Proton pump inhibitors display antitumor effects in barrett's adenocarcinoma cells

Recent evidence has reported that proton pump inhibitors (PPIs) can exert antineoplastic effects through the disruption of pH homeostasis by inhibiting vacuolar ATPase (H+-VATPase), a proton pump overexpressed in several tumor cells, but this aspect has not been deeply investigated in EAC yet. In the present study, the expression of H+-VATPase was assessed through the metaplasia-dysplasia-adenocarcinoma sequence in Barrett''s esophagus (BE) and the antineoplastic effects of PPIs and cellular mechanisms involved were evaluated in vitro. H+-VATPase expression was assessed by immunohistochemistry in paraffined-embedded samples or by immunofluorescence in cultured BE and EAC cell lines. Cells were treated with different concentrations of PPIs and parameters of citotoxicity, oxidative stress, and autophagy were evaluated. H+-VATPase expression was found in all biopsies and cell lines evaluated, showing differences in the location of the pump between the cell lines. Esomeprazole inhibited proliferation and cell invasion and induced apoptosis of EAC cells. Production of reactive oxygen species (ROS) seemed to be involved in the cytotoxic effects observed since the addition of N-acetylcysteine significantly reduced esomeprazole-induced apoptosis in EAC cells. Esomeprazole also reduced intracellular pH of tumor cells, whereas only disturbed the mitochondrial membrane potential in OE33 cells. Esomeprazole induced autophagy in both EAC cells, but also triggered a blockade in autophagic flux in the metastatic cell line. These data provide in vitro evidence supporting the potential use of PPIs as novel antineoplastic drugs for EAC and also shed some light on the mechanisms that trigger PPIs cytotoxic effects, which differ upon the cell line evaluated

The Role of the Striatum in Learning to Orthogonalize CD Action and Valence: A Combined PET and 7 T MRI Aging Study

Pavlovian biases influence instrumental learning by coupling reward seeking with action invigoration and punishment avoidance with action suppression. Using a probabilistic go/no-go task designed to orthogonalize action (go/no-go) and valence (reward/punishment), recent studies have shown that the interaction between the two is dependent on the striatum and its key neuromodulator dopamine. Using this task, we sought to identify how structural and neuromodulatory age-related differences in the striatum may influence Pavlovian biases and instrumental learning in 25 young and 31 older adults. Computational modeling revealed a significant age-related reduction in reward and punishment sensitivity and marked (albeit not significant) reduction in learning rate and lapse rate (irreducible noise). Voxel-based morphometry analysis using 7 Tesla MRI images showed that individual differences in learning rate in older adults were related to the volume of the caudate nucleus. In contrast, dopamine synthesis capacity in the dorsal striatum, assessed using [18F]-DOPA positron emission tomography in 22 of these older adults, was not associated with learning performance and did not moderate the relationship between caudate volume and learning rate. This multiparametric approach suggests that age-related differences in striatal volume may influence learning proficiency in old age

IL-33 expression in response to SARS-CoV-2 correlates with seropositivity in COVID-19 convalescent individuals

Our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still developing. We perform an observational study to investigate seroprevalence and immune responses in subjects professionally exposed to SARS-CoV-2 and their family members (155 individuals; ages 5-79 years). Seropositivity for SARS-CoV-2 Spike glycoprotein aligns with PCR results that confirm the previous infection. Anti-Spike IgG/IgM titers remain high 60 days post-infection and do not strongly associate with symptoms, except for fever. We analyze PBMCs from a subset of seropositive and seronegative adults. TLR7 agonist-activation reveals an increased population of IL-6+TNF-IL-1β+ monocytes, while SARS-CoV-2 peptide stimulation elicits IL-33, IL-6, IFNa2, and IL-23 expression in seropositive individuals. IL-33 correlates with CD4+ T cell activation in PBMCs from convalescent subjects and is likely due to T cell-mediated effects on IL-33-producing cells. IL-33 is associated with pulmonary infection and chronic diseases like asthma and COPD, but its role in COVID-19 is unknown. Analysis of published scRNAseq data of bronchoalveolar lavage fluid (BALF) from patients with mild to severe COVID-19 reveals a population of IL-33-producing cells that increases with the disease. Together these findings show that IL-33 production is linked to SARS-CoV-2 infection and warrant further investigation of IL-33 in COVID-19 pathogenesis and immunity

Surface Feature-Guided Mapping of Cerebral Metabolic Changes in Cognitively Normal and Mildly Impaired Elderly

Purpose: The aim of this study was to investigate the longitudinal positron emission tomography (PET) metabolic changes in the elderly. Procedures: Nineteen nondemented subjects (mean Mini-Mental Status Examination 29.4±0.7 SD) underwent two detailed neuropsychological evaluations and resting 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-PET scan (interval 21.7±3.7 months), baseline structural 3T magnetic resonance (MR) imaging, and apolipoprotein E4 genotyping. Cortical PET metabolic changes were analyzed in 3-D using the cortical pattern matching technique. Results: Baseline vs. follow-up whole-group comparison revealed significant metabolic decline bilaterally in the posterior temporal, parietal, and occipital lobes and the left lateral frontal cortex. The declining group demonstrated 10–15 % decline in bilateral posterior cingulate/precuneus, posterior temporal, parietal, and occipital cortices. The cognitively stable group showed 2.5–5% similarly distributed decline. ApoE4-positive individuals underwent 5–15 % metabolic decline in the posterior association cortices. Conclusions: Using 3-D surface-based MR-guided FDG-PET mapping, significant metaboli

Die polnische Freiheit und Preußens Friedrich : Oder: Über die Furcht der Hohenzollern vor dem polnischen Freiheitsbazillus

Aus Anlass des 300. Geburtstags von „Friedrich dem Großen“ im Jahr 2012 erinnert der Autor daran, dass der Preußenkönig nicht nur ein Philosoph und Aufklärer war, sondern auch ein Verächter von „polnischer Freiheit“ und dass er mit seiner Politik erheblich zur deutsch-polnischen Verfeindung mit beigetragen hat

Associations between hippocampal morphometry and neuropathologic markers of Alzheimer's disease using 7 T MRI

Hippocampal atrophy, amyloid plaques, and neurofibrillary tangles are established pathologic markers of Alzheimer's disease. We analyzed the temporal lobes of 9 Alzheimer's dementia (AD) and 7 cognitively normal (NC) subjects. Brains were scanned post-mortem at 7 Tesla. We extracted hippocampal volumes and radial distances using automated segmentation techniques. Hippocampal slices were stained for amyloid beta (Aβ), tau, and cresyl violet to evaluate neuronal counts. The hippocampal subfields, CA1, CA2, CA3, CA4, and subiculum were manually traced so that the neuronal counts, Aβ, and tau burden could be obtained for each region. We used linear regression to detect associations between hippocampal atrophy in 3D, clinical diagnosis and total as well as subfield pathology burden measures. As expected, we found significant correlations between hippocampal radial distance and mean neuronal count, as well as diagnosis. There were subfield specific associations between hippocampal radial distance and tau in CA2, and cresyl violet neuronal counts in CA1 and subiculum. These results provide further validation for the European Alzheimer's Disease Consortium Alzheimer's Disease Neuroimaging Initiative Center Harmonized Hippocampal Segmentation Protocol (HarP)

CSF and Brain Structural Imaging Markers of the Alzheimer's Pathological Cascade

10.1371/journal.pone.0047406PLoS ONE712

Fusion Techniques in Biomedical Information Retrieval

For difficult cases clinicians usually use their experience and also the information found in textbooks to determine a diagnosis. Computer tools can help them supply the relevant information now that much medical knowledge is available in digital form. A biomedical search system such as developed in the Khresmoi project (that this chapter partially reuses) has the goal to fulfil information needs of physicians. This chapter concentrates on information needs for medical cases that contain a large variety of data, from free text, structured data to images. Fusion techniques will be compared to combine the various information sources to supply cases similar to an example case given. This can supply physicians with answers to problems similar to the one they are analyzing and can help in diagnosis and treatment planning

Scale-dependent plant diversity in Palaearctic grasslands: a comparative overview

Here we present an extensive overview of plant diversity values in Palaearctic grasslands for seven standard grain sizes from 0.0001 to 100 m². The data originate from 20 studies, including the Field Workshops of the Eurasian Dry Grassland Group (EDGG), ranging geographically from Spain in the west to Siberia in the east, from Sicily in the south to Estonia in the north and from the sea coast up to 3100 m a.s.l. The majority of data is from dry grasslands (Festuco-Brometea, Koelerio-Corynephoretea, Cleistogenetea squarrosae), but there are also some mesic, wet, saline, acidic, alpine and Mediterranean grasslands included. Among others, we compiled data from 1795 1-m², 1109 10-m² and 338 100-m² plots. In all cases we present mean, minimum and maximum richness for the seven grain sizes, plus, in cases where also terricolous bryophytes and lichens had been recorded, the same values for total “plant” species richness, non-vascular plant species richness and fraction of non-vascular plants. The maximum richness values were 82, 101 and 134 for all “plants”, and 79, 98 and 127 vascular plants at grain sizes of 1 m², 10 m² and 100 m², respectively (all in Transylvania, Romania). Our overview comprises new, hitherto unpublished world records of vascular plant species richness at the scales of 0.0001 m² (9) and 0.001 m² (19, both shoot presence), from meso-xeric, basiphilous grasslands in Navarre, Spain, which is much higher than the previously known maxima. The highest values of non-vascular plant richness at 1 m², 10 m² and 100 m², respectively, were 49, 64 and 64, respectively (all in Sedo-Scleranthenea communities of Öland, Sweden, and Saaremaa, Estonia). In general, the dry, alpine and Mediterranean grasslands were much richer than the studied mesic, wet or saline grasslands at any spatial scale. The presented set of mean, minimum and maximum values and their metadata is publically available and will be continuously updated. These data can serve as a reference of “normal” richness, both in fundamental and applied research. To facilitate the application, we provide an easy formula based on the power-law species-area relationship that allows the estimation of richness values at intermediate grain sizes not included in our dataset. In conclusion, our data emphasise the role of Palaearctic grasslands as global hotspot of small-scale vascular plant diversity, while at the same time highlighting that in some grassland types also the bryophyte and lichen diversity can be extraordinarily high