tbuckley/cabot-search huggingface dataset:
Cystic fibrosis neutrophils have normal intrinsic reactive oxygen species generation
Authors: D. J. McKeon, K. A. Cadwallader, S. Idris, A. S. Cowburn, M. C. Pasteur, H. Barker, C. S. Haworth, D. Bilton, E. R. Chilvers, A. M. Condliffe
Journal: European Respiratory Journal (2009)

Previous studies have identified abnormalities in the oxidative responses of the neutrophil in cystic fibrosis (CF), but it is unclear whether such changes relate to loss of membrane cystic fibrosis transmembrane conductance regulator (CFTR) or to the inflammatory environment present in this disease. The aim of the present study was to determine whether neutrophils from CF patients demonstrate an intrinsic abnormality of the respiratory burst. The respiratory burst activity of neutrophils isolated from stable ΔF508 homozygote CF patients and matched healthy controls was quantified by both chemiluminscence and cytochrome C reduction. Expression of NADPH oxidase components and CFTR was determined by Western blotting and RT-PCR. The oxidative output from neutrophils from CF in response to receptor-linked and particulate stimuli did not differ from that of controls. Expression of NADPH oxidase components was identical in CF and non-CF neutrophils. While low levels of CFTR mRNA could be identified in the normal human neutrophil, we were unable to detect CFTR protein in human neutrophil lysates or immunoprecipitates. CFTR has no role in controlling neutrophil oxidative activity; previously reported differences in neutrophil function between CF and non-CF subjects most likely relate to the inflammatory milieu from which the cells were isolated.
PTU-033 The Utility Of Narrow Band Imaging Endoscopy In Identifying Potential Causes Of Iron Deficiency Anaemia In The Absence Of Any Overt Gi Cause: Abstract PTU-033 Table 1
Authors: JR White, S Sami, J Ortiz Fernández-Sordo, J Mannath, K Ragunath
Journal: Gut (2014)

<h3>Introduction</h3> IDA is prevalent in up to 5% of the developed world and endoscopy remains the most utilised investigation. Magnified white light endoscopy has been shown to accurately identify gastric atrophy, <i>H. pylori</i> gastritis and coeliac disease but the role of magnified NBI endoscopy (NBI-Z) in this context has not been evaluated. The study aim was to assess the ability of NBI-Z to make a real time diagnosis of these conditions compared to histology as the gold standard. <h3>Methods</h3> This prospective cohort study recruited patients undergoing endoscopic evaluation for IDA. All procedures were performed with an Olympus video endoscopy system by clinicians with advanced imaging experience. Systematic NBI-Z imaging in parts of the duodenum and gastric mucosa were taken with corresponding biopsies. A previously validated Nottingham Type 1–4 classification system was used to classify the characteristic gastric mucosal pit pattern, and magnified morphological features were used to describe intestinal metaplasia and villous atrophy. This allowed for a real time diagnosis to be made for villous atrophy, gastric atrophy and <i>H. pylori</i> gastritis. The specimens were examined by a single blinded GI pathologist. <h3>Results</h3> 105 patients were recruited over 3 years. Excluding those with an obvious cause (n = 11), a total of 94 patients were included in the final analysis. Female: male ratio was 1: 0.7, median age 66 years (range 21–85). 38% had significant co-morbidities. At time of endoscopy 52% were taking iron therapy, 19% aspirin, 30% PPI and 4% NSAIDs. The median (range) anaemia parameters were: Hb 10.8g/dL (7.7–12.6), MCV 82fl (60–97), Ferritin 10g/L (1–379) and iron 7.5 µmol/L (1–22). 73% had the procedure under sedation with median doses of 2.5 mg midazolam and 25 mg pethidine. <h3>Conclusion</h3> In patients with IDA, NBI-Z is highly specific in providing a real time diagnosis of gastric atrophy and coeliac disease. It is a useful technique to exclude <i>H. pylori</i> gastritis. The clinical relevance is that this technique allows for targeted biopsies, reducing the miss rate and thus increasing the diagnostic yield. <h3>Disclosure of Interest</h3> J. White: None Declared, S. Sami: None Declared, J. Ortiz Fernández-Sordo: None Declared, J. Mannath: None Declared, K. Ragunath Grant/research support from: Olympus-Keymed UK, Speaker honoraria and consultancy fees from: Olympus-Keymed UK.
The histone deacetylase 4/SP1/microrna-200a regulatory network contributes to aberrant histone acetylation in hepatocellular carcinoma
Authors: Ji-hang Yuan, Fu Yang, Bi-feng Chen, Zhi Lu, Xi-song Huo, Wei-ping Zhou, Fang Wang, Shu-han Sun
Journal: Hepatology (2010)

Abstract As an important epigenetic mechanism, histone acetylation modulates the transcription of many genes and plays important roles in hepatocellular carcinoma (HCC). Aberrations in histone acetylation have been observed in HCC, but the factors that contribute to the aberrations have not been fully elucidated. MicroRNAs (miRNAs), which are noncoding RNAs that regulate gene expression, are involved in important epigenetic mechanisms. In this study, we determined that miR-200a and the level of histone H3 acetylation at its promoter were reduced in human HCC tissues in comparison with adjacent noncancerous hepatic tissues. Furthermore, our results suggested that the histone deacetylase 4 (HDAC4) inhibited the expression of miR-200a and its promoter activity and reduced the histone H3 acetylation level at the mir-200a promoter through a Sp1-dependent pathway. Interestingly, we observed that the miR-200a directly targeted the 3′-untranslated region of the HDAC4 messenger RNA and repressed expression of HDAC4. Therefore, miR-200a ultimately induced its own transcription and increased the histone H3 acetylation level at its own promoter. Through targeting HDAC4, miR-200a also induced the up-regulation of total acetyl-histone H3 levels and increased the histone H3 acetylation level at the p21 WAF/Cip1 promoter. Finally, we determined that miR-200a inhibited the proliferation and migration of HCC cells in vivo and in vitro . Conclusion: Our findings suggest that the HDAC4/Sp1/miR-200a regulatory network induces the down-regulation of miR-200a and the up-regulation of HDAC4 in HCC. As a result, down-regulation of miR-200a enhances the proliferation and migration of HCC cells and induces aberrant histone acetylation in HCC. These findings highlight a potential therapeutic approach in targeting the HDAC4/Sp1/miR-200a regulatory network for the treatment of HCC. (Hepatology 2011
Dual Effect of Metformin on Breast Cancer Proliferation in a Randomized Presurgical Trial
Authors: Bernardo Bonanni, Matteo Puntoni, Massimiliano Cazzaniga, Giancarlo Pruneri, Davide Serrano, Aliana Guerrieri-Gonzaga, Alessandra Gennari, Maria Stella Trabacca, Viviana Galimberti, Paolo Veronesi, Harriet Johansson, Valentina Aristarco, Fabio Bassi, Alberto Luini, Matteo Lazzeroni, Clara Varricchio, Giuseppe Viale, Paolo Bruzzi, Andrea DeCensi
Journal: Journal of Clinical Oncology (2012)

Metformin is associated with reduced breast cancer risk in observational studies in patients with diabetes, but clinical evidence for antitumor activity is unclear. The change in Ki-67 between pretreatment biopsy and post-treatment surgical specimen has prognostic value and may predict antitumor activity in breast cancer.After tumor biopsy, we randomly allocated 200 nondiabetic women with operable breast cancer to either metformin 850 mg/twice per day (n = 100) or placebo (n = 100). The primary outcome measure was the difference between arms in Ki-67 after 4 weeks adjusted for baseline values.Overall, the metformin effect on Ki-67 change relative to placebo was not statistically significant, with a mean proportional increase of 4.0% (95% CI, -5.6% to 14.4%) 4 weeks apart. However, there was a different drug effect depending on insulin resistance (homeostasis model assessment [HOMA] index > 2.8, fasting glucose [mmol/L] × insulin [mU/L]/22.5; P(interaction) = .045), with a nonsignificant mean proportional decrease in Ki-67 of 10.5% (95% CI, -26.1% to 8.4%) in women with HOMA more than 2.8 and a nonsignificant increase of 11.1% (95% CI, -0.6% to 24.2%) with HOMA less than or equal to 2.8. A different effect of metformin according to HOMA index was noted also in luminal B tumors (P(interaction) = .05). Similar trends to drug effect modifications were observed according to body mass index (P = .143), waist/hip girth-ratio (P = .058), moderate alcohol consumption (P = .005), and C-reactive protein (P = .080).Metformin before surgery did not significantly affect Ki-67 overall, but showed significantly different effects according to insulin resistance, particularly in luminal B tumors. Our findings warrant further studies of metformin in breast cancer with careful consideration to the metabolic characteristics of the study population.
Prophylactic use of filgrastim at nadir: Impact of haematological parameters on recovery of grade IV neutropenia induced by standard dose chemotherapy
Authors: A. Bononi, M. Gusella, F. Lanza, D. Menon, F. Albertini, L. Stievano, L. Ferrari, S. Toso, E. Ferrazzi, F. Pasini
Journal: Journal of Clinical Oncology (2008)

20659 Background: Recent data suggest that rHu-G-CSF administered 24–48 hours before the expected nadir is likely to be as effective as standard schedules. This study was aimed at evaluating if peripheral blood automated flow cytochemistry (ADVIA 120 automated flow cytochemistry analyzer) and flow cytometry analysis (Facscan flow cytometer) may predict the response to rHu-G-CSF when administered at the nadir. Methods: rHuG-CSF at nadir was given prophylactically in 30 patients (median age 55 yrs, range 35–75) receiving regimens with known hematological toxicity. Pts with myeloperoxidase deficiencies, previous CT, concomitant radiotherapy, presence of major comorbidities were excluded. Blood counts were performed before CT and at 3-day-interval before the expected nadir. When the neutrophil count reached <500/μL the blood counts were done daily, monitoring Large UnstainedCells (LUCs), myeloperoxidase index (MPXI), Blasts and Lymphocyte subpopulations. Pts were divided into 2 groups according to doses required to reach at least 2,000 neutrophils: fast recovery group (300–600 μgr) and slow recovery group (900–1200 μgr). 81 chemotherapy cycles were evaluated. Results: In the days preceeding nadir phase LUC% increased progressively over time in all pts. The LUCs versus time regression line slopes in the two groups were significantly different (p<0.005) with a LUCs increase per day of 56% and 25% in the fast recovery and slow recovery group, respectively. In addition the fast recovery pts had significantly lower MPXI and significantly higher Blast and CD34+/CD45+ count than the slow recovery group. Conclusions: rHu-G-CSF administration at the nadir was feasible and one or two doses allowed a faster recovery from grade 4 neutropenia than 3–4 doses when the prenadir haematological profile was characterized by low MPXI and high blast and CD34+/CD45+ count and high increase of LUCs per day. Variable Median p Group 1 Group 2 MPXI 11,3 27,7 0.05 Blasts/μL 36,7 19,5 0.05 CD34+/CD45+/μL 2,2 0.82 0.01 CD3+/HLA-DR+/μL 49,6 67,3 NS CD3+/CD4+/μL 356,1 199,8 NS CD3+/CD8+/μL 179,5 162,2 NS CD3-D56+/CD2+/μL 129,6 82,9 NS No significant financial relationships to disclose.
Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study
Authors: Matthew Cotten, Simon J Watson, Paul Kellam, Abdullah A Al-Rabeeah, Hatem Q Makhdoom, Abdullah Assiri, Jaffar A Al-Tawfiq, Rafat F Alhakeem, Hossam Madani, Fahad A AlRabiah, Sami Al Hajjar, Wafa N Al-nassir, Ali Albarrak, Hesham Flemban, Hanan H Balkhy, Sarah Alsubaie, Anne L Palser, Astrid Gall, Rachael Bashford-Rogers, Andrew Rambaut, Alimuddin I Zumla, Ziad A Memish
Journal: The Lancet (2013)

BackgroundSince June, 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) has, worldwide, caused 104 infections in people including 49 deaths, with 82 cases and 41 deaths reported from Saudi Arabia. In addition to confirming diagnosis, we generated the MERS-CoV genomic sequences obtained directly from patient samples to provide important information on MERS-CoV transmission, evolution, and origin.MethodsFull genome deep sequencing was done on nucleic acid extracted directly from PCR-confirmed clinical samples. Viral genomes were obtained from 21 MERS cases of which 13 had 100%, four 85–95%, and four 30–50% genome coverage. Phylogenetic analysis of the 21 sequences, combined with nine published MERS-CoV genomes, was done.FindingsThree distinct MERS-CoV genotypes were identified in Riyadh. Phylogeographic analyses suggest the MERS-CoV zoonotic reservoir is geographically disperse. Selection analysis of the MERS-CoV genomes reveals the expected accumulation of genetic diversity including changes in the S protein. The genetic diversity in the Al-Hasa cluster suggests that the hospital outbreak might have had more than one virus introduction.InterpretationWe present the largest number of MERS-CoV genomes (21) described so far. MERS-CoV full genome sequences provide greater detail in tracking transmission. Multiple introductions of MERS-CoV are identified and suggest lower R0 values. Transmission within Saudi Arabia is consistent with either movement of an animal reservoir, animal products, or movement of infected people. Further definition of the exposures responsible for the sporadic introductions of MERS-CoV into human populations is urgently needed.FundingSaudi Arabian Ministry of Health, Wellcome Trust, European Community, and National Institute of Health Research University College London Hospitals Biomedical Research Centre.
Can Statins Pass the Aspirin Litmus Test in Cancer?
Authors: John Kauh, Fadlo R. Khuri
Journal: Journal of Clinical Oncology (2007)

Much like aspirin has found new roles during the years (from headache remedy to cardiovascular disease prevention), new potential benefits for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are coming to light. Statins limit the biosynthesis of the cholesterol precursor mevalonate. In addition to cholesterol biosynthesis, mevalonate is also a precursor of farnesyl and geranylgeranyl moieties, which are critical to post-translational modification of intracellular signaling pathway proteins such as Ras. Inhibition of farnesylation and geranylgeranylation of messenger molecules have been major targetsofcancerdrugdevelopment.Thefarnesyltransferaseinhibitor tipifarnib is in active development for the treatment of acute myelogenous leukemia, and the farnesyl transferase inhibitor lonafarnib is being developed for myelodysplastic syndrome. Statins have been observed as having protean properties such as antiangiogenesis and apoptosis induction. In vivo mouse models have reported potential chemopreventive effects of statins in colorectal carcinogenesis. 1
Double‐blind evaluation of effectiveness and safety of flunisolide aerosol for treatment of bronchial asthma in children
Authors: G. L. Piacentini, L. Sette, D. G. Peroni, C. Bonizzato, S. Bonetti, A. L. Boner
Journal: Allergy (1990)

A double‐blind study was carried out in 20 asthmatic children in order to evaluate the therapeutic efficacy and safety of inhaled corticosteroid flunisolide. 0.5 mg of the drug was administered by a jet nebulizer twice daily for 2 months. Respiratory symptoms. pulmonary function values and methacholine PC 2 ‐FEV 2 were evaluated, as also morning cortisol levels, plasma cortisol increase alter ACTH test, and 24‐h urinary cortisol excretion. The data obtained show the efficacy of the drug in reducing symptoms. No significant difference was observed in pulmonary function values and in bronchial reactivity results between the two groups. No effect of flunisolide was observed on hypothalamic‐pituitary‐adrenal function. This study confirms the efficacy and safety of flunisolide (0.5 mg b.i.d.) in the treatment of asthmatic children.
Age- and Sex-Dependent Upper Reference Limits for the High-Sensitivity Cardiac Troponin T Assay
Authors: M. Odette Gore, Stephen L. Seliger, Christopher R. deFilippi, Vijay Nambi, Robert H. Christenson, Ibrahim A. Hashim, Ron C. Hoogeveen, Colby R. Ayers, Wensheng Sun, Darren K. McGuire, Christie M. Ballantyne, James A. de Lemos
Journal: Journal of the American College of Cardiology (2014)

The study sought to determine the 99th percentile upper reference limit for the high-sensitivity cardiac troponin T assay (hs-cTnT) in 3 large independent cohorts. The presently recommended 14 ng/l cut point for the diagnosis of myocardial infarction using the hs-cTnT assay was derived from small studies of presumably healthy individuals, with relatively little phenotypic characterization. Data were included from 3 well-characterized population-based studies: the Dallas Heart Study (DHS), the Atherosclerosis Risk in Communities (ARIC) Study, and the Cardiovascular Health Study (CHS). Within each cohort, reference subcohorts were defined excluding individuals with recent hospitalization, overt cardiovascular disease, and kidney disease (subcohort 1), and further excluding those with subclinical structural heart disease (subcohort 2). Data were analyzed stratified by age, sex, and race. The 99th percentile values for the hs-cTnT assay in DHS, ARIC, and CHS were 18, 22, and 36 ng/l (subcohort 1) and 14, 21, and 28 ng/l (subcohort 2), respectively. These differences in 99th percentile values paralleled age differences across cohorts. Analyses within sex/age strata yielded similar results between cohorts. Within each cohort, 99th percentile values increased with age and were higher in men. More than 10% of men 65 to 74 years of age with no cardiovascular disease in our study had cardiac troponin T values above the current myocardial infarction threshold. Use of a uniform 14 ng/l cutoff for the hs-cTnT assay may lead to over-diagnosis of myocardial infarction, particularly in men and the elderly. Clinical validation is needed of new age- and sex-specific cutoff values for this assay.
Suboptimal gastroprotective coverage of NSAID use and the risk of upper gastrointestinal bleeding and ulcers: an observational study using three European databases
Authors: E. M. van Soest, V. E. Valkhoff, G. Mazzaglia, R. Schade, M. Molokhia, J. L. Goldstein, S. Hernandez-Diaz, G. Trifiro, J. P. Dieleman, E. J. Kuipers, M. C. J. M. Sturkenboom
Journal: Gut (2011)

<h3>Background</h3> Gastro-protective agents (GPA) are co-prescribed with non-steroidal anti-inflammatory drugs (NSAID) to lower the risk of upper gastrointestinal (UGI) events. It is unknown to what extent the protective effect is influenced by therapy adherence. <h3>Aim</h3> To study the association between GPA adherence and UGI events among non-selective (ns) NSAID users. <h3>Methods</h3> The General Practice Research Database (UK 1998–2008), the Integrated Primary Care Information database (the Netherlands 1996–2007) and the Health Search/CSD Longitudinal Patient Database (Italy 2000–2007) were used. A nested case-control design was employed within a cohort of nsNSAID users aged ≥50 years, who also used a GPA. UGI event cases (UGI bleeding and/or symptomatic ulcer with/without obstruction/perforation) were matched to event-free members of the cohort for age, sex, database and calendar time. Adherence to GPA was calculated as the proportion of nsNSAID treatment days covered by a GPA prescription. Adjusted OR with 95% CI were calculated. <h3>Results</h3> The cohort consisted of 618 684 NSAID users, generating 1 107 266 nsNSAID episodes. Of these, 117 307 (10.6%) were (partly) covered by GPA, 4.9% of which with a GPA coverage &lt;20% (non-adherence), and 68.1% with a GPA coverage &gt;80% (full adherence). 339 patients experienced an event. Among non-adherers, the OR was 2.39 (95% CI 1.66 to 3.44) for all UGI events and 1.89 (95% CI 1.09 to 3.28) for UGI bleeding alone, compared to full adherers. <h3>Conclusions</h3> The risk of UGI events was significantly higher in nsNSAID users with GPA non-adherence. This underlines the importance of strategies to improve GPA adherence.
Interferon-β Signaling Is Enhanced in Patients With Insufficient Coronary Collateral Artery Development and Inhibits Arteriogenesis in Mice
Authors: Stephan H. Schirmer, Joost O. Fledderus, Pieter T.G. Bot, Perry D. Moerland, Imo E. Hoefer, Jan Baan, José P.S. Henriques, René J. van der Schaaf, Marije M. Vis, Anton J.G. Horrevoets, Jan J. Piek, Niels van Royen
Journal: Circulation Research (2008)

Stimulation of collateral artery growth in patients has been hitherto unsuccessful, despite promising experimental approaches. Circulating monocytes are involved in the growth of collateral arteries, a process also referred to as arteriogenesis. Patients show a large heterogeneity in their natural arteriogenic response on arterial obstruction. We hypothesized that circulating cell transcriptomes would provide mechanistic insights and new therapeutic strategies to stimulate arteriogenesis. Collateral flow index was measured in 45 patients with single-vessel coronary artery disease, separating collateral responders (collateral flow index, &gt;0.21) and nonresponders (collateral flow index, ≤0.21). Isolated monocytes were stimulated with lipopolysaccharide or taken into macrophage culture for 20 hours to mimic their phenotype during arteriogenesis. Genome-wide mRNA expression analysis revealed 244 differentially expressed genes (adjusted P , &lt;0.05) in stimulated monocytes. Interferon (IFN)-β and several IFN-related genes showed increased mRNA levels in 3 of 4 cellular phenotypes from nonresponders. Macrophage gene expression correlated with stimulated monocytes, whereas resting monocytes and progenitor cells did not display differential gene regulation. In vitro, IFN-β dose-dependently inhibited smooth muscle cell proliferation. In a murine hindlimb model, perfusion measured 7 days after femoral artery ligation showed attenuated arteriogenesis in IFN-β–treated mice compared with controls (treatment versus control: 31.5±1.2% versus 41.9±1.9% perfusion restoration, P &lt;0.01). In conclusion, patients with differing arteriogenic response as measured with collateral flow index display differential transcriptomes of stimulated monocytes. Nonresponders show increased expression of IFN-β and its downstream targets, and IFN-β attenuates proliferation of smooth muscle cells in vitro and hampers arteriogenesis in mice. Inhibition of IFN-β signaling may serve as a novel approach for the stimulation of collateral artery growth.
Management of suspected viral encephalitis in children – Association of British Neurologists and British Paediatric Allergy, Immunology and Infection Group National Guidelines
Authors: R. Kneen, B.D. Michael, E. Menson, B. Mehta, A. Easton, C. Hemingway, P.E. Klapper, A. Vincent, M. Lim, E. Carrol, T. Solomon
Journal: Journal of Infection (2011)
Modulation of orocaecal transit time by hypnosis.
Authors: L Beaugerie, A J Burger, J F Cadranel, P Lamy, J P Gendre, Y Le Quintrec
Journal: Gut (1991)

The ability of hypnosis to modulate the orocaecal transit time of 10 g lactulose was tested in six healthy volunteers. Orocaecal transit time was measured by the hydrogen breath test during three periods in random order. During the control period the subjects remained throughout the test in a semirecumbent position without moving. During the hypnotic relaxation period subjects were hypnotised before lactulose ingestion and were instructed to experience relaxation till the orocaecal transit time had elapsed. During the acceleration suggestion period subjects were hypnotised before lactulose ingestion and were repeatedly instructed to imagine the acceleration of lactulose through the intestine until transit time had elapsed. The mean orocaecal transit time was significantly longer during the hypnotic relaxation period (mean (SEM) 133 (8) min) than during the control period (93 (13) min). The mean orocaecal transit time during the acceleration suggestion period was 105 (26) minutes and was not significantly different from the mean transit time during the control period. The individual values during the acceleration suggestion period were scattered. We conclude that lactulose orocaecal transit time is delayed during hypnotic relaxation.