tbuckley/cabot-search huggingface dataset:
OC-081 Defining Cirrhosis with Fibroscan for entry to Hepatocellular Carcinoma Surveillance in Chronic Hepatitis C: a UK Cost Effectiveness Analysis
Authors: C Canavan, K Corey, C Hur
Journal: Gut (2013)

<h3>Introduction</h3> Chronic hepatitis C (HCV) is a significant risk factor for cirrhosis and subsequently hepatocellular carcinoma (HCC). HCV patients with cirrhosis are screened for HCC every 6 months. Surveillance for progression to cirrhosis, and consequently access to HCC screening, is not standardised. Liver biopsy, the usual test to determine cirrhosis, carries a risk of significant morbidity. Ultrasound elastography (Fibroscan) is a non-invasive test for cirrhosis. This study assesses the cost effectiveness of annual surveillance for cirrhosis in chronic HCV and the effect of replacing biopsy with fibroscan to diagnose cirrhosis. <h3>Methods</h3> A Markov decision analytic model simulated a hypothetical cohort of 10000 patients with chronic HCV initially without fibrosis over their lifetime. Cirrhosis surveillance strategies assessed were: (A) no surveillance; (B) current practise; (C) fibroscan in current practise with biopsy to confirm cirrhosis; (D) fibroscan completely replacing biopsy in current practise (definitive); (E) annual biopsy; (F) annual fibroscan with biopsy to confirm cirrhosis; (G) annual definitive fibroscan. <h3>Results</h3> The model was calibrated with good visual fit. Annual definitive fibroscan is the optimal strategy choice. Sensitivity analysis shows this outcome to be robust. The cost-effective frontier holds strategies A and G with E dominated by extension. All other strategies are strictly dominated. It diagnoses 20% more cirrhosis than the current strategy, with 549 extra patients per 10000 accessing screening over a lifetime; consequently 76 additional HCCs are diagnosed. Lifetime cost is an additional £98.78 per patient compared to current strategy for an additional 1.72 unadjusted life years. Annual fibroscan surveillance of 132 patients diagnoses one additional HCC over a lifetime. The ICER for annual definitive fibroscan is £6557.06/QALY gained. <h3>Conclusion</h3> Annual definitive fibroscan may be a cost-effective surveillance strategy to identify cirrhosis in patients with chronic HCV to allow access to HCC screening. <h3>Disclosure of Interest</h3> None Declared
Fhit-Deficient Hematopoietic Stem Cells Survive Hydroquinone Exposure Carrying Precancerous Changes
Authors: Hideshi Ishii, Koshi Mimori, Kazuhiro Ishikawa, Hiroshi Okumura, Flavia Pichiorri, Teresa Druck, Hiroshi Inoue, Andrea Vecchione, Toshiyuki Saito, Masaki Mori, Kay Huebner
Journal: Cancer Research (2008)

Abstract The fragile FHIT gene is among the first targets of DNA damage in preneoplastic lesions, and recent studies have shown that Fhit protein is involved in surveillance of genome integrity and checkpoint response after genotoxin exposure. We now find that Fhit-deficient hematopoietic cells, exposed to the genotoxin hydroquinone, are resistant to the suppression of stem cell in vitro colony formation observed with wild-type (Wt) hematopoietic cells. In vivo–transplanted, hydroquinone-exposed, Fhit-deficient bone marrow cells also escaped the bone marrow suppression exhibited by Wt-transplanted bone marrow. Comparative immunohistochemical analyses of bone marrow transplants showed relative absence of Bax in Fhit-deficient bone marrow, suggesting insensitivity to apoptosis; assessment of DNA damage showed that occurrence of the oxidized base 8-hydroxyguanosine, a marker of DNA damage, was also reduced in Fhit-deficient bone marrow, as was production of intracellular reactive oxygen species. Treatment with the antioxidant N-acetyl-l-cysteine relieved hydroquinone-induced suppression of colony formation by Wt hematopoietic cells, suggesting that the decreased oxidative damage to Fhit-deficient cells, relative to Wt hematopoietic cells, accounts for the survival advantage of Fhit-deficient bone marrow. Homology-dependent recombination repair predominated in Fhit-deficient cells, although not error-free repair, as indicated by a higher incidence of 6-thioguanine–resistant colonies. Tissues of hydroquinone-exposed Fhit-deficient bone marrow–transplanted mice exhibited preneoplastic alterations, including accumulation of histone H2AX-positive DNA damage. The results indicate that reduced oxidative stress, coupled with efficient but not error-free DNA damage repair, allows unscheduled long-term survival of genotoxin-exposed Fhit-deficient hematopoietic stem cells carrying deleterious mutations. [Cancer Res 2008;68(10):3662–70]
2013 ACCF/AHA Guideline for the Management of Heart Failure
Authors: Clyde W. Yancy, Mariell Jessup, Biykem Bozkurt, Javed Butler, Donald E. Casey, Mark H. Drazner, Gregg C. Fonarow, Stephen A. Geraci, Tamara Horwich, James L. Januzzi, Maryl R. Johnson, Edward K. Kasper, Wayne C. Levy, Frederick A. Masoudi, Patrick E. McBride, John J.V. McMurray, Judith E. Mitchell, Pamela N. Peterson, Barbara Riegel, Flora Sam, Lynne W. Stevenson, W.H. Wilson Tang, Emily J. Tsai, Bruce L. Wilkoff
Journal: Journal of the American College of Cardiology (2013)
Operating characteristics of the negative expiratory pressure technique in predicting obstructive sleep apnoea syndrome in snoring patients
Authors: A Van Meerhaeghe
Journal: Thorax (2004)

This study examines the operating characteristics of the expiratory flow response to a negative pressure (NEP) applied to the mouth in the prediction of obstructive sleep apnoea syndrome (OSAS) in snoring patients.Two hundred and thirty eight patients with normal spirometric values were studied. Full laboratory polysomnography was performed and an NEP of -5 cm H(2)O was applied in the sitting and supine positions.A significant correlation was found between the degree of flow limitation measured by NEP in both positions (expressed as the percentage of the expired tidal volume over which NEP induced flow did not exceed spontaneous flow) and the apnoea-hypopnoea index (AHI). This correlation was significantly higher in the supine position (p<0.0001) where an expiratory flow limitation cut off value of >/=27.5% of the tidal volume produced a sensitivity of 81.9% and a specificity of 69.1% in predicting OSAS.These findings show that the degree of instability of the upper airway measured by NEP is correlated with the severity of OSAS. NEP had moderate sensitivity and specificity and may be useful in predicting OSAS in a clinic based population.
Case of Grave Lesion of Both Corpora Striata: Recovery from Hemiplegia; Extensive Cerebral Degeneration; Dementia; Death Twelve Days after Rupture of Intrathoracic Aneurism
Authors: W. J. Mickle
Journal: BMJ (1875)

of the teeth, thereby alring themselves with another weapon with which to combat pain anid suffering.In future lectures, I shall hope to have opportunities of showinig you examples of those direct and in- direct results of dental lesion to which I have alluded to-day, whilst I shall especially demonstrate to you those operations necessary to alle- viate pain or to arrest discase, whether temporarily or permanently, by more complicated means.AMy task will be a labour of love, if I can impress upon you the iilmportanice of my subject when considered in its highest rapports; whilst I shall feel that, in disseminating amongst you what little knowlcdge I lpossess, I shall be contributing in some small way towards the lightening of those burdens, and the assuage- ment of those miiany ills to whiclh fleslh is heir.
A Functional Tom70 in the Human Parasite Blastocystis sp.: Implications for the Evolution of the Mitochondrial Import Apparatus
Authors: A. D. Tsaousis, D. Gaston, A. Stechmann, P. B. Walker, T. Lithgow, A. J. Roger
Journal: Molecular Biology and Evolution (2010)

Core proteins of mitochondrial protein import are found in all mitochondria, suggesting a common origin of this import machinery. Despite the presence of a universal core import mechanism, there are specific proteins found only in a few groups of organisms. One of these proteins is the translocase of outer membrane 70 (Tom70), a protein that is essential for the import of preproteins with internal targeting sequences into the mitochondrion. Until now, Tom70 has only been found in animals and Fungi. We have identified a tom70 gene in the human parasitic anaerobic stramenopile Blastocystis sp. that is neither an animal nor a fungus. Using a combination of bioinformatics, genetic complementation, and immunofluorescence microscopy analyses, we demonstrate that this protein functions as a typical Tom70 in Blastocystis mitochondrion-related organelles. Additionally, we identified putative tom70 genes in the genomes of other stramenopiles and a haptophyte, that, in phylogenies, form a monophyletic group distinct from the animal and the fungal homologues. The presence of Tom70 in these lineages significantly expands the evolutionary spectrum of eukaryotes that contain this protein and suggests that it may have been part of the core mitochondrial protein import apparatus of the last common ancestral eukaryote.
Irreversible binding of zomepirac to plasma protein in vitro and in vivo.
Authors: P C Smith, A F McDonagh, L Z Benet
Journal: Journal of Clinical Investigation (1986)

Zomepirac is a nonsteroidal anti-inflammatory drug recently withdrawn from use because of an unexplained high incidence of immunological reactions. It is metabolized in humans to a reactive, unstable acyl glucuronide which accumulates in plasma. Because of the similarity of zomepirac glucuronide to bilirubin glucuronide in structure and stability and the documented irreversible binding of bilirubin to albumin through its acyl glucuronide, we studied the reaction of zomepirac acyl glucuronide with albumin in vitro from pH 5 to 9 and in vivo in six healthy human volunteers who had received a single 100-mg oral dose of zomepirac. Irreversible binding of zomepirac to protein was determined by exhaustive washing of protein, followed by hydrolysis of bound zomepirac-protein adduct with base, extraction of the liberated drug, and chromatographic measurement. Irreversible binding was observed both in vitro and in vivo. The extent of binding in vitro was time- and pH-dependent. In vitro drug binding was also observed for the isomers of zomepirac glucuronide which were formed by intramolecular acyl migration. Irreversible binding in vivo correlated with overall exposure to zomepirac glucuronide when exposure was expressed as the area under the plasma concentration vs. time curve. When probenecid (500 mg, twice daily), which decreases the plasma clearance of zomepirac glucuronide, was administered concurrently with zomepirac, irreversible binding of zomepirac was increased. The nature of the zomepirac protein binding is probably covalent. Formation of irreversibly protein-bound zomepirac occurs via the acyl glucuronide as previously shown for bilirubin glucuronide, and the reaction may be general for other drugs that are metabolized to acyl glucuronides.
Cytokines and pulmonary fibrosis.
Authors: J Gauldie, M Jordana, G Cox
Journal: Thorax (1993)

Chronically inflamed and fibrotic tissue of the respiratory tract can be shown to actively express the genes and products of a number of powerful growth and differentiating factors. The initial activation of lung inflammatory cells, including alveolar macrophages, is presumed to result in the release of early acting cytokines such as IL-1 and TNF. Subsequent activation and possible phenotype alteration of the structural cells results in release of other growth factors and accumulation of blood derived inflammatory cells. These cells, once they have entered the tissue and become further activated, may begin to release their own autocrine factors and "feed back" some of the similar signals to the tissue cells in a paracrine manner, further inducing differentiation and phenotype change. These internal tissue cell and cytokine cascades could account for the chronic nature of the inflammation. Therapeutic intervention must therefore take into account the inflammatory component as well as the nature of the cytokines and structural cells involved in the propagation of the disease.
CROHN'S DISEASE OF THE MOUTH
Authors: L. STANKLER, S. W. B. EWEN, N. W. KERR
Journal: British Journal of Dermatology (1972)

Journal Article CROHN'S DISEASE OF THE MOUTH Get access L. STANKLER, L. STANKLER Department of Dermatology, Aberdeen Royal Infirmary Search for other works by this author on: Oxford Academic Google Scholar S. W. B. EWEN, S. W. B. EWEN Department of Pathology, University of Aberdeen Search for other works by this author on: Oxford Academic Google Scholar N. W. KERR N. W. KERR Department of Dentistry, Aberdeen Royal Infirmary Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 87, Issue 5, 1 November 1972, Pages 501–504, https://doi.org/10.1111/j.1365-2133.1972.tb01599.x Published: 01 November 1972 Article history Accepted: 06 May 1972 Published: 01 November 1972
High-Density Lipoprotein Transport Through Aortic Endothelial Cells Involves Scavenger Receptor BI and ATP-Binding Cassette Transporter G1
Authors: Lucia Rohrer, Pascale M. Ohnsorg, Marc Lehner, Franziska Landolt, Franz Rinninger, Arnold von Eckardstein
Journal: Circulation Research (2009)

Cholesterol efflux from macrophage foam cells is a rate-limiting step in reverse cholesterol transport. In this process cholesterol acceptors like high-density lipoproteins (HDL) and apolipoprotein (apo)A-I must cross the endothelium to get access to the donor cells in the arterial intima. Previously, we have shown that apoA-I passes a monolayer of aortic endothelial cells (ECs) from the apical to the basolateral side by transcytosis, which is modulated by the ATP-binding cassette transporter (ABC)A1. Here, we analyzed the interaction of mature HDL with ECs. ECs bind HDL in a specific and saturable manner. Both cell surface biotinylation experiments and immunofluorescence microscopy of HDL recovered ≈30% of the cell-associated HDL intracellularly. Cultivated on inserts ECs bind, internalize, and translocate HDL from the apical to the basolateral compartment in a specific and temperature-dependent manner. The size of the translocated particle was reduced, but its protein moiety remained intact. Using RNA interference, we investigated the impact of SR-BI, ABCA1, and ABCG1 on binding, internalization, and transcytosis of HDL by ECs. HDL binding was reduced by 50% and 30% after silencing of SR-BI and ABCG1, respectively, but not at all after diminishing ABCA1 expression. Knock down of SR-BI and, even more so, ABCG1 reduced HDL transcytosis but did not affect inulin permeability. Cosilencing of both proteins did not further reduce HDL binding, internalization, or transport. In conclusion, ECs transcytose HDL by mechanisms that involve either SR-BI or ABCG1 but not ABCA1.
Quantitative analysis of potassium channel mRNA expression in atrial and ventricular muscle of rats.
Authors: J E Dixon, D McKinnon
Journal: Circulation Research (1994)

The expression of 15 different potassium channel genes in rat atrial and ventricular muscle was quantitatively compared by use of an RNase protection assay. Of these genes, only five, Kv1.2, Kv1.4, Kv1.5, Kv2.1, and Kv4.2, were expressed at significant levels in cardiac muscle. In comparisons of atrial and ventricular RNA samples, transcripts from the Kv1.2 and Kv4.2 genes showed the largest differences in relative abundance. There was an approximately twofold decrease in total Kv4 subfamily mRNA expression in atrial muscle relative to ventricular muscle and a 70% increase in total Kv1 subfamily mRNA. Variation of potassium channel mRNA expression within the left ventricular wall was also examined. There was a large gradient of Kv4.2 expression across the ventricular wall, and Kv4.2 expression in epicardial muscle was more than eight times higher than in papillary muscle. Other potassium channel genes were expressed at relatively uniform levels across the ventricular wall. The results suggest that transcriptional regulation makes a significant contribution to the control of potassium channel expression in cardiac muscle and to the variation of the electrophysiological phenotype of myocytes from different regions of the myocardium.
Healthy Eating and Risks of Total and Cause-Specific Death among Low-Income Populations of African-Americans and Other Adults in the Southeastern United States: A Prospective Cohort Study
Authors: Danxia Yu, Jennifer Sonderman, Maciej S. Buchowski, Joseph K. McLaughlin, Xiao-Ou Shu, Mark Steinwandel, Lisa B. Signorello, Xianglan Zhang, Margaret K. Hargreaves, William J. Blot, Wei Zheng
Journal: PLoS Medicine (2015)

Background A healthy diet, as defined by the US Dietary Guidelines for Americans (DGA), has been associated with lower morbidity and mortality from major chronic diseases in studies conducted in predominantly non-Hispanic white individuals. It is unknown whether this association can be extrapolated to African-Americans and low-income populations. Methods and Findings We examined the associations of adherence to the DGA with total and cause-specific mortality in the Southern Community Cohort Study, a prospective study that recruited 84,735 American adults, aged 40–79 y, from 12 southeastern US states during 2002–2009, mostly through community health centers that serve low-income populations. The present analysis included 50,434 African-Americans, 24,054 white individuals, and 3,084 individuals of other racial/ethnic groups, among whom 42,759 participants had an annual household income less than US$15,000. Usual dietary intakes were assessed using a validated food frequency questionnaire at baseline. Adherence to the DGA was measured by the Healthy Eating Index (HEI), 2010 and 2005 editions (HEI-2010 and HEI-2005, respectively). During a mean follow-up of 6.2 y, 6,906 deaths were identified, including 2,244 from cardiovascular disease, 1,794 from cancer, and 2,550 from other diseases. A higher HEI-2010 score was associated with lower risks of disease death, with adjusted hazard ratios (HRs) of 0.80 (95% CI, 0.73–0.86) for all-disease mortality, 0.81 (95% CI, 0.70–0.94) for cardiovascular disease mortality, 0.81 (95% CI, 0.69–0.95) for cancer mortality, and 0.77 (95% CI, 0.67–0.88) for other disease mortality, when comparing the highest quintile with the lowest (all p-values for trend < 0.05). Similar inverse associations between HEI-2010 score and mortality were observed regardless of sex, race, and income (all p-values for interaction > 0.50). Several component scores in the HEI-2010, including whole grains, dairy, seafood and plant proteins, and ratio of unsaturated to saturated fatty acids, showed significant inverse associations with total mortality. HEI-2005 score was also associated with lower disease mortality, with a HR of 0.86 (95% CI, 0.79–0.93) when comparing extreme quintiles. Given the observational study design, however, residual confounding cannot be completely ruled out. In addition, future studies are needed to evaluate the generalizability of these findings to African-Americans of other socioeconomic status. Conclusions Our results showed, to our knowledge for the first time, that adherence to the DGA was associated with lower total and cause-specific mortality in a low-income population, including a large proportion of African-Americans, living in the southeastern US.
Delivery of siRNA to the Mouse Lung via a Functionalized Lipopolyamine
Authors: Kevin J Polach, Majed Matar, Jennifer Rice, Gregory Slobodkin, Jeff Sparks, Richard Congo, Angela Rea-Ramsey, Diane McClure, Elaine Brunhoeber, Monika Krampert, Andrea Schuster, Kerstin Jahn-Hofmann, Matthias John, Hans-Peter Vornlocher, Jason G Fewell, Khursheed Anwer, Anke Geick
Journal: Molecular Therapy (2011)

We have designed a series of versatile lipopolyamines which are amenable to chemical modification for in vivo delivery of small interfering RNA (siRNA). This report focuses on one such lipopolyamine (Staramine), its functionalized derivatives and the lipid nanocomplexes it forms with siRNA. Intravenous (i.v.) administration of Staramine/siRNA nanocomplexes modified with methoxypolyethylene glycol (mPEG) provides safe and effective delivery of siRNA and significant target gene knockdown in the lungs of normal mice, with much lower knockdown in liver, spleen, and kidney. Although siRNA delivered via Staramine is initially distributed across all these organs, the observed clearance rate from the lung tissue is considerably slower than in other tissues resulting in prolonged siRNA accumulation on the timescale of RNA interference (RNAi)-mediated transcript depletion. Complete blood count (CBC) analysis, serum chemistry analysis, and histopathology results are all consistent with minimal toxicity. An in vivo screen of mPEG modified Staramine nanocomplexes-containing siRNAs targeting lung cell-specific marker proteins reveal exclusive transfection of endothelial cells. Safe and effective delivery of siRNA to the lung with chemically versatile lipopolyamine systems provides opportunities for investigation of pulmonary cell function in vivo as well as potential treatments of pulmonary disease with RNAi-based therapeutics.
Genetic Differentiation of Hypothalamus Parentally Biased Transcripts in Populations of the House Mouse Implicate the Prader–Willi Syndrome Imprinted Region as a Possible Source of Behavioral Divergence
Authors: Anna Lorenc, Miriam Linnenbrink, Inka Montero, Markus B. Schilhabel, Diethard Tautz
Journal: Molecular Biology and Evolution (2014)

Parentally biased expression of transcripts (genomic imprinting) in adult tissues, including the brain, can influence and possibly drive the evolution of behavioral traits. We have previously found that paternally determined cues are involved in population-specific mate choice decisions between two populations of the Western house mouse (Mus musculus domesticus). Here, we ask whether this could be mediated by genomically imprinted transcripts that are subject to fast differentiation between these populations. We focus on three organs that are of special relevance for mate choice and behavior: The vomeronasal organ (VNO), the hypothalamus, and the liver. To first identify candidate transcripts at a genome-wide scale, we used reciprocal crosses between M. m. domesticus and M. m. musculus inbred strains and RNA sequencing of the respective tissues. Using a false discovery cutoff derived from mock reciprocal cross comparisons, we find a total of 66 imprinted transcripts, 13 of which have previously not been described as imprinted. The largest number of imprinted transcripts were found in the hypothalamus; fewer were found in the VNO, and the least were found in the liver. To assess molecular differentiation and imprinting in the wild-derived M. m. domesticus populations, we sequenced the RNA of the hypothalamus from individuals of these populations. This confirmed the presence of the above identified transcripts also in wild populations and allowed us to search for those that show a high genetic differentiation between these populations. Our results identify the Ube3a-Snrpn imprinted region on chromosome 7 as a region that encompasses the largest number of previously not described transcripts with paternal expression bias, several of which are at the same time highly differentiated. For four of these, we confirmed their imprinting status via single nucleotide polymorphism-specific pyrosequencing assays with RNA from reciprocal crosses. In addition, we find the paternally expressed Peg13 transcript within the Trappc9 gene region on chromosome 15 to be highly differentiated. Interestingly, both regions have been implicated in Prader-Willi nervous system disorder phenotypes in humans. We suggest that these genomically imprinted regions are candidates for influencing the population-specific mate-choice in mice.