tbuckley/cabot-search huggingface dataset:
Defective TAFI activation in hemophilia A mice is a major contributor to joint bleeding
Authors: Tine Wyseure, Esther J. Cooke, Paul J. Declerck, Niels Behrendt, Joost C. M. Meijers, Annette von Drygalski, Laurent O. Mosnier
Journal: Blood (2018)

Joint bleeds are common in congenital hemophilia but rare in acquired hemophilia A (aHA) for reasons unknown. To identify key mechanisms responsible for joint-specific bleeding in congenital hemophilia, bleeding phenotypes after joint injury and tail transection were compared in aHA wild-type (WT) mice (receiving an anti-factor VIII [FVIII] antibody) and congenital HA (FVIII
Reduction of measurement noise in a continuous glucose monitor by coating the sensor with a zwitterionic polymer
Authors: Xi Xie, Joshua C. Doloff, Volkan Yesilyurt, Atieh Sadraei, James J. McGarrigle, Mustafa Omami, Omid Veiseh, Shady Farah, Douglas Isa, Sofia Ghani, Ira Joshi, Arturo Vegas, Jie Li, Weiheng Wang, Andrew Bader, Hok Hei Tam, Jun Tao, Hui-jiuan Chen, Boru Yang, Katrina Ann Williamson, Jose Oberholzer, Robert Langer, Daniel G. Anderson
Journal: Nature Biomedical Engineering (2018)
Macrophage Migration Inhibitory Factor in Cardiovascular Disease
Authors: AlmaZernecke, JürgenBernhagen, ChristianWeber
Journal: Circulation (2008)

The highly conserved and archetypical yet atypical cytokine macrophage migration inhibitory factor (MIF) fulfills pleiotropic immune functions in many acute and chronic inflammatory diseases. Recent evidence has emerged from both expression and functional studies to implicate MIF in various aspects of cardiovascular disease. The present review is aimed at providing a synopsis of the involvement of MIF in the inflammatory pathogenesis of atherosclerosis and its consequences, namely unstable plaque formation, remodeling after arterial injury, aneurysm formation, myocardial infarction, or ischemia-reperfusion injury. In addition, other forms of myocardial dysfunction and inflammation and the role of MIF in angiogenesis are reviewed. The functional data are reconciled with recent progress in the identification of heptahelical (CXC chemokine) receptors for MIF, its prototypic role as their noncanonical ligand, and its signal transduction profile operative in atherogenic and inflammatory recruitment of mononucl...
Multi-OMICS analyses unveil <i>STAT1</i> as a potential modifier gene in mevalonate kinase deficiency
Authors: Raphael Carapito, Christine Carapito, Aurore Morlon, Nicodème Paul, Alvaro Sebastian Vaca Jacome, Ghada Alsaleh, Véronique Rolli, Ouria Tahar, Ismail Aouadi, Magali Rompais, François Delalande, Angélique Pichot, Philippe Georgel, Laurent Messer, Jean Sibilia, Sarah Cianferani, Alain Van Dorsselaer, Seiamak Bahram
Journal: Annals of the Rheumatic Diseases (2018)

Objectives The objective of the present study was to explain why two siblings carrying both the same homozygous pathogenic mutation for the autoinflammatory disease hyper IgD syndrome, show opposite phenotypes, that is, the first being asymptomatic, the second presenting all classical characteristics of the disease. Methods Where single omics (mainly exome) analysis fails to identify culprit genes/mutations in human complex diseases, multiomics analyses may provide solutions, although this has been seldom used in a clinical setting. Here we combine exome, transcriptome and proteome analyses to decipher at a molecular level, the phenotypic differences between the two siblings. Results This multiomics approach led to the identification of a single gene —STAT1 —which harboured a rare missense variant and showed a significant overexpression of both mRNA and protein in the symptomatic versus the asymptomatic sister. This variant was shown to be of gain of function nature, involved in an increased activation of the Janus kinase/signal transducer and activator of transcription signalling (JAK/STAT) pathway, known to play a critical role in inflammatory diseases and for which specific biotherapies presently exist. Pathway analyses based on information from differentially expressed transcripts and proteins confirmed the central role of STAT1 in the proposed regulatory network leading to an increased inflammatory phenotype in the symptomatic sibling. Conclusions This study demonstrates the power of a multiomics approach to uncover potential clinically actionable targets for a personalised therapy. In more general terms, we provide a proteogenomics analysis pipeline that takes advantage of subject-specific genomic and transcriptomic information to improve protein identification and hence advance individualised medicine.
Residential Surrounding Greenness and Cognitive Decline: A 10-Year Follow-up of the Whitehall II Cohort
Authors: Carmen de Keijzer, Cathryn Tonne, Xavier Basagaña, Antònia Valentín, Archana Singh-Manoux, Jordi Alonso, Josep Maria Antó, Mark J. Nieuwenhuijsen, Jordi Sunyer, Payam Dadvand
Journal: Environmental Health Perspectives (2018)

Evidence on beneficial associations of green space with cognitive function in older adults is very scarce and mainly limited to cross-sectional studies.We aimed to investigate the association between long-term residential surrounding greenness and cognitive decline.This longitudinal study was based on three waves of data from the Whitehall II cohort, providing a 10-y follow-up (1997-1999 to 2007-2009) of 6,506 participants (45-68 y old) from the United Kingdom. Residential surrounding greenness was obtained across buffers of 500 and around the participants' residential addresses at each follow-up using satellite images on greenness (Normalized Difference Vegetation Index; NDVI) from a summer month in every follow-up period. Cognitive tests assessed reasoning, short-term memory, and verbal fluency. The cognitive scores were standardized and summarized in a global cognition z-score. To quantify the impact of greenness on repeated measurements of cognition, linear mixed effect models were developed that included an interaction between age and the indicator of greenness, and controlled for covariates including individual and neighborhood indicators of socioeconomic status (SES).In a fully adjusted model, an interquartile range (IQR) increase in NDVI was associated with a difference in the global cognition z-score of 0.020 [95% confidence interval (CI): 0.003, 0.037; p=0.02] in the 500-m buffer and of 0.021 (95% CI: 0.003, 0.039; p=0.02) in the 1,000-m buffer over 10 y. The associations with cognitive decline over the study period were stronger among women than among men.Higher residential surrounding greenness was associated with slower cognitive decline over a 10-y follow-up period in the Whitehall II cohort of civil servants. https://doi.org/10.1289/EHP2875.
Prevalence of Prenatal Depression Symptoms Among 2 Generations of Pregnant Mothers
Authors: Rebecca M. Pearson, Rebecca E. Carnegie, Callum Cree, Claire Rollings, Louise Rena-Jones, Jonathan Evans, Alan Stein, Kate Tilling, Melanie Lewcock, Debbie A. Lawlor
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Depression during pregnancy (prenatal depression) is common and has important consequences for mother and child. Evidence suggests an increasing prevalence of depression, especially in young women. It is unknown whether this is reflected in an increasing prevalence of prenatal depression. <h3>Objective</h3> To compare the prevalence of depression during pregnancy in today's young mothers with their mothers' generation. <h3>Design, Setting, and Participants</h3> In a longitudinal cohort study, we compared prenatal depressive symptoms in 2 generations of women who participated in the Avon Longitudinal Study of Parents and Children. Participants were the original mothers (recruited when they were pregnant) and their female offspring, or female partners of male offspring, who became pregnant. Both groups were limited to the same age range (19-24 years). The first generation of pregnancies occurred in 1990 to 1992 (n = 2390) and the second in 2012 to 2016 (n = 180). In both generations, women were born in the same geographical area (southwest England). <h3>Main Outcomes and Measures</h3> Depressed mood measured prenatally using the Edinburgh Postnatal Depression Scale in self-reported surveys in both generations. A score of 13 or greater on a scale of 0 to 30 indicated depressed mood. <h3>Results</h3> Of 2390 pregnant women in the first generation who were included in analysis (mean [SD] age, 22.1 [2.5] years), 408 (17%) had high depressive symptom scores (≥13). Of 180 pregnant women in the second generation who were included in the analysis (mean [SD] age, 22.8 [1.3] years), 45 (25%) had high depressive symptom scores. Having high depressive symptom scores was more common in the second generation of young pregnant women than in their mothers' generation (relative risk, 1.51; 95% CI, 1.15-1.97), with imputation for missing confounding variable data and adjustment for age, parity, education, smoking, and body mass index not substantially changing this difference. Results were essentially the same when analyses were restricted to the 66 mother-offspring pairs. Maternal prenatal depression was associated with daughters' prenatal depression (relative risk, 3.33; 95% CI, 1.65-6.67). <h3>Conclusions and Relevance</h3> In this unique study of 2 generations of women who answered identical questionnaires in pregnancy, evidence was found that depressed mood may be higher in young pregnant women today than in their mothers' generation. Because of the multiple and diverse consequences of prenatal depression, an increase in prevalence has important implications for families, health care professionals, and society.
Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression
Authors: Khaled Aziz, Cynthia J. Sieben, Karthik B. Jeganathan, Masakazu Hamada, Brian A. Davies, Raul O. Fierro Velasco, Nazneen Rahman, David J. Katzmann, Jan M. van Deursen
Journal: Journal of Clinical Investigation (2018)

A homozygous truncating frameshift mutation in CEP57 (CEP57T/T) has been identified in a subset of mosaic-variegated aneuploidy (MVA) patients; however, the physiological roles of the centrosome-associated protein CEP57 that contribute to disease are unknown. To investigate these, we have generated a mouse model mimicking this disease mutation. Cep57T/T mice died within 24 hours after birth with short, curly tails and severely impaired vertebral ossification. Osteoblasts in lumbosacral vertebrae of Cep57T/T mice were deficient for Fgf2, a Cep57 binding partner implicated in diverse biological processes, including bone formation. Furthermore, a broad spectrum of tissues of Cep57T/T mice had severe aneuploidy at birth, consistent with the MVA patient phenotype. Cep57T/T mouse embryonic fibroblasts and patient-derived skin fibroblasts failed to undergo centrosome maturation in G2 phase, causing premature centriole disjunction, centrosome amplification, aberrant spindle formation, and high rates of chromosome missegregation. Mice heterozygous for the truncating frameshift mutation or a Cep57-null allele were overtly indistinguishable from WT mice despite reduced Cep57 protein levels, yet prone to aneuploidization and cancer, with tumors lacking evidence for loss of heterozygosity. This study identifies Cep57 as a haploinsufficient tumor suppressor with biologically diverse roles in centrosome maturation and Fgf2-mediated bone formation.
Activation of Lung p53 by Nutlin-3a Prevents and Reverses Experimental Pulmonary Hypertension
Authors: NathalieMouraret, ElisabethMarcos, ShariqAbid, GuillaumeGary-Bobo, MirnaSaker, AmalHoussaini, Jean-LucDubois-Rande, LaurentBoyer, JorgeBoczkowski, GenevièveDerumeaux, ValérieAmsellem, SergeAdnot
Journal: Circulation (2013)

Background—Induction of cellular senescence through activation of the p53 tumor suppressor protein is a new option for treating proliferative disorders. Nutlins prevent the ubiquitin ligase MDM2 (murine double minute 2), a negative p53 regulator, from interacting with p53. We hypothesized that cell senescence induced by Nutlin-3a exerted therapeutic effects in pulmonary hypertension (PH) by limiting the proliferation of pulmonary artery smooth muscle cells (PA-SMCs). Methods and Results—Nutlin-3a treatment of cultured human PA-SMCs resulted in cell growth arrest with the induction of senescence but not apoptosis; increased phosphorylated p53 protein levels; and expression of p53 target genes including p21, Bax, BTG2, and MDM2. Daily intraperitoneal Nutlin-3a treatment for 3 weeks dose-dependently reduced PH, right ventricular hypertrophy, and distal pulmonary artery muscularization in mice exposed to chronic hypoxia or SU5416/hypoxia. Nutlin-3a treatment also partially reversed PH in chronically hypoxic o...
Risk factors for colistin-resistant Enterobacteriaceae in a low-endemicity setting for carbapenem resistance – a matched case–control study
Authors: Andrea C Büchler, Christian Gehringer, Andreas F Widmer, Adrian Egli, Sarah Tschudin-Sutter
Journal: Eurosurveillance (2018)

BackgroundEmergence of colistin resistance has been related to increased use in clinical settings, following global spread of carbapenem-resistant Gram-negative bacteria. Use of colistin in animal production may constitute a further source of spread of resistant strains to humans. We sought to determine risk factors for human colonisation or infection with colistin-resistant Escherichia coli and Klebsiella pneumoniae in a setting where colistin is mainly used for animal production. Methods: This retrospective matched case-control study was performed during a 5-year period at two university-affiliated hospitals in Basel, Switzerland. Conditional univariable logistic regression was used to calculate odds ratios (OR) for colistin resistance. All variables found to be significant in univariable analyses were included in the conditional multivariable regression model using stepwise forward and backward selection. Results: Forty-two cases (33 with colistin-resistant E. coli, 9 with colistin-resistant K. pneumoniae) and 126 matched controls were identified. Baseline characteristics, comorbidities, prior exposure to antibiotics and healthcare settings did not differ between cases and controls, except for prior exposure to carbapenems, hospitalisation and stay abroad during the prior 3 months. In multivariable analyses, only prior exposure to carbapenems remained associated with colistin resistance (OR: 5.00; 95% confidence interval (95% CI): 1.19-20.92; p = 0.028). Conclusion: In a low-endemicity setting for carbapenem resistance, prior exposure to carbapenems was the only risk factor for colonisation or infection with colistin-resistant E. coli or K. pneumoniae. Prior exposure to colistin was not significantly associated with detection of colistin resistance, which mainly occurred in the absence of concurrent carbapenem resistance.
Research for health in the Americas
Authors: Carissa Etienne, Kamran Abbasi, Luis Gabriel Cuervo
Journal: BMJ (2018)

This article is part of a series proposed by PAHO and commissioned by The BMJ, which peer reviewed, edited, and made the decision to publish the article with no involvement from PAHO. Open access fees for the series are funded by PAHO. Provenance and peer review: Commissioned; not externally peer reviewed.
Abstract 14178: Incidence of Bleeding Events in Patients with Atrial Fibrillation
Authors: Tarita Murray-Thomas, Arlene Gallagher, Andreas Clemens, Diana Ackermann, Dorothee Bartels
Journal: Circulation (2012)

Objective:  To describe the characteristics of patients with non-valvular atrial fibrillation (NVAF) and to estimate the incidence of major bleeding events in patients with AF.   Methods:  A cohort study in newly diagnosed NVAF patients (2005-2010) was performed in the General Practice Research Database (GPRD). Linked data to the Hospital Episode Statistics and death certificates from the Office for National Statistics were included. Major bleeding was defined as primary hospital admission diagnosis based on previously published ICD-10 algorithms and stratified by intra-, extracranial and gastrointestinal (GI) bleeding. Current vitamin K antagonists (VKA) treatment was defined as a valid prescription/INR measurement during the last 28 days, recent as a treatment period from 28 to 90 days, and past treatment as more than 90 days. No treatment was the time between diagnosis of AF and first prescription/INR measurement, or the whole follow-up for patients that have never been treated.   Results:  Data from 16,513 AF patients could be linked; 48% were female, the mean age (std) was 74 (12) years, the median duration of follow-up was 1.7 years (range 0-5). According to CHADS 2  score 21% were at low risk, 61% at moderate and 18% at high risk for stroke. Overall 55.8% of the patients had at least one period of VKA use, and 782 bleeding events were recorded (n=120 intra-, n=662 extracranial including n=209 GI). The crude incidence rate (IR) per 100 patient years (95% CIs)) of all bleeds was 2.5 (2.3-2.7) and for fatal bleeds 0.2 (0.2-0.3). The IR of intracranial bleeds was 0.4 (0.3-0.5), 38% of them were fatal. The IR of extracranial bleeds was 2.1 (2.0-2.3), 3% were fatal; GI bleeds occurred with an IR of 0.7 (0.6-0.8), 8% were fatal. Stratification by period of VKA use resulted in IR for current, recent, past and no use for all bleeds of 3.0 (2.6-3.3), 3.4 (2.7-4.3), 2.0 (1.5-2.5), and 2.2 (1.9-2.4).   Conclusion:  Current and recent users of VKAs had higher bleeding rates than past/no users. The IR of bleedings in non-users might indicate contra-indications for VKA use and/or presence of additional risk factors for bleeding, such as e.g. concomitant medications (aspirin) or comorbidities (renal impairment). However, no causal conclusions can be drawn from these crude incidence estimates.
Treatments for Crohn’s Disease–Associated Bowel Damage: A Systematic Review
Authors: Benjamin Pariente, Shurong Hu, Dominik Bettenworth, Silvia Speca, Pierre Desreumaux, Marie-Alice Meuwis, Silvio Danese, Florian Rieder, Edouard Louis
Journal: Clinical Gastroenterology and Hepatology (2018)
Parenteral Opioid Shortage — Treating Pain during the Opioid-Overdose Epidemic
Authors: Eduardo Bruera
Journal: New England Journal of Medicine (2018)

Parenteral Opioid Shortage Various measures have resulted in a reduction in the quantity of opioids prescribed in the United States, but there have been unintended consequences — including severe shortages of the three most commonly used parenteral opioids: morphine, hydromorphone, and fentanyl.
Phyto-phospholipid complexes (phytosomes): A novel strategy to improve the bioavailability of active constituents
Authors: Mei Lu, Qiujun Qiu, Xiang Luo, Xinrong Liu, Jing Sun, Cunyang Wang, Xiangyun Lin, Yihui Deng, Yanzhi Song
Journal: Asian Journal of Pharmaceutical Sciences (2018)

Although active constituents extracted from plants show robust in vitro pharmacological effects, low in vivo absorption greatly limits the widespread application of these compounds. A strategy of using phyto-phospholipid complexes represents a promising approach to increase the oral bioavailability of active constituents, which is consist of ''label-friendly" phospholipids and active constituents. Hydrogen bond interactions between active constituents and phospholipids enable phospholipid complexes as an integral part. This review provides an update on four important issues related to phyto-phospholipid complexes: active constituents, phospholipids, solvents, and stoichiometric ratios. We also discuss recent progress in research on the preparation, characterization, structural verification, and increased bioavailability of phyto-phospholipid complexes.
Asthma diagnosis using integrated analysis of eosinophil microRNAs
Authors: José M. Rodrigo‐Muñoz, José A. Cañas, Beatriz Sastre, Natalia Rego, Gonzalo Greif, Manuel Rial, Pablo Mínguez, Ignacio Mahíllo‐Fernández, Mar Fernández‐Nieto, Inés Mora, Pilar Barranco, Santiago Quirce, Joaquín Sastre, Victoria del Pozo
Journal: Allergy (2018)

Asthma is a syndrome characterized by airway inflammation and obstruction. Due to its heterogeneity, the difficulties in asthma diagnosis and treatment make the discovery of new biomarkers a focus of research. So, we determined the differential miRNA expression of eosinophils between healthy and asthmatic patients and to establish a differentially expressed miRNA profile detectable in sera for use as biomarker.MicroRNAs from peripheral eosinophils from healthy and asthmatic subjects were isolated and analyzed by next-generation sequencing and confirmed by quantitative PCR in 29 asthmatics and 10 healthy individuals. The levels of serum miRNAs were performed by quantitative PCR in 138 asthmatics and 39 healthy subjects. Regression analysis and Random Forest models were performed.We found a set of miRNAs whose expression differs between eosinophils from asthmatics and healthy subjects. These miRNAs can classify asthmatics into two clusters that differed in the number of eosinophils and periostin concentration in serum. Some of these miRNAs were also confirmed in sera, as miR-185-5p which discriminates asthmatics from healthy subjects. Together with other two miRNAs, miR-185-5p allowed us to create a logistic regression model to discriminate better both conditions and a Random Forest model that can even sort the asthmatics into intermittent, mild persistent, moderate persistent, and severe persistent asthma.Our data show that miRNAs profile in eosinophils can be used as asthma diagnosis biomarker in serum and that this profile is able to rank asthma severity.
Serotonin Transporter Inhibition Prevents and Reverses Monocrotaline-Induced Pulmonary Hypertension in Rats
Authors: ChristopheGuignabert, BernadetteRaffestin, RimaBenferhat, WilliamRaoul, PatriciaZadigue, DominiqueRideau, MichelHamon, SergeAdnot, SaadiaEddahibi
Journal: Circulation (2005)

Background— Progression of pulmonary hypertension (PH) is associated with increased lung expression of the serotonin transporter (5-HTT), which leads to hyperplasia of the pulmonary artery smooth muscle cells (PA-SMCs). Given the postulated causal relation between 5-HTT overexpression and PH, we herein investigated whether the highly selective 5-HTT inhibitor fluoxetine prevented and/or reversed PH induced by monocrotaline (MCT) in rats. Selective 5-HT1B/1D, 5-HT2A, and 5-HT2B receptor antagonists were used for comparative testing. Methods and Results— MCT injection (60 mg/kg SC) was followed by an early peak in lung 5-HTT expression on day 1, which preceded the onset of PH. Established PH on day 15 was associated with a sustained 5-HTT increase. Continued fluoxetine treatment completely prevented PA-SMC proliferation and PH development and also suppressed the late 5-HTT increase, without affecting the early peak. The 5-HT receptor antagonists did not affect PH. Fluoxetine (10 mg · kg−1 · d−1 PO) started ...
Adjustment of dendritic cells to the breast-cancer microenvironment is subset specific
Authors: Paula Michea, Floriane Noël, Eve Zakine, Urszula Czerwinska, Philémon Sirven, Omar Abouzid, Christel Goudot, Alix Scholer-Dahirel, Anne Vincent-Salomon, Fabien Reyal, Sebastian Amigorena, Maude Guillot-Delost, Elodie Segura, Vassili Soumelis
Journal: Nature Immunology (2018)
FDG PET/CT of Metabolic Myopathy With Posttreatment Follow-up
Authors: Anitia McNamee, Thomas Robertson, Brett Sounness, Patricia O’Gorman
Journal: Clinical Nuclear Medicine (2018)

Abstract A 38-year-old woman presented with extreme fatigue and multiple lung nodules. She was referred for a PET/CT, which demonstrated multiple FDG-avid pulmonary nodules and lymph nodes with intense uptake within multiple muscle groups predominantly involving the paraspinal muscles and muscles of mastication. Histopathology of a paraspinal muscle biopsy revealed increased skeletal muscle lipid stores and increased mitochondria with normal morphology. This abnormality is seen in metabolic myopathy due to a disorder of fatty acid oxidation. Transbronchial biopsy showed no evidence of sarcoidosis. The patient was commenced on carnitine and riboflavin supplementation, and a follow-up PET/CT was performed.