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Temporal information processing in short- and long-term memory of patients with schizophrenia
(2011)
Cognitive deficits of patients with schizophrenia have been largely recognized as core symptoms of the disorder. One neglected factor that contributes to these deficits is the comprehension of time. In the present study, we assessed temporal information processing and manipulation from short- and long-term memory in 34 patients with chronic schizophrenia and 34 matched healthy controls. On the short-term memory temporal-order reconstruction task, an incidental or intentional learning strategy was deployed. Patients showed worse overall performance than healthy controls. The intentional learning strategy led to dissociable performance improvement in both groups. Whereas healthy controls improved on a performance measure (serial organization), patients improved on an error measure (inappropriate semantic clustering) when using the intentional instead of the incidental learning strategy. On the long-term memory script-generation task, routine and non-routine events of everyday activities (e.g., buying groceries) had to be generated in either chronological or inverted temporal order. Patients were slower than controls at generating events in the chronological routine condition only. They also committed more sequencing and boundary errors in the inverted conditions. The number of irrelevant events was higher in patients in the chronological, non-routine condition. These results suggest that patients with schizophrenia imprecisely access temporal information from short- and long-term memory. In short-term memory, processing of temporal information led to a reduction in errors rather than, as was the case in healthy controls, to an improvement in temporal-order recall. When accessing temporal information from long-term memory, patients were slower and committed more sequencing, boundary, and intrusion errors. Together, these results suggest that time information can be accessed and processed only imprecisely by patients who provide evidence for impaired time comprehension. This could contribute to symptomatic cognitive deficits and strategic inefficiency in schizophrenia.
Background: Oral anticoagulant therapy (OAT) with warfarin is the standard of stroke prevention in patients with atrial fibrillation. Approximately 30% of patients with cardioembolic strokes are on OAT at the time of symptom onset. We investigated whether warfarin exacerbates the risk of thrombolysis-associated hemorrhagic transformation (HT) in a mouse model of ischemic stroke.
Methods: 62 C57BL/6 mice were used for this study. To achieve effective anticoagulation, warfarin was administered orally. We performed right middle cerebral artery occlusion (MCAO) for 3 h and assessed functional deficit and HT blood volume after 24 h.
Results: In non-anticoagulated mice, treatment with rt-PA (10 mg/kg i.v.) after 3 h MCAO led to a 5-fold higher degree of HT compared to vehicle-treated controls (4.0±0.5 µl vs. 0.8±0.1, p<0.001). Mice on warfarin revealed larger amounts of HT after rt-PA treatment in comparison to non-anticoagulated mice (9.2±3.2 µl vs. 2.8±1.0, p<0.05). The rapid reversal of anticoagulation by means of prothrombin complex concentrates (PCC, 100 IU/kg) at the end of the 3 h MCAO period, but prior to rt-PA administration, neutralized the exacerbated risk of HT as compared to sham-treated controls (3.8±0.7 µl vs. 15.0±3.8, p<0.001).
Conclusion: In view of the vastly increased risk of HT, it seems to be justified to withhold tPA therapy in effectively anticoagulated patients with acute ischemic stroke. The rapid reversal of anticoagulation with PCC prior to tPA application reduces the risk attributed to warfarin pretreatment and may constitute an interesting therapeutic option.
Recent work has demonstrated that the formation of platelet neutrophil complexes (PNCs) affects inflammatory tissue injury. Vasodilator-stimulated phosphoprotein (VASP) is crucially involved into the control of PNC formation and myocardial reperfusion injury. Given the clinical importance of hepatic IR injury we pursued the role of VASP during hepatic ischemia followed by reperfusion. We report here that VASP−/− animals demonstrate reduced hepatic IR injury compared to wildtype (WT) controls. This correlated with serum levels of lactate dehydrogenase (LDH), aspartate (AST) and alanine (ALT) aminotransferase and the presence of PNCs within ischemic hepatic tissue and could be confirmed using repression of VASP through siRNA. In studies employing bone marrow chimeric mice we identified hematopoietic VASP to be of crucial importance for the extent of hepatic injury. Phosphorylation of VASP on Ser153 through Prostaglandin E1 or on Ser235 through atrial natriuretic peptide resulted in a significant reduction of hepatic IR injury. This was associated with a reduced presence of PNCs in ischemic hepatic tissue. Taken together, these studies identified VASP and VASP phosphorylation as crucial target for future hepatoprotective strategies.
Accumulating evidence indicates that increased generation of reactive oxygen species (ROS) contributes to the development of exaggerated pain hypersensitivity during persistent pain. In the present study, we investigated the antinociceptive efficacy of the antioxidants vitamin C and vitamin E in mouse models of inflammatory and neuropathic pain. We show that systemic administration of a combination of vitamins C and E inhibited the early behavioral responses to formalin injection and the neuropathic pain behavior after peripheral nerve injury, but not the inflammatory pain behavior induced by Complete Freund's Adjuvant. In contrast, vitamin C or vitamin E given alone failed to affect the nociceptive behavior in all tested models. The attenuated neuropathic pain behavior induced by the vitamin C and E combination was paralleled by a reduced p38 phosphorylation in the spinal cord and in dorsal root ganglia, and was also observed after intrathecal injection of the vitamins. Moreover, the vitamin C and E combination ameliorated the allodynia induced by an intrathecally delivered ROS donor. Our results suggest that administration of vitamins C and E in combination may exert synergistic antinociceptive effects, and further indicate that ROS essentially contribute to nociceptive processing in special pain states.
The duration of use is usually significantly longer for marine vessels than for roadside vehicles. Therefore, these vessels are often powered by relatively old engines which may propagate air pollution. Also, the quality of fuel used for marine vessels is usually not comparable to the quality of fuels used in the automotive sector and therefore, port areas may exhibit a high degree of air pollution. In contrast to the multitude of studies that addressed outdoor air pollution due to road traffic, only little is known about ship-related air pollution. Therefore the present article aims to summarize recent studies that address air pollution, i.e. particulate matter exposure, due to marine vessels. It can be stated that the data in this area of research is still largely limited. Especially, knowledge on the different air pollutions in different sea areas is needed.
Background: Drowning is a constant global problem which claims proximately half a million victims worldwide each year, whereas the number of near-drowning victims is considerably higher. Public health strategies to reduce the burden of death are still limited. While research activities in the subject drowning grow constantly, yet there is no scientometric evaluation of the existing literature at the present time.
Methods: The current study uses classical bibliometric tools and visualizing techniques such as density equalizing mapping to analyse and evaluate the scientific research in the field of drowning. The interpretation of the achieved results is also implemented in the context of the data collection of the WHO.
Results: All studies related to drowning and listed in the ISI-Web of Science database since 1900 were identified using the search term "drowning". Implementing bibliometric methods, a constant increase in quantitative markers such as number of publications per state, publication language or collaborations as well as qualitative markers such as citations were observed for research in the field of drowning. The combination with density equalizing mapping exposed different global patterns for research productivity and the total number of drowning deaths and drowning rates respectively. Chart techniques were used to illustrate bi- and multilateral research cooperation.
Conclusions: The present study provides the first scientometric approach that visualizes research activity on the subject of drowning. It can be assumed that the scientific approach to this topic will achieve even greater dimensions because of its continuing actuality.
Background and Objective: The slow delayed rectifier current (IKs) is important for cardiac action potential termination. The underlying channel is composed of Kv7.1 α-subunits and KCNE1 β-subunits. While most evidence suggests a role of KCNE1 transmembrane domain and C-terminus for the interaction, the N-terminal KCNE1 polymorphism 38G is associated with reduced IKs and atrial fibrillation (a human arrhythmia). Structure-function relationship of the KCNE1 N-terminus for IKs modulation is poorly understood and was subject of this study.
Methods: We studied N-terminal KCNE1 constructs disrupting structurally important positively charged amino-acids (arginines) at positions 32, 33, 36 as well as KCNE1 constructs that modify position 38 including an N-terminal truncation mutation. Experimental procedures included molecular cloning, patch-clamp recording, protein biochemistry, real-time-PCR and confocal microscopy.
Results: All KCNE1 constructs physically interacted with Kv7.1. IKs resulting from co-expression of Kv7.1 with non-atrial fibrillation ‘38S’ was greater than with any other construct. Ionic currents resulting from co-transfection of a KCNE1 mutant with arginine substitutions (‘38G-3xA’) were comparable to currents evoked from cells transfected with an N-terminally truncated KCNE1-construct (‘Δ1-38’). Western-blots from plasma-membrane preparations and confocal images consistently showed a greater amount of Kv7.1 protein at the plasma-membrane in cells co-transfected with the non-atrial fibrillation KCNE1-38S than with any other construct.
Conclusions: The results of our study indicate that N-terminal arginines in positions 32, 33, 36 of KCNE1 are important for reconstitution of IKs. Furthermore, our results hint towards a role of these N-terminal amino-acids in membrane representation of the delayed rectifier channel complex.
Background: MicroRNA-21 (miR-21) is up-regulated in tumor tissue of patients with malignant diseases, including hepatocellular carcinoma (HCC). Elevated concentrations of miR-21 have also been found in sera or plasma from patients with malignancies, rendering it an interesting candidate as serum/plasma marker for malignancies. Here we correlated serum miR-21 levels with clinical parameters in patients with different stages of chronic hepatitis C virus infection (CHC) and CHC-associated HCC.
Methodology/Principal Findings: 62 CHC patients, 29 patients with CHC and HCC and 19 healthy controls were prospectively enrolled. RNA was extracted from the sera and miR-21 as well as miR-16 levels were analyzed by quantitative real-time PCR; miR-21 levels (normalized by miR-16) were correlated with standard liver parameters, histological grading and staging of CHC. The data show that serum levels of miR-21 were elevated in patients with CHC compared to healthy controls (P<0.001); there was no difference between serum miR-21 in patients with CHC and CHC-associated HCC. Serum miR-21 levels correlated with histological activity index (HAI) in the liver (r = −0.494, P = 0.00002), alanine aminotransferase (ALT) (r = −0.309, P = 0.007), aspartate aminotransferase (r = −0.495, P = 0.000007), bilirubin (r = −0.362, P = 0.002), international normalized ratio (r = −0.338, P = 0.034) and γ-glutamyltransferase (r = −0.244, P = 0.034). Multivariate analysis revealed that ALT and miR-21 serum levels were independently associated with HAI. At a cut-off dCT of 1.96, miR-21 discriminated between minimal and mild-severe necroinflammation (AUC = 0.758) with a sensitivity of 53.3% and a specificity of 95.2%.
Conclusions/Significance: The serum miR-21 level is a marker for necroinflammatory activity, but does not differ between patients with HCV and HCV-induced HCC.
Tubular carbonate concretions of up to 1 m in length and perpendicular to bedding, occur abundantly in the Upper Pliensbachian (upper Amaltheus margaritatus Zone, Gibbosus Subzone) in outcrops (Fontaneilles section) in the vicinity of Rivière-sûr-Tarn, southern France. Stable isotope analyses of these concretions show negative δ13C values that decrease from the rim to the center from −18.8‰ to −25.7‰ (V-PDB), but normal marine δ18O values (−1.8‰). Carbon isotope analyses of Late Pliensbachian bulk carbonate (matrix) samples from the Fontaneilles section show clearly decreasing C-isotope values across the A. margaritatus Zone, from +1‰ to −3‰ (V-PDB). Isotope analyses of coeval belemnite rostra do not document such a negative C-isotope trend with values remaining stable around +2‰ (V-PDB). Computer tomographic (CT) scanning of the tubular concretions show multiple canals that are lined or filled entirely with pyrite. Previously, the formation of these concretions with one, two, or more central tubes, has been ascribed to the activity of an enigmatic organism, possibly with annelid or arthropod affinities, known as Tisoa siphonalis. Our results suggest tisoan structures are abiogenic. Based on our geochemical analyses and sedimentological observations we suggest that these concretions formed as a combination of the anaerobic oxidation of methane (AOM) and sulfate reduction within the sediment. Fluids rich in methane and/or hydrocarbons likely altered local bulk rock carbon isotope records, but did not affect the global carbon cycle. Interestingly, Tisoa siphonalis has been described from many locations in the Grands Causses Basin in southern France, and from northern France and Luxemburg, always occurring at the same stratigraphic level. Upper Pliensbachian authigenic carbonates thus possibly cover an area of many thousand square kilometers. Greatly reduced sedimentation rates are needed to explain the stabilization of the sulfate-methane transition zone in the sedimentary column in order for the tubular concretions to form. Late Pliensbachian cooling, reducing run-off, and/or the influx of colder water and more vigorous circulation could be responsible for a halt in sedimentation. At the same time (thermogenic) methane may have destabilized during a major phase of Late Pliensbachian sea level fall. As such Tisoa siphonalis is more than a geological curiosity, and its further study could prove pivotal in understanding Early Jurassic paleoenvironmental change.
Background: Intraosseous (IO) access represents a reliable alternative to intravenous vascular access and is explicitly recommended in the current guidelines of the European Resuscitation Council when intravenous access is difficult or impossible. We therefore aimed to study the efficacy of the intraosseous needle driver EZ-IO(R) in the prehospital setting.
Methods: During a 24-month period, all cases of prehospital IO access using the EZ-IO(R) needle driver within three operational areas of emergency medical services were prospectively recorded by a standardized questionnaire that needed to be filled out by the rescuer immediately after the mission and sent to the primary investigator. We determined the rate of successful insertion of the IO needle, the time required, immediate procedure-related complications, the level of previous experience with IO access, and operator's subjective satisfaction with the device.
Results: 77 IO needle insertions were performed in 69 adults and five infants and children by emergency physicians (n=72 applications) and paramedics (n=5 applications). Needle placement was successful at the first attempt in all but 2 adults (one patient with unrecognized total knee arthroplasty, one case of needle obstruction after placement). The majority of users (92%) were relative novices with less than five previous IO needle placements. Of 22 responsive patients, 18 reported pain upon fluid administration via the needle. The rescuers' subjective rating regarding handling of the device and ease of needle insertion, as described by means of an analogue scale (0 = entirely unsatisfied, 10 = most satisfied), provided a median score of 10 (range 1-10).
Conclusions: The EZ-IO(R) needle driver was an efficient alternative to establish immediate out-of-hospital vascular access. However, significant pain upon intramedullary infusion was observed in the majority of responsive patients.
The role of peroxisome proliferator-activated receptor gamma during sepsis-induced lymphopenia
(2011)
Sepsis is one of the most common diseases on intensive care units all over the world and accounts there for the highest mortality rate. One of the hallmarks of sepsis is an accelerated T-cell apoptosis, resulting in a compromised immune state with the inability to eradicate pathogens. This promotes organ damage or even organ failure. A multiple organ dysfunction evolves, which often ends up in septic shock and death. Recently, it was shown that severe T-cell depletion correlates with sepsis mortality. When inhibiting T-cell apoptosis, an increased mouse survival was observed in experimental sepsis. ...
We recently reported that expression levels of tumor necrosis factor (TNF) receptors, TNFR1 and TNFR2, are significantly changed in the brains and cerebral spinal cerebral fluid (CSF) with Alzheimer's disease (AD). Moreover, we also found that, in an Alzheimer's mouse model, genetic deletion of TNF receptor (TNFR1) reduces amyloid plaques and amyloid beta peptides (Abeta) production through beta-secretase (BACE1) regulation. TNF-alpha converting enzyme (TACE/ADAM-17) does not only cleave pro- TNF-alpha but also TNF receptors, however, whether the TACE activity was changed in the CSF was not clear. In this study, we examined TACE in the CSF in 32 AD patients and 27 age-matched healthy controls (HCs). Interestingly, we found that TACE activity was significantly elevated in the CSF from AD patients compared with HCs. Furthermore, we also assayed the CSF levels of TACE cleaved soluble forms of TNFR1 and TNFR2 in the same patients. We found that AD patients had higher levels of both TACE cleaved soluble TNFR1 (sTNFR1) and TNFR2 (sTNFR2) in the CSF compared with aged- and gender-matched healthy controls. Levels of sTNFR1 correlated strongly with the levels of sTNFR2 (rs = 0.567-0.663, p < 0.01). The levels of both sTNFR1 and sTNFR2 significantly correlated with the TACE activity (rs = 0.491-0.557, p < 0.05). To examine if changes in TACE activity and in levels of cleaved soluble TNFRs are an early event in the course of Alzheimer's disease, we measured these molecules in the CSF from 47 patients with mild cognitive impairment (MCI) which is considered as a preclinical stage of AD. Unexpectedly, we found significantly higher levels of TACE activity and soluble TNFR in the MCI group. These results suggest that TACE activity and soluble TNF receptors may be potential diagnostic candidate biomarkers in AD and MCI.
Background: We assessed the hemodynamic performance of various prostheses and the clinical outcomes after aortic valve replacement, in different age groups.
Methods: One-hundred-and-twenty patients with isolated aortic valve stenosis were included in this prospective randomized randomised trial and allocated in three age-groups to receive either pulmonary autograft (PA, n = 20) or mechanical prosthesis (MP, Edwards Mira n = 20) in group 1 (age < 55 years), either stentless bioprosthesis (CE Prima Plus n = 20) or MP (Edwards Mira n = 20) in group 2 (age 55-75 years) and either stentless (CE Prima Plus n = 20) or stented bioprosthesis (CE Perimount n = 20) in group 3 (age > 75). Clinical outcomes and hemodynamic performance were evaluated at discharge, six months and one year.
Results: In group 1, patients with PA had significantly lower mean gradients than the MP (2.6 vs. 10.9 mmHg, p = 0.0005) with comparable left ventricular mass regression (LVMR). Morbidity included 1 stroke in the PA population and 1 gastrointestinal bleeding in the MP subgroup. In group 2, mean gradients did not differ significantly between both populations (7.0 vs. 8.9 mmHg, p = 0.81). The rate of LVMR and EF were comparable at 12 months; each group with one mortality. Morbidity included 1 stroke and 1 gastrointestinal bleeding in the stentless and 3 bleeding complications in the MP group. In group 3, mean gradients did not differ significantly (7.8 vs 6.5 mmHg, p = 0.06). Postoperative EF and LVMR were comparable. There were 3 deaths in the stented group and no mortality in the stentless group. Morbidity included 1 endocarditis and 1 stroke in the stentless compared to 1 endocarditis, 1 stroke and one pulmonary embolism in the stented group.
Conclusions: Clinical outcomes justify valve replacement with either valve substitute in the respective age groups. The PA hemodynamically outperformed the MPs. Stentless valves however, did not demonstrate significantly superior hemodynamics or outcomes in comparison to stented bioprosthesis or MPs.
The chitinase-like protein YKL-40 was found to be increased in patients with severe asthma and chronic obstructive pulmonary disease (COPD), two disease conditions featuring neutrophilic infiltrates. Based on these studies and a previous report indicating that neutrophils secrete YKL-40, we hypothesized that YKL-40 plays a key role in cystic fibrosis (CF) lung disease, a prototypic neutrophilic disease. The aim of this study was (i) to analyze YKL-40 levels in human and murine CF lung disease and (ii) to investigate whether YKL-40 single-nucleotide polymorphisms (SNPs) modulate CF lung disease severity. YKL-40 protein levels were quantified in serum and sputum supernatants from CF patients and control individuals. Levels of the murine homologue BRP-39 were analyzed in airway fluids from CF-like βENaC-Tg mice. YKL-40SNPs were analyzed in CF patients. YKL-40 levels were increased in sputum supernatants and in serum from CF patients compared to healthy control individuals. Within CF patients, YKL-40 levels were higher in sputum than in serum. BRP-39 levels were increased in airways fluids from βENaC-Tg mice compared to wild-type littermates. In both CF patients and βENaC-Tg mice, YKL-40/BRP-39 airway levels correlated with the severity of pulmonary obstruction. Two YKL-40 SNPs (rs871799 and rs880633) were found to modulate age-adjusted lung function in CF patients. YKL-40/BRP-39 levelsare increased in human and murine CF airway fluids, correlate with pulmonary function and modulate CF lung disease severity genetically. These findings suggest YKL-40 as a potential biomarker in CF lung disease.
Background
Cytochrome-P450 (CYP450) epoxygenases metabolise arachidonic acid (AA) into four different biologically active epoxyeicosatrienoic acid (EET) regioisomers. Three of the EETs (i.e., 8,9-, 11,12- and 14,15-EET) are rapidly hydrolysed by the enzyme soluble epoxide hydrolase (sEH). Here, we investigated the role of sEH in nociceptive processing during peripheral inflammation.
Results
In dorsal root ganglia (DRG), we found that sEH is expressed in medium and large diameter neurofilament 200-positive neurons. Isolated DRG-neurons from sEH-/- mice showed higher EET and lower DHET levels. Upon AA stimulation, the largest changes in EET levels occurred in culture media, indicating both that cell associated EET concentrations quickly reach saturation and EET-hydrolyzing activity mostly effects extracellular EET signaling. In vivo, DRGs from sEH-deficient mice exhibited elevated 8,9-, 11,12- and 14,15-EET-levels. Interestingly, EET levels did not increase at the site of zymosan-induced inflammation. Cellular imaging experiments revealed direct calcium flux responses to 8,9-EET in a subpopulation of nociceptors. In addition, 8,9-EET sensitized AITC-induced calcium increases in DRG neurons and AITC-induced calcitonin gene related peptide (CGRP) release from sciatic nerve axons, indicating that 8,9-EET sensitizes TRPA1-expressing neurons, which are known to contribute to mechanical hyperalgesia. Supporting this, sEH-/- mice showed increased nociceptive responses to mechanical stimulation during zymosan-induced inflammation and 8,9-EET injection reduced mechanical thresholds in naive mice.
Conclusion
Our results show that the sEH can regulate mechanical hyperalgesia during inflammation by inactivating 8,9-EET, which sensitizes TRPA1-expressing nociceptors. Therefore we suggest that influencing the CYP450 pathway, which is actually highly considered to treat cardiovascular diseases, may cause pain side effects.
Background: We aimed to investigate the influences of attention deficit/hyperactivity disorder (ADHD) on response evaluation, as reflected by the postimperative negative variation (PINV), a slow event-related potential. Methods: We investigated PINV as an indicator of performance uncertainty in an audio-visual contingent negative variation (CNV) paradigm with an interstimulus interval of 3 seconds. A constant, unilateral, quick motor reaction with either the right or the left thumb was required after an auditory forewarned (S1) visual imperative stimulus (S2). We examined 18 ADHD patients (combined or hyperactive-impulsive subtype) aged between 8 and 14 years and an age-, sex and IQ-matched control group of 19 healthy subjects using 64-channel high-density EEG. A first run was recorded drug-free, a second one under methylphenidate (MPH) medication in the ADHD group. Results: We found a significantly increased negativity of the PINV-component over the ventrolateral prefrontal cortex in ADHD children compared to the healthy control group. PINV amplitude was influenced by movement side, most likely due to the slightly more difficult task when left hand responses were required. After the intake of MPH, PINV amplitudes of ADHD children normalized. Conclusions: We conclude that children with ADHD are likely to be more uncertain about the correctness of their performance and interpret the increased PINV as a hint towards compensatory mechanisms for a deficit in the evaluation of contingencies. Further studies are needed to assess the exact extent to which remainders of eye-movement related potentials contribute to PINV amplitude despite the correction for eye-artifacts.
Introduction: Endovascular aortic repair, if technically feasible, is the treatment of choice for patients with a contained ruptured aortic aneurysm who are unfit for open surgery. Case presentation: We report the case of an 80-year-old Caucasian man who presented with an unusually configured, symptomatic infrarenal aortic aneurysm. His aneurysm showed an erosion of the fourth lumbar vertebra and a severely arteriosclerotic pelvic axis. A high thigh amputation of his right leg had been performed 15 months previously. On his right side, occlusion of his external iliac artery, common femoral artery, and deep femoral artery had occurred. His aneurysm was treated by a left-sided aortomonoiliac stent graft without femorofemoral revascularization, resulting in occlusions of both internal iliac arteries. No ischemic symptoms appeared, although perfusion of his right side was maintained only over epigastric collaterals. Conclusions: The placement of aortomonoiliac stent grafts for endovascular treatment of infrarenal aortic aneurysms without contralateral revascularization is a feasible treatment option in isolated cases. In this report, access problems and revascularization options in endovascular aneurysm repair are discussed.
Purpose: The use of the 2009 H1N1 vaccine has generated much debate concerning safety issues among the general population and physicians. Therefore, we investigated the safety of an inactivated monovalent H1N1 pandemic influenza vaccine Methods: We focused on the H1N1 pandemic influenza vaccine Pandemrix(R) and applied a self reporting questionnaire in a population of healthcare workers (HCWs) and medical students at a major university hospital. Results: In total, 4337 individuals were vaccinated, consisting of 3808 HCWs and 529 medical students. The vaccination rate of the employees was higher than 40%.The majority of individuals were vaccinated in November 2009. In total, 291 of the 4337 vaccinations were reported to lead to one or more adverse reactions (6.7%). Local reactions were reported in 3.8%, myalgia and arthralgia in 3.7%, fatigue in 3.7%, headache in 3.1%. Conclusions: Our data together with available data from several national and international institutions points to a safe pandemic influenza vaccine.
Background: Single drug use has not achieved satisfactory results in the treatment of prostate cancer, despite application of increasingly widespread targeted therapeutics. In the present study, the combined impact of the mammalian target of rapamycin (mTOR)-inhibitor RAD001, the dual EGFr and VGEFr tyrosine kinase inhibitor AEE788 and the histone deacetylase (HDAC)-inhibitor valproic acid (VPA) on prostate cancer growth and adhesion in vitro was investigated. Methods: PC-3, DU-145 and LNCaP cells were treated with RAD001, AEE788 or VPA or with a RAD-AEE-VPA combination. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by MTT-assay, flow cytometry and western blotting, respectively. Furthermore, tumor cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins as well as migratory properties of the cells was evaluated, and integrin alpha and beta subtypes were analyzed. Finally, effects of drug treatment on cell signaling pathways were determined. Results: All drugs, separately applied, reduced tumor cell adhesion, migration and growth. A much stronger anti-cancer effect was evoked by the triple drug combination. Particularly, cdk1, 2 and 4 and cyclin B were reduced, whereas p27 was elevated. In addition, simultaneous application of RAD001, AEE788 and VPA altered the membranous, cytoplasmic and gene expression pattern of various integrin alpha and beta subtypes, reduced integrin-linked kinase (ILK) and deactivated focal adhesion kinase (FAK). Signaling analysis revealed that EGFr and the downstream target Akt, as well as p70S6k was distinctly modified in the presence of the drug combination. Conclusions: Simultaneous targeting of several key proteins in prostate cancer cells provides an advantage over targeting a single pathway. Since strong anti-tumor properties became evident with respect to cell growth and adhesion dynamics, the triple drug combination might provide progress in the treatment of advanced prostate cancer.
Visual selective attention and visual working memory (WM) share the same capacity-limited resources. We investigated whether and how participants can cope with a task in which these 2 mechanisms interfere. The task required participants to scan an array of 9 objects in order to select the target locations and to encode the items presented at these locations into WM (1 to 5 shapes). Determination of the target locations required either few attentional resources (“popout condition”) or an attention-demanding serial search (“non pop-out condition”). Participants were able to achieve high memory performance in all stimulation conditions but, in the non popout conditions, this came at the cost of additional processing time. Both empirical evidence and subjective reports suggest that participants invested the additional time in memorizing the locations of all target objects prior to the encoding of their shapes into WM. Thus, they seemed to be unable to interleave the steps of search with those of encoding. We propose that the memory for target locations substitutes for perceptual pop-out and thus may be the key component that allows for flexible coping with the common processing limitations of visual WM and attention. The findings have implications for understanding how we cope with real-life situations in which the demands on visual attention and WM occur simultaneously. Keywords: attention, working memory, interference, encoding strategies