, diversity of cell populations used, and lack of adequate controls. Further controlled studies are clearly needed to establish the real potential of ASC in veterinary medicine.

Objective: To measure the effectiveness of modifications to reduce sound and vibration during interhospital ground transport of a simulated infant with very low birth weight (VLBW) and a gestational age of 30 weeks, a period of high susceptibility to germinal matrix and intraventricular hemorrhage., Study Design: Researchers measured vibration and sound levels during infant transport, and compared levels after modifications to the transport incubator mattresses, addition of vibration isolators under incubator wheels, addition of mass to the incubator mattress and addition of incubator acoustic cover., Result: Modifications did not decrease sound levels inside the transport incubator during transport. The combination of a gel mattress over an air chambered mattress was effective in decreasing vibration levels for the 1368 g simulated infant., Conclusion: Transport mattress effectiveness in decreasing vibration is influenced by infant weight. Modifications that decrease vibration for infants weighing 2000 g are not effective for infants with VLBW. Sound levels are not affected by incubator covers, suggesting that sound is transmitted into the incubator as a low-frequency vibration through the incubator's contact with the ambulance. Medical transportation can apply industrial methods of vibration and sound control to protect infants with VLBW from excessive physical strain of transport during vulnerable periods of development.

Pro-sociality, i.e., the preference for outcomes that produce benefits for other individuals, is ubiquitous in humans. Recently, cross-species comparisons of social behavior have offered important new insights into the evolution of pro-sociality. Here, we present a rodent analog of the Pro-social Choice Task that controls strategic components, de-confounds other-regarding choice motives from the animals' natural tendencies to maximize own food access and directly tests the effect of social context on choice allocation. We trained pairs of rats-an actor and a partner rat-in a double T-maze task where actors decided between two alternatives only differing in the reward delivered to the partner. The "own reward" choice yielded a reward only accessible to the actor whereas the "both reward" choice produced an additional reward for a partner (partner condition) or an inanimate toy (toy Condition), located in an adjacent compartment. We found that actors chose "both reward" at levels above chance and more often in the partner than in the toy condition. Moreover, we show that this choice pattern adapts to the current social context and that the observed behavior is stable over time.

Background: Physical inactivity has been associated with obesity and related chronic diseases. Understanding built environment (BE) influences on specific domains of physical activity (PA) around homes and workplaces is important for public health interventions to increase population PA., Purpose: To examine the association of home and workplace BE features with PA occurring across specific life domains (work, leisure, and travel)., Methods: Between 2012 and 2013, telephone interviews were conducted with participants in four Missouri metropolitan areas. Questions included sociodemographic characteristics, home and workplace supports for PA, and dietary behaviors. Data analysis was conducted in 2013; logistic regression was used to examine associations between BE features and domain-specific PA., Results: In home neighborhoods, seven of 12 BE features (availability of fruits and vegetables, presence of shops and stores, bike facilities, recreation facilities, crime rate, seeing others active, and interesting things) were associated with leisure PA. The global average score of home neighborhood BE features was associated with greater odds of travel PA (AOR=1.99, 95% CI=1.46, 2.72); leisure PA (AOR=1.84, 95% CI=1.44, 2.34); and total PA (AOR=1.41, 95% CI=1.04, 1.92). Associations between workplace neighborhoods' BE features and workplace PA were small but in the expected direction., Conclusions: This study offers empirical evidence on BE supports for domain-specific PA. Findings suggest that diverse, attractive, and walkable neighborhoods around workplaces support walking, bicycling, and use of public transit. Public health practitioners, researchers, and worksite leaders could benefit by utilizing worksite domains and measures from this study for future BE assessments., (Copyright © 2015 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Lung cancer is the leading cause of cancer mortality. Great advances in non-small cell lung cancer therapy have been seen in the last decade, beginning with the success in treating lung cancer harboring EGFR mutations and ALK-gene rearrangements. The potential of these biomarker-driven therapies has propelled research in biomarker targeted approaches to the forefront of lung cancer research. The successful development of immunotherapeutic agents targeting PD-L1 and PD-1 with an associated non-genomic biomarker has opened a new front in the effort for targeted approaches. Although early-phase lung cancer studies have hinted at the potential to use biomarkers to select patients for allocation to treatment in the conduct of clinical trials, data from late-phase studies have tempered expectations. The data leave unclear the wisdom of routinely restricting enrollment on lung cancer clinical trials to biomarker restricted populations, particularly non-genomic biomarkers.

Since polyphenol-rich products such as red wine, grape juice, and grape extracts have been shown to induce potent endothelium-dependent relaxations, we have evaluated whether commercial fruit juices such as those from berries are also able to induce endothelium-dependent relaxations of isolated coronary arteries and, if so, to determine whether this effect is related to their phenolic content. Among the 51 fruit juices tested, 2/12 grape juices, 3/7 blackcurrant juices, 4/5 cranberry juices, 1/6 apple juices, 0/5 orange juices, 2/6 red fruit and berry juices, 3/6 blends of red fruit juices, and 0/4 non-red fruit juices were able to induce relaxations achieving more than 50% at a volume of 1%. The active fruit juices had phenolic contents ranging from 0.31 to 1.86 g GAE/L, which were similar to those of most of the less active juices with the exception of one active grape juice (2.14 g GAE/L) and one active blend of red fruit juices (3.48 g GAE/L). Altogether, these findings indicate that very few commercial fruit juices have the ability to induce potent endothelium-dependent relaxations, and that this effect is not related to their quantitative phenolic content, but rather to their qualitative phenolic composition.

Background: Children and adolescents, who either acquire HIV infection perinatally, from contaminated blood products or via sexual transmission early in life, have the greatest cumulative exposure to the negative direct and indirect effects of HIV infection and ART on bone, which may lead to increased lifetime risk for osteoporosis and fracture. We conducted a systematic review to evaluate the literature on bone health in children and adolescents with HIV., Methods: We performed a comprehensive search of the Medline, Scopus, and Cochrane Library databases (up to April 1, 2014) for studies that reported on bone imaging or bone fractures in HIV-infected children, adolescents, or young adults., Results: A total of 32 publications met our inclusion criteria. Seventeen studies were cross-sectional and 15 were longitudinal. The majority of studies were conducted in high-income countries, three in middle-income countries and none in low-income countries. Overall, the studies we reviewed indicate that measures of bone mass are reduced, with increased prevalence of low BMD in children and adolescents with HIV. However, the studies are highly variable with respect to comparison sources, measurement methods, adjustment techniques for body size or growth retardation, and highlighted risk factors, including aspects related to medication exposures as well as the effects of HIV infection per se ., Conclusion: HIV infection appears to be associated with decreased bone accrual throughout childhood and adolescence. Initial studies indicate that sub-optimal bone accrual may be persistent and result in reduced peak bone mass, an important determinant of future risk of osteoporosis and fracture. Important areas for future research include evaluation of bone mass, bone quality and fracture risk across the life course among those with early-life infection with HIV, particularly in resource-limited settings where the majority of children with HIV live.

Bilingual inhibitory control advantages are well established. An open question is whether inhibitory superiority also extends to visual perceptual phenomena that involve inhibitory processes. This research used ambiguous figures to assess inhibitory bilingual superiority in 3-, 4-, and 5-year-old mono- and bilingual children (N=141). Findings show that bilinguals across all ages are superior in inhibiting a prevalent interpretation of an ambiguous figure to perceive the alternative interpretation. In contrast, mono- and bilinguals revealed no differences in understanding that an ambiguous figure can have two distinct referents. Together, these results suggest that early bilingual inhibitory control superiority is also evident in visual perception. Bilinguals' conceptual understanding of figure ambiguity is comparable to that of their monolingual peers., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In a research project on risk management of harmful substances in water cycles, clindamycin and 12 further antibiotics were determined in different sewage samples. In contrast to other antibiotics, an increase of the clindamycin concentration in the final effluent in comparison to the influent of the sewage treatment plant (STP) was observed. A back transformation from the main metabolite clindamycin sulfoxide to clindamycin during the denitrification process has been discussed. Therefore, the concentration of this metabolite was measured additionally. Clindamycin sulfoxide was stable in the STP and the assumption of back transformation of the metabolite to clindamycin was confuted. To explain the increasing clindamycin concentration in the STP, the ratio of clindamycin sulfoxide to clindamycin was observed. The ratio increased in dry spells with concentrated samples and with long dwell time in the sewer system. A short hydraulic retention in waste water system and diluted samples in periods of extreme rainfall lead to a lower ratio of clindamycin sulfoxide to clindamycin concentration. A plausible explanation of this behavior could be that clindamycin was adsorbed strongly to a component of the sewage during this long residence time and in the STP, clindamycin was released. In the common sample preparation in the lab, clindamycin was not released. Measurements of clindamycin and clindamycin sulfoxide in the influent and effluent of STP is advised for sewage monitoring.

In the first decade of the twenty-first century, whole-body magnetic resonance scanners with high field strengths (and thus potentially better signal-to-noise ratios) were developed. At the same time, parallel imaging and "echo-sharing" techniques were refined to allow for increasingly high spatial and temporal resolution in dynamic magnetic resonance angiography ("time-resolved" = TR-MRA). This technological progress facilitated tracking the passage of intra-venously administered contrast agent boluses as well as the acquisition of volume data sets at high image refresh rates ("4D-MRA"). This opened doors for many new applications in non-invasive vascular imaging, including simultaneous anatomic and functional analysis of many vascular pathologies including arterio-venous malformations. Different methods were established to acquire 4D-MRA using various strategies to acquire k-space trajectories over time in order to optimize imaging according to clinical needs. These include "keyhole"-based techniques (e. g. 4D-TRAK), TRICKS - both with and without projection - and HYPR-reconstruction, TREAT, and TWIST. Some of these techniques were first introduced in the 1980 s and 1990 s, were later enhanced and modified, and finally implemented in the products of major vendors. In the last decade, a large number of studies on the clinical applications of TR-MRA was published. This manuscript provides an overview of the development of TR-MRA methods and the 4D-MRA techniques as they are currently used in the diagnosis, treatment and follow-up of vascular diseases in various parts of the body., (© Georg Thieme Verlag KG Stuttgart · New York.)

Carbon monoxide dehydrogenase (CO dehydrogenase) from Oligotropha carboxidovorans is a structurally characterized member of the molybdenum hydroxylase enzyme family. It catalyzes the oxidation of CO (CO+H2O→CO2+2e(-)+2H(+)) which proceeds at a unique [CuSMo(O)OH] metal cluster. Because of changing activities of CO dehydrogenase, particularly in subcellular fractions, we speculated whether the enzyme would be subject to regulation by thiols (RSH). Here we establish inhibition of CO dehydrogenase by thiols and report the corresponding Ki-values (mM): l-cysteine (5.2), d-cysteine (9.7), N-acetyl-l-cysteine (8.2), d,l-homocysteine (25.8), l-cysteine-glycine (2.0), dithiothreitol (4.1), coenzyme A (8.3), and 2-mercaptoethanol (9.3). Inhibition of the enzyme was reversed by CO or upon lowering the thiol concentration. Electron paramagnetic resonance spectroscopy (EPR) and X-ray absorption spectroscopy (XAS) of thiol-inhibited CO dehydrogenase revealed a bimetallic site in which the RSH coordinates to the Cu-ion as a third ligand {[Mo(VI)(O)OH(2)SCu(I)(SR)S-Cys]} leaving the redox state of the Cu(I) and the Mo(VI) unchanged. Collectively, our findings establish a regulation of CO dehydrogenase activity by thiols in vitro. They also corroborate the hypothesis that CO interacts with the Cu-ion first. The result that thiol compounds much larger than CO can freely travel through the substrate channel leading to the bimetallic cluster challenges previous concepts involving chaperone function and is of importance for an understanding how the sulfuration step in the assembly of the bimetallic cluster might proceed., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Bipolar disorders (BD) are among the most severe mental disorders with first clinical signs and symptoms frequently appearing in adolescence and early adulthood. The long latency in clinical diagnosis (and subsequent adequate treatment) adversely affects the course of disease, effectiveness of interventions and health-related quality of life, and increases the economic burden of BD. Despite uncertainties about risk constellations and symptomatology in the early stages of potentially developing BD, many adolescents and young adults seek help, and most of them suffer substantially from symptoms already leading to impairments in psychosocial functioning in school, training, at work and in their social relationships. We aimed to identify subjects at risk of developing BD and investigate the efficacy and safety of early specific cognitive-behavioural psychotherapy (CBT) in this subpopulation., Methods/design: EarlyCBT is a randomised controlled multi-centre clinical trial to evaluate the efficacy and safety of early specific CBT, including stress management and problem solving strategies, with elements of mindfulness-based therapy (MBT) versus unstructured group meetings for 14 weeks each and follow-up until week 78. Participants are recruited at seven university hospitals throughout Germany, which provide in- and outpatient care (including early recognition centres) for psychiatric patients. Subjects at high risk must be 15 to 30 years old and meet the combination of specified affective symptomatology, reduction of psychosocial functioning, and family history for (schizo)affective disorders. Primary efficacy endpoints are differences in psychosocial functioning and defined affective symptomatology at 14 weeks between groups. Secondary endpoints include the above mentioned endpoints at 7, 24, 52 and 78 weeks and the change within groups compared to baseline; perception of, reaction to and coping with stress; and conversion to full BD., Discussion: To our knowledge, this is the first study to evaluate early specific CBT in subjects at high risk for BD. Structured diagnostic interviews are used to map the risk status and development of disease. With our study, the level of evidence for the treatment of those young patients will be significantly raised., Trial Registration: WHO International Clinical Trials Platform (ICTRP), identifier: DRKS00000444, date of registration: 16 June 2010.

Scope: Hyperglycemia is a hallmark of diabetes mellitus but slighter increases of blood glucose levels are observed also during ageing. Using the Caenorhabditis elegans mev-1 mutant, we identified molecular mechanisms underlying the protection from glucose toxicity by the polyphenol quercetin., Methods and Results: We fed C. elegans mev-1 mutants on a liquid medium supplemented with 10 mM glucose, which resulted in a reduced survival at 37°C. The polyphenol quercetin (1 μM) was able to prevent glucose-induced lifespan reduction completely. RNA interference revealed that the sirtuin SIR-2.1, the nuclear hormone receptor DAF-12, and its putative co-activator MDT-15 were critical for the quercetin effects. Moreover, RNA interference for key factors of proteostasis reduced survival, which was not further affected by glucose or quercetin, suggesting that those proteins are a target for both substances. Besides unfolded protein response, proper functionality of the proteasome was shown to be crucial for the survival enhancing effects of quercetin and the polyphenol was finally demonstrated to activate proteasomal degradation., Conclusion: Our studies demonstrate that lowest concentrations of quercetin prevent a glucose-induced reduction of survival. SIR-2.1, DAF-12, and MDT-15 were identified as targets that activate unfolded protein response and proteasomal degradation to limit the accumulation of functionally restricted proteins., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Survivin belongs to the family of apoptosis inhibitors (IAPs), which antagonizes the induction of cell death. Dysregulated expression of IAPs is frequently observed in cancers, and the high levels of survivin in tumors compared to normal adult tissues make it an attractive target for pharmacological interventions. The small imidazolium-based compound YM155 has recently been reported to block the expression of survivin via inhibition of the survivin promoter. Recent data, however, question that this is the sole and main effect of this drug, which is already being tested in ongoing clinical studies. Here, we critically review the current data on YM155 and other new experimental agents supposed to antagonize survivin. We summarize how cells from various tumor entities and with differential expression of the tumor suppressor p53 respond to this agent in vitro and as murine xenografts. Additionally, we recapitulate clinical trials conducted with YM155. Our article further considers the potency of YM155 in combination with other anti-cancer agents and epigenetic modulators. We also assess state-of-the-art data on the sometimes very promiscuous molecular mechanisms affected by YM155 in cancer cells., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Histone deacetylase inhibitors (HDACi) are promising antineoplastic agents, but their precise mechanisms of actions are not well understood. In particular, the relevance of p53 for HDACi-induced effects has not been fully elucidated. We investigated the anticancer effects of four structurally distinct HDACi, vorinostat, entinostat, apicidin and valproic acid, using isogenic HCT-116 colon cancer cell lines differing in p53 status., Methods: Effects were assessed by MTT assay, flow-cytometric analyses of propidium iodide uptake, mitochondrial depolarisation and cell-cycle distribution, as well as by gene expression profiling., Results: Vorinostat was equally effective in p53 wild-type and null cells, whereas entinostat was less effective in p53 null cells. Histone deacetylase inhibitors treatment suppressed the expression of MDM2 and increased the abundance of p53. Combination treatments showed that vorinostat enhanced the cytotoxic activity of TRAIL and bortezomib, independent of the cellular p53 status. Investigations into the effects of an inhibitor of the sirtuin class of HDAC, tenovin-1, revealed that tenovin-1-mediated cell death hinged on p53., Conclusion: These results demonstrate that vorinostat activates p53, but does not require p53 for inducing its anticancer action. Yet they also demonstrate that entinostat-induced cytotoxic effects partially depend on p53, indicating that different HDACi have a different requirement for p53.

Background: Human milk oligosaccharides (HMO) represent the third most abundant component of human breast milk. More than a hundred structurally distinct HMO have been identified, and the HMO composition varies between mothers as well as over the course of lactation. Some newborn infants receive donor milk (DM) when their mother's own milk (MOM) volume is inadequate or unavailable., Objective: This study aimed to compare HMO content between DM and MOM., Methods: We used high performance liquid chromatography analysis of fluorescently labeled HMO to analyze the variation in HMO amount and composition of 31 different batches of DM (each pooled from 3 individual donors) provided by the Mothers' Milk Bank in San Jose, California, and compared it to 26 different MOM samples donated by mothers with infants in our neonatal intensive care unit (NICU)., Results: Total HMO amount as well as concentrations of lacto-N-tetraose, lacto-N-neotetraose, lacto-N-fucopentaose 1, and disialyllacto-N-tetraose were significantly lower in DM than in MOM, whereas the concentrations of 3'-sialyllactose and 3-fucosyllactose were significantly higher in DM., Conclusion: Our data show that infants in our NICU who receive DM are likely to ingest HMO at different total amounts and relative composition from what they would receive with their MOM. Recent in vitro and animal studies have started to link individual HMO to infant health and disease. Future studies are needed to assess the importance of a mother-infant match with regard to HMO composition.

Aim: Accumulating data show that patients with bipolar disorder (BD) experience substantial symptomatology months or years before full manifestation. Based on the need for early preventive interventions in BD as well as data suggesting effectiveness of psychotherapeutic interventions for BD, we aimed to review the evidence for psychotherapeutic treatments in help-seeking individuals considered at risk for BD (At-Risk-BD)., Methods: Searching PubMed and PsycINFO, clinical trial registries and recently published systematic reviews, a systematic review was performed of psychoeducational and psychotherapeutic intervention studies in At-Risk-BD individuals., Results: Only three completed studies were identified, two of which were randomized trials (n = 77) and one was an open pilot study (n = 13). Two ongoing studies (projected n = 150 and n = 100, respectively) were found in trial registries. The available evidence suggests potential effectiveness of multi-family psychoeducational psychotherapy and family-focussed therapy for symptom reduction and prevention of BD conversion., Conclusions: Psychotherapeutic treatments are a reasonable starting point for At-Risk-BD subjects when symptom severity, distress and impairment are sufficiently significant to initiate treatment. Ongoing studies will further clarify the effectiveness and timing of psychotherapeutic interventions for At-Risk-BD individuals and whether or not they should be given alone or in conjunction with other treatments. Large multi-site studies with standardized procedures/manuals are needed to advance the field., (© 2013 Wiley Publishing Asia Pty Ltd.)

Stem cells isolated from adipose tissue show great therapeutic potential in veterinary medicine, but some points such as the use of fresh or cultured cells and route of administration need better knowledge. This study aimed to evaluate the effect of autologous stromal vascular fraction (SVF, n = 4) or allogeneic cultured adipose-derived stem cells (ASCs, n = 5) injected into acupuncture points in dogs with hip dysplasia and weak response to drug therapy. Canine ASCs have proliferation and differentiation potential similar to ASCs from other species. After the first week of treatment, clinical evaluation showed marked improvement compared with baseline results in all patients treated with autologous SVF and three of the dogs treated with allogeneic ASCs. On days 15 and 30, all dogs showed improvement in range of motion, lameness at trot, and pain on manipulation of the joints, except for one ASC-treated patient. Positive results were more clearly seen in the SVF-treated group. These results show that autologous SVF or allogeneic ASCs can be safely used in acupoint injection for treating hip dysplasia in dogs and represent an important therapeutic alternative for this type of pathology. Further studies are necessary to assess a possible advantage of SVF cells in treating joint diseases.

Background. The early detection of rheumatic diseases and the treatment to target have become of utmost importance to control the disease and improve its prognosis. However, establishing a diagnosis in early stages is challenging as many diseases initially present with similar symptoms and signs. Expert systems are computer programs designed to support the human decision making and have been developed in almost every field of medicine. Methods. This review focuses on the developments in the field of rheumatology to give a comprehensive insight. Medline, Embase, and Cochrane Library were searched. Results. Reports of 25 expert systems with different design and field of application were found. The performance of 19 of the identified expert systems was evaluated. The proportion of correctly diagnosed cases was between 43.1 and 99.9%. Sensitivity and specificity ranged from 62 to 100 and 88 to 98%, respectively. Conclusions. Promising diagnostic expert systems with moderate to excellent performance were identified. The validation process was in general underappreciated. None of the systems, however, seemed to have succeeded in daily practice. This review identifies optimal characteristics to increase the survival rate of expert systems and may serve as valuable information for future developments in the field.

Purpose: This study was designed to assess the additional value of SPECT/CT of the trunk used in conjunction with conventional nuclear imaging and its effects on patient management in a large patient series., Methods: In 353 patients, whole-body scintigraphy (WBS), SPECT, and SPECT/CT were prospectively performed for staging and restaging. SPECT/CT of the trunk was performed in all patients. In the 308 evaluable patients (211 with breast cancer, 97 with prostate cancer), clinical follow-up was used as the gold standard. Bone metastases were confirmed in 72 patients and excluded in 236. Multistep analyses per lesion and per patient were performed. Clinical relevance was expressed in terms of downstaging and upstaging rates on a per-patient basis., Results: In the total patient group, sensitivities, specificities, and negative and positive predictive values on a per-patient basis were 93 %, 78 %, 95 % and 59 % for WBS, 94 %, 71 %, 97 % and 53 % for SPECT, and 97 %, 94 %, 97 % and 88 % for SPECT/CT, respectively. In all subgroups, specificity and positive predictive value were significantly (p<0.01) better with SPECT/CT. Downstaging of metastatic disease in the total, breast cancer and prostate cancer groups using SPECT/CT was possible in 32.1 %, 33.8 % and 29.5 % of patients, respectively. Upstaging in previously negative patients by additional SPECT/CT was observed in three breast cancer patients (2.1 %). Further diagnostic imaging procedures for unclear scintigraphic findings were necessary in only 2.5 % of patients. SPECT/CT improved diagnostic accuracy for defining the extent of multifocal metastatic disease in 34.6 % of these patients., Conclusions: SPECT/CT significantly improved the specificity and positive predictive value of bone scintigraphy in cancer patients. In breast cancer patients, we found a slight increase in sensitivity. SPECT/CT had a significant effect on clinical management because of correct downstaging and upstaging, better definition of the extent of metastases, and a reduction in further diagnostic procedures.

The spindle cell rhabdomyosarcoma is a rare variant of the embryonal rhabdomyosarcoma, mostly occurring in childhood. Only a few cases are described in adults. To date, no case of the spindle cell subtype of the prostatic embryonal rhabdomyosarcoma has been published. We report on a 23-year-old man, initially presenting with obstructive micturition problems, perineal pain and night sweat. After diagnosis by transrectal biopsy of the prostate, radiochemotherapy within the CWS 2002 P study was applied: nine cycles of vincristine, doxorubicin, actinomycin D, ifosfamide, and fractionated radiotherapy of the tumor and suspect lymph nodes (final dose 50.4 Gy). The tumor initially shrank, but an early local recurrence arose. Second-line chemotherapy was applied, followed by a salvage radical cytoprostatectomy. The patient died of disseminated disease 14 months after diagnosis., (© 2013 The Japanese Urological Association.)

Human milk oligosaccharides (HMO) are complex glycans that are highly abundant in human milk, but not in infant formula. Accumulating data, mostly from in vitro and animal studies, indicate that HMO benefit the breast-fed infant in multiple ways and in different target organs. In vitro incubation studies suggest that HMO can resist the low pH in the infant's stomach and enzymatic degradation in the small intestine and reach the colon in the same composition as in the mother's milk. The oligosaccharide composition in faeces of breast-fed infants is, however, very different from that in the mother's milk, raising questions on when, where and how HMO are metabolised between ingestion and excretion. To answer some of these questions, we established a pulse-chase model in neonatal rats and analysed HMO profiles to track their composition over time in five consecutive equal-length intestinal segments as well as in serum and urine. The relative abundance of individual HMO changed significantly within the first 2 h after feeding and already in the segments of the small intestine prior to reaching the colon. Only 3'-sialyllactose, the major oligosaccharide in rat milk, and hardly any other HMO appeared in the serum and the urine of HMO-fed rats, indicating a selective absorption of rat milk-specific oligosaccharides. The present results challenge the paradigm that HMO reach the colon and other target organs in the same composition as originally secreted with the mother's milk. The present results also raise questions on whether rats and other animals represent suitable models to study the effects of HMO.

Maturation of chloroplast psaA pre-mRNA from the green alga Chlamydomonas reinhardtii requires the trans-splicing of two split group II introns. Several nuclear-encoded trans-splicing factors are required for the correct processing of psaA mRNA. Among these is the recently identified Raa4 protein, which is involved in splicing of the tripartite intron 1 of the psaA precursor mRNA. Part of this tripartite group II intron is the chloroplast encoded tscA RNA, which is specifically bound by Raa4. Using Raa4 as bait in a combined tandem affinity purification and mass spectrometry approach, we identified core components of a multisubunit ribonucleoprotein complex, including three previously identified trans-splicing factors (Raa1, Raa3, and Rat2). We further detected tscA RNA in the purified protein complex, which seems to be specific for splicing of the tripartite group II intron. A yeast-two hybrid screen and co-immunoprecipitation identified chloroplast-localized Raa4-binding protein 1 (Rab1), which specifically binds tscA RNA from the tripartite psaA group II intron. The yeast-two hybrid system provides evidence in support of direct interactions between Rab1 and four trans-splicing factors. Our findings contribute to our knowledge of chloroplast multisubunit ribonucleoprotein complexes and are discussed in support of the generally accepted view that group II introns are the ancestors of the eukaryotic spliceosomal introns.

Background and Objective: Although evidence-based medical guidelines are widely accepted it is not clear how they are implemented in daily clinical work. The aim of this study was a Thuringia-wide analysis of hypertension diagnosis and treatment in clinical practice of internists and general practitioners, combined with the evaluation of guideline implementation., Methods: 1884 Thuringian internists and general practitioners were interviewed using a postally delivered, validated questionnaire to assess knowledge and implementation of the hypertension guidelines., Results: 33,4 % of the physicians participated in our survey (433 general practitioners, 197 internists). 98 % of the participants routinely treat hypertension. Internists reported significantly more frequently to treat patients with resistance to antihypertensive therapy. Compared with older physicians and general practitioners, internists were significantly more likely to initiate diagnostic procedures for secondary hypertension according to the guidelines. Long-term measurement of arterial blood pressure in patients with more than three antihypertensive drugs and in cases of suspected endorgan damage or sleep apnea syndrome was more frequently applied by internists. 82,1 % of the participants reported to prescribe nonpharmacological therapies because of their efficacy. ACE-inhibitors (41,6 %) and beta-blockers (34,6 %) were preferred for monotherapy of hypertension without risk factors. ACE-inhibitors (80,1 %), followed by angiotensin receptor antagonists (12,1 %), were primarily selected in hypertensive patients with diabetic nephropathy. In left-ventricular hypertrophy, ACE inhibitors were favoured, too (67%)., Conclusion: This survey indicates that in clinical practice doctors treat hypertensives according to official guidelines. However, there is a need for further education especially regarding indication of long-term measurement of arterial blood pressure. Continued education related to diagnosis and treatment of arterial hypertension and implementation of guidelines remains a permanent challenge for doctors., (© Georg Thieme Verlag KG Stuttgart · New York.)

The neuraminidase (NA) genes of A(H1N1)pdm09 influenza virus isolates from 306 infected patients were analysed. The circulation of oseltamivir-resistant viruses in Brazil has not been reported previously. Clinical samples were collected in the state of Rio Grande do Sul (RS) from 2009-2011 and two NA inhibitor-resistant mutants were identified, one in 2009 (H275Y) and the other in 2011 (S247N). This study revealed a low prevalence of resistant viruses (0.8%) with no spread of the resistant mutants throughout RS.

Background/aims: Topically administered glucocorticoids such as budesonide have the potential of being established as first-line medical treatment of eosinophilic esophagitis (EoE). Safety of budesonide is based on high elimination by cytochrome P450 3A (CYP3A) enzymes. We aimed to investigate systemic absorption and elimination of a new budesonide formulation in patients with active EoE in comparison with healthy controls., Methods: After single and multiple doses of orodispersible budesonide (4 mg/day) the parent drug, its CYP3A-dependent metabolites, and endogenous cortisol were determined in 12 adult patients with active EoE and 12 healthy controls. An approved ileal-release formulation of budesonide was taken for reference. Molar ratios of metabolite formation in plasma were used as indices of CYP3A metabolic function., Results: CYP3A-dependent metabolite formation was significantly reduced in patients with active EoE as compared to healthy controls. Impaired biotransformation was reflected by a significantly higher extent of budesonide absorption and elongated elimination half-life in EoE patients. Comparison of morning serum cortisol levels at baseline with those after 1 week of treatment with budesonide revealed a significant decrease in EoE patients but not in healthy subjects., Conclusion: Active EoE is associated with reduced elimination of budesonide via CYP3A, the major subfamily of drug-metabolizing enzymes in humans., (Copyright © 2013 S. Karger AG, Basel.)

This paper deals with adaption capacity of nitrifiers to allylthiourea (ATU) as a model inhibitor at two temperature levels. Nitrifying communities were developed at 15 (BM15) and 30 °C (BM30). The activity of the nitrifiers was determined by using short-time respiration (STR) tests, oxygen monitoring and in-situ measurements. The oxygen monitoring provided information about the temperature-dependent time delay between the dosage of NH4(+)-N or ATU and reaching its characteristic level of effect. The greatly scattered results from the STR tests for BM15 were thus explained by the time delay, which was two to three times higher than for BM30. Furthermore, combining the results of oxygen-monitoring and in-situ measurements it can be stated that an adaption to ATU at psychrophilic temperature conditions was not achieved, whereby up to 40% of nitrification was sustained for BM30 at an ATU-concentration over 7 mg/l. The nitrification by BM15 did not start until ATU was degraded to 1-2 mg/l, the typical inhibition concentration for ATU. Hence, the results indicate a population drift to adapted nitrifiers at mesophilic conditions and ATU-degrading microorganisms at psychrophilic temperature conditions, which can have a considerable influence on domestic wastewater treatment in cold climates receiving industrial effluents.

Sleep is highly altered during affective episodes in patients with bipolar disorder. There is accumulating evidence that sleep is also altered in euthymic states. A deficit in sleep regulation may be a vulnerability factor with aetiological relevance in the development of the disease. This study aims to explore the objective, subjective and lifetime sleep characteristics of patients with manifest bipolar disorder and persons with an elevated risk of developing the disease. Twenty-two patients with bipolar I and II disorder, nine persons with an elevated risk of developing the disorder and 28 healthy controls were evaluated with a structured interview to characterize subjective and lifetime sleeping habits. In addition, participants wore an actimeter for six nights. Patients with bipolar disorder had longer sleep latency and duration compared with healthy controls as determined by actigraphy. The subjective and lifetime sleep characteristics of bipolar patients differed significantly from healthy controls. The results of participants with an elevated risk of developing the disorder had subjective and lifetime characteristics that were largely analogous to those of patients with manifest bipolar disorder. In particular, both groups described recurring insomnia and hypersomnia, sensitivity to shifts in circadian rhythm, difficulties awakening and prolonged sleep latency. This study provides further evidence that sleep and circadian timing are profoundly altered in patients with bipolar disorder. It may also tentatively suggest that sleep may be altered prior to the first manic episode in subjects at high risk.

As advocated by Nasca, our teaching programs must nurture professionalism and the effacement of self interest that is the core of the practice of medicine and the profession. The evidence to date suggests that work-hour restrictions based solely on clock-defined time limits discourage, rather than promote, the professional behavior that we desire in tomorrow's physicians. Notwithstanding any issues related to duty hours or fitness for duty, a competency-based system of medical education is both desirable and necessary in the current environment of medical education. In the absence of evidence to suggest that duty-hour limits reduce medical errors and enhance patient safety, and until we have evolved to a competency-based system of resident education, a misguided and overzealous focus on limiting work hours should not be allowed to exert the unintended consequence of eroding the ethos of professionalism that we, and our patients, have come to expect of a physician.

Plasmodium falciparum causes severe malaria infections in millions of people every year. The parasite is developing resistance to the most common antimalarial drugs, which creates an urgent need for new therapeutics. A promising and attractive target for antimalarial drug design is the bifunctional enzyme glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (PfGluPho) of P. falciparum, which catalyzes the key step in the parasites' pentose phosphate pathway. In this study, we describe the development of a high-throughput screening assay to identify small-molecule inhibitors of recombinant PfGluPho. The optimized assay was used to screen three small-molecule compound libraries-namely, LOPAC (Sigma-Aldrich, 1280 compounds), Spectrum (MicroSource Discovery Systems, 1969 compounds), and DIVERSet (ChemBridge, 49 971 compounds). These pilot screens identified 899 compounds that inhibited PfGluPho activity by at least 50%. Selected compounds were further studied to determine IC(50) values in an orthogonal assay, the type of inhibition and reversibility, and effects on P. falciparum growth. Screening results and follow-up studies for selected PfGluPho inhibitors are presented. Our high-throughput screening assay may provide the basis to identify novel and urgently needed antimalarial drugs.

Over the last two decades, HIV and AIDS have been framed as a "global problem". In the process, transnational advocacy networks have emerged as important actors, and particular places are recognised as key nodes in global HIV and AIDS governance. Using the example of London, UK, this paper examines how these networks are involved in local articulations of global governance and reveals that 'global' processes are inflected by the locations through which networks are routed. The example suggests the need for further analysis of the geographies through which HIV and AIDS is reconfiguring power relations at a variety of spatial scales., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Conflicts in spatial stimulus-response tasks occur when the task-relevant feature of a stimulus implies a response toward a certain location which does not match the location of stimulus presentation. This conflict leads to increased error rates and longer reaction times, which has been termed Simon effect. A model of dual route processing (automatic and intentional) of stimulus features has been proposed, predicting response conflicts if the two routes are incongruent. Although there is evidence that the prefrontal cortex, notably the anterior cingulate cortex (ACC), plays a crucial role in conflict processing, the neuronal basis of dual route architecture is still unknown. In this study, we pursue a novel approach using positron emission tomography (PET) to identify relevant brain areas in a rat model of an auditory Simon task, a neuropsychological interference task, which is commonly used to study conflict processing in humans. For combination with PET we used the metabolic tracer [(18)F]fluorodeoxyglucose, which accumulates in metabolically active brain cells during the behavioral task. Brain areas involved in conflict processing are supposed to be activated when automatic and intentional route processing lead to different responses (dual route model). Analysis of PET data revealed specific activation patterns for different task settings applicable to the dual route model as established for response conflict processing. The rat motor cortex (M1) may be part of the automatic route or involved in its facilitation, while premotor (M2), prelimbic, and ACC seemed to be essential for inhibiting the incorrect, automatic response, indicating conflict monitoring functions. Our findings and the remarkable similarities to the pattern of activated regions reported during conflict processing in humans demonstrate that our rodent model opens novel opportunities to investigate the anatomical basis of conflict processing and dual route architecture.

Background: The precise characterisation of a high risk status for the development of a psychiatric disorder and the question of how well this predicts disease manifestation is of major importance as negative consequences of late diagnosis and treatment have been well demonstrated. In the absence of well defined and disease specific biological markers for bipolar disorder, the recognition of premature stages must rely on combinations of risk factors that have been associated with later disease manifestation., Methods: A review of the literature and our experience from the Early Recognition Centre led us to identify symptom constellations., Results: Individual categories defined and grouped included: (I) genetic risk, (II) substance use, misuse or dependence, (III) diagnosis/suspected diagnosis of attention deficit hyperactivity disorder, (IV) pronounced creativity, (V) impairment in psychosocial functioning, (VI) subthreshold affective symptoms, and (VII) early symptomatology including (a) changes in sleep and circadian rhythm, (b) changes in mood, mood swings/affective lability, (c) fearfulness/anxiety, and (d) dissociative symptoms. These risk constellations were operationalised and a new risk assessment instrument, the Early Phase Inventory for Bipolar Disorders (EPIbipolar) was developed., Limitations: Challenges regarding the validity of the data on which the instrument is based, specificity of and correlations between risk categories, and ethical considerations were encountered., Conclusions: Further use of EPIbipolar in research should help to refine prodromal features and narrow these down to a less cumbersome core that can be used to develop a shortened tool for use in clinical care. Prospective longitudinal research is needed to establish the predictive validity of this novel bipolar disorder risk assessment tool., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Context: Newborns may present a range of motor phenomena that are not epileptic in nature. Chin tremor is an unusual movement disorder that typically starts in early childhood and may be precipitated by stress and emotion. Its pathophysiology has not been fully elucidated., Case Report: We describe a full-term newborn that, immediately after neonatal anoxia, presented body and chin tremors that were unresponsive to anti-epileptic drugs. Subsequent neurological evaluation revealed signs of pyramidal tract damage and chin tremor triggered by percussion and crying. We discuss the hypothesis that the anatomopathological abnormality may lie at the level of the higher cortical centers or midbrain., Conclusions: Further studies are needed in order to gain greater comprehension of neonatal tremors. Recognition of the various etiological possibilities and consequent management of treatable causes is essential for care optimization.

Plants from the genus Piper are economically useful and some species have been indicated because of their medicinal properties in the central nervous system. However, few studies about toxicity and neurobehavioral effects have been conducted. In this study, two Piper species, P. amalago and P. mikanianum were investigated in rats to determine acute toxicity and to evaluate the ansiogenic/ansiolytic properties in the elevated plus-maze and the effects on locomotion and exploration in an open field. Additionally, genotoxic activities were evaluated, using the comet assay in several tissues and the micronucleus assay in bone marrow. The phytochemical analysis of both Piper species leaves suggests the presence of amide, essential oils, flavonoids and phenolic compounds. The LD(50) of P. amalago and P. mikanianum were estimated as 2,545 and 1,661 mg/kg, respectively. The behavioral and genotoxic parameters were determined after an intraperitoneal administration of P. amalago (250 or 420 mg/kg) or P. mikanianum (160 or 270 mg/kg). Both plants decreased the number of entries and time spent in the open arms in the plus-maze test, indicating an anxiogenic effect. Only P. mikanianum affected locomotion and exploration in the open field behavior test. No genotoxic or mutagenic effect was observed. Our results suggest that these Piper species act on the central nervous system, without induce genetic toxicity., (Copyright © 2010 Elsevier GmbH. All rights reserved.)