tbuckley/cabot-search huggingface dataset:
Methylene blue but not indigo carmine causes DNA damage to colonocytes in vitro and in vivo at concentrations used in clinical chromoendoscopy
Authors: J Davies, D Burke, J R Olliver, L J Hardie, C P Wild, M N Routledge
Journal: Gut (2006)

Identification of mucosal abnormalities is aided by the use of dyes during colonoscopy (chromoendoscopy).1 Two dyes that have found particular favour are methylene blue and indigo carmine.2,3

Methylene blue, which, unlike indigo carmine, is taken up by cells, induces cellular DNA damage in vitro via the generation of singlet oxygen when photoexcited by white light.4 In contrast, indigo carmine appears to be photostable and to possess little potential to damage genetic material in vitro.5,6 A recent clinical study has shown that the extent of DNA damage (particularly oxidative DNA damage) in human oesophageal cells is increased after methylene blue chromoendoscopy.7 Additional iatrogenic oxidative DNA damage to epithelial cells is of particular concern in such precancerous tissue because of the association between oxidative DNA damage, mutagenesis and the development of malignancy.8 We hypothesised that indigo carmine would induce less DNA damage than methylene blue both in vitro in cultured colon cells during simulated chromoendoscopy conditions and in vivo in colonic biopsy samples collected at chromoendoscopy.

We used the alkaline comet assay …
PMO-241 Conveying medication benefits to ulcerative colitis patients: what thresholds for adherence are applied?
Authors: C Selinger, Y Kinjo, J McLaughlin, A Robinson, R Leong
Journal: Gut (2012)

Introduction Non-adherence to maintenance 5-ASA occurs in at least 30% of ulcerative colitis (UC) patients and is associated with adverse health outcomes and increased healthcare expenditure. Targeted strategies to convey information about benefits of medication to patients may improve adherence. We undertook to discover the preferred mode of information delivery among UC patients; the thresholds of benefit that would produce adherence were also assessed. Methods Four methods of displaying information about the benefits of maintenance therapy in remission were explained to UC patients in remission, during face to face structured interviews. These were largely conventional numerical approaches: relative risk reduction [RR], absolute risk reduction [AR], number needed to treat [NNT]. The fourth was an optical representation via Cates plot [CP]). Patients understanding and preference for each approach were recorded. Patients were asked to state the minimum thresholds required to adhere to a hypothetical medication (with 5-ASA like properties) for the benefits of relapse and cancer reduction respectively. Thresholds were determined for each method of display. Results Of 50 participants (mean age 50 years; 58% male) 48% preferred data presentation by RR over CP (28%), AR (20%) and NNT (4%). 94% found RR easy to understand, better than CP (74%), AR (88%) or NNT (48%). Thresholds required for adherence also differed between methods. For bowel cancer prevention, 94% indicated adherence for benefit levels of 61% RR or lower but only 57% would adhere when presented with the corresponding CP (p<0.001). For relapse prevention, 78% of patients chose a threshold of 40% or lower but only 43% chose the corresponding CP (p<0.001). When presented with RR, adherence minimum thresholds equivalent or lower to the actual 5-ASA benefits were applied by 98% of patients for cancer reduction and 78% for flare reduction. Conclusion Ulcerative colitis patients prefer RR and CP as methods to display medication benefit. NNT is poorly understood and unpopular. Patients apply significantly higher thresholds for adherence when presented with CP in comparison to RR. Presented with information in this way, most patients would choose to adhere to 5-ASA medication when offered the actual benefit profile. Reduction of cancer risk may be a stronger motivator than maintenance of remission. Interventions to improve 5-ASA adherence should use RR and convey benefits for cancer and flare prevention. Competing interests C Selinger: Grant/Research Support from: Shire, Ferring, Nycomed, Y Kinjo: None declared, J McLaughlin: None declared, A Robinson: None declared, R Leong: Grant/Research Support from: Shire, Ferring, Nycomed.
P16.05 * CHARACTERISING REGIONAL HETEROGENEITY OF GLIOBLASTOMA USING MULTIMODAL IMAGING: REGIONS OF AGGRESSIVE GROWTH
Authors: N. R. Boonzaier, T. Larkin, V. Lupson, O. Thomas, A. Young, S. J. Price
Journal: Neuro-Oncology (2014)

BACKGROUND: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumour. Understanding intra-tumour heterogeneity associated with GBM, which is considered a primary contributing factor to treatment failure, involves the analysis of tumour tissue obtained using biopsy samples. Due to the risks involved in performing multiple biopsies on patients, non-invasive methods are needed for tumour analysis. This study aimed to identify imaging signatures of aggressive tumour belonging to different regions of high-grade gliomas using multimodal imaging methods, including diffusion-weighted imaging and MR spectroscopy. METHODS: 32 Patients (mean age 57.2, range 28-75 years) with confirmed GBM were imaged at 3T on a Siemens Trio. Maps of apparent diffusion coefficient (ADC) were coregistered to T2-weighted images. Regions of interest (ROIs) were selected per tumour: FLAIR enhancement with T1-weighted post-contrast enhancement (CE); and FLAIR enhancement without CE (FLAIR). Within these sub-regions, an ADC cut-off value was developed using MATLAB. Metabolic maps of choline/N-acetylaspartate (Cho/tNAA) ratios belonging to these ADC ROIs were calculated using LCModel to determine whether they demonstrated metabolic features of aggression as described in the literature, where a higher ratio value indicates more aggressive tumour. Metabolic ratios from CE and FLAIR were compared to each other and to ratios of ROIs above the ADC threshold within tumour (high ADC) and contralateral normal appearing white matter (NAWM). RESULTS: Metabolic results were obtained for CE in 11/32 patients, and for FLAIR in 29/32 patients. When comparing Cho/tNAA ratio mean values of CE and FLAIR to NAWM (0.26 ± 0.09), both low ADC tumour regions demonstrated ratio means that were significantly higher than those of NAWM (0.60 ± 0.21, p < 0.001; 0.45 ± 0.22; p < 0.001 for CE and FLAIR, respectively). ROIs of high ADC had a mean ratio value (0.39 ± 0.16) that was significantly lower than that of CE (p < 0.01). CONCLUSION: Findings suggest that regional heterogeneity of GBM can be detected and possibly characterised using advanced imaging. Low ADC ROIs within CE regions appear to have metabolic profiles representing aggressive tumour. Combining imaging modalities could potentially help differentiate regions that will respond/fail to respond to treatment.
Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: Entering a new century, do we do better?
Authors: Andrew R. Gennery, Mary A. Slatter, Laure Grandin, Pierre Taupin, Andrew J. Cant, Paul Veys, Persis J. Amrolia, H. Bobby Gaspar, E. Graham Davies, Wilhelm Friedrich, Manfred Hoenig, Luigi D. Notarangelo, Evelina Mazzolari, Fulvio Porta, Robbert G.M. Bredius, Arjen C. Lankester, Nico M. Wulffraat, Reinhard Seger, Tayfun Güngör, Anders Fasth, Petr Sedlacek, Benedicte Neven, Stephane Blanche, Alain Fischer, Marina Cavazzana-Calvo, Paul Landais
Journal: Journal of Allergy and Clinical Immunology (2010)
Performance of MRI-TRUS-guided fusion biopsy to detect progression on active surveillance for low- and intermediate-risk prostate cancer.
Authors: Thomas P. Frye, Nabeel Ahmad Shakir, Steven Abboud, Arvin Koruthu George, Maria J Merino, Peter L. Choyke, Baris Turkbey, Bradford J. Wood, Peter A. Pinto
Journal: Journal of Clinical Oncology (2015)

43 Background: Active surveillance (AS) is an established treatment option for men with low risk prostate cancer. Its role in intermediate prostate cancer is still being investigated. Recent studies have shown that multiparametric-MRI (mp-MRI) along with MRI-TRUS fusion-guided biopsy may better assess risk in patients eligible for AS, compared to 12-core biopsy, due to improved detection of clinically significant cancers. The objective is to determine the performance of MRI-TRUS guided biopsy for men on AS with both low and intermediate risk disease. Methods: Between 2007-2014 men on AS were included if they had complete mp-MRI and pathology data for 2 or more MRI-TRUS biopsy sessions. Fusion guided biopsy procedures consisted of MRI identified targeted biopsies as well as random 12 core biopsies. Men were allowed to participate in AS with low and intermediate risk prostate cancer, Gleason score ≤ 3+4=7. Progression was defined by patients with initial Gleason 3+3=6 to any Gleason 4, and Gleason 3+4=7 disease progressing to a primary Gleason 4 or higher. Results: 89 men met our study criteria with an average age of 62 years old (range 45-79). 75 men had low risk Gleason 3+3=6 at the outset of AS by 1st biopsy session with a median PSA 5.1 ng/ml. The other 14 men had intermediate risk prostate cancer Gleason 3+4=7 at the outset of AS and a median PSA 4.6 ng/ml. During follow-up, 25 (33%) low risk men progressed to 3+4 or above at a median of 20.6 months. Of these, 19 were found by targeted biopsy. 6 (43%) of the intermediate risk men progressed to Gleason 4+3=7 at a median of 36.8 months. 4 of these progressed on targeted fusion biopsy. In the intermediate risk men, 84 random biopsy cores were require to detect 1 progression versus 15 targeted biopsy cores to detect 1 progression. Conclusions: The majority of patients on AS who progressed were identified by MRI-TRUS targeted biopsy. Less biopsy cores are required to detect progression with targeted biopsy. These results are preliminary and a larger cohort with longer follow-up would be beneficial.
Proline Residues in Cd28 and the Src Homology (Sh)3 Domain of Lck Are Required for T Cell Costimulation
Authors: Amy D. Holdorf, Jonathan M. Green, Steven D. Levin, Michael F. Denny, David B. Straus, Vinzenz Link, Paul S. Changelian, Paul M. Allen, Andrey S. Shaw
Journal: The Journal of Experimental Medicine (1999)

The Src family tyrosine kinases Lck and Fyn are critical for signaling via the T cell receptor. However, the exact mechanism of their activation is unknown. Recent crystal structures of Src kinases suggest that an important mechanism of kinase activation is via engagement of the Src homology (SH)3 domain by proline-containing sequences. To test this hypothesis, we identified several T cell membrane proteins that contain potential SH3 ligands. Here we demonstrate that Lck and Fyn can be activated by proline motifs in the CD28 and CD2 proteins, respectively. Supporting a role for Lck in CD28 signaling, we demonstrate that CD28 signaling in both transformed and primary T cells requires Lck as well as proline residues in CD28. These data suggest that Lck plays an essential role in CD28 costimulation.
Clinical relevance of flow cytometric immunophenotyping of the cerebrospinal fluid in patients with diffuse large B-cell lymphoma
Authors: R. Alvarez, J. Dupuis, A. Plonquet, C. Christov, C. Copie-Bergman, F. Hemery, I. Gaillard, T. El Gnaoui, F. Kuhnowski, M. Bedoui, K. Belhadj, P. Brugières, C. Haioun
Journal: Annals of Oncology (2011)
Continuous intravenous infusions of famotidine maintain high intragastric pH in duodenal ulcer.
Authors: H S Merki, L Witzel, D Kaufman, M Kempf, J Neumann, J Rohmel, R P Walt
Journal: Gut (1988)

Three double blind crossover studies were carried out to assess the ability of primed infusions of famotidine to raise intragastric pH over 24 hours in 12 duodenal ulcer patients. pH was measured continuously using intragastric electrodes and solid state recording devices. The studies compared the effects of placebo, famotidine 10 mg bolus injection iv followed by continuous infusions of 3.2 mg/h and 4 mg/h in random order. Gastric acidity decreased significantly with both dose regimens (p less than 0.0005) but the effects of either dosage were similar. During fasting median pH rose from 1.35 to 7.1 and 7.05 respectively. During the day, when standard meals were taken, median pH rose from 1.30 to 4.3 and 3.65 respectively. Despite continuous infusions the H2-antagonist was less effective during this time. The latter finding raises questions about gastric secretory control during the day when food is eaten.
Prevalence and predictors of fatigue in glioblastoma: a prospective study
Authors: P. O. Valko, A. Siddique, C. Linsenmeier, K. Zaugg, U. Held, S. Hofer
Journal: Neuro-Oncology (2014)

The main goal of this study was to assess frequency, clinical correlates, and independent predictors of fatigue in a homogeneous cohort of well-defined glioblastoma patients at baseline prior to combined radio-chemotherapy. We prospectively included 65 glioblastoma patients at postsurgical baseline and assessed fatigue, sleepiness, mean bedtimes, mood disturbances, and clinical characteristics such as clinical performance status, presenting symptomatology, details on neurosurgical procedure, and tumor location and diameter as well as pharmacological treatment including antiepileptic drugs, antidepressants, and use of corticosteroids. Data on fatigue and sleepiness were measured with the Fatigue Severity Scale and the Epworth Sleepiness Scale, respectively, and compared with 130 age- and sex-matched healthy controls. We observed a significant correlation between fatigue and sleepiness scores in both patients (r = 0.26; P = .04) and controls (r = 0.36; P < .001). Only fatigue appeared to be more common in glioblastoma patients than in healthy controls (48% vs 11%; P < .001) but not the frequency of sleepiness (22% vs 19%; P = .43). Female sex was associated with increased fatigue frequency among glioblastoma patients but not among control participants. Multiple linear regression analyses identified depression, left-sided tumor location, and female sex as strongest associates of baseline fatigue severity. Our findings indicate that glioblastoma patients are frequently affected by fatigue at baseline, suggesting that factors other than those related to radio- or chemotherapy have significant impact, particularly depression and tumor localization.
<i>Gata6</i>is required for complete acinar differentiation and maintenance of the exocrine pancreas in adult mice
Authors: Paola Martinelli, Marta Cañamero, Natalia del Pozo, Francesc Madriles, Agustín Zapata, Francisco X Real
Journal: Gut (2012)

<h3>Objectives</h3> Previous studies have suggested an important role of the transcription factor <i>Gata6</i> in endocrine pancreas, while <i>GATA6</i> haploinsufficient inactivating mutations cause pancreatic agenesis in humans. We aimed to analyse the effects of <i>Gata6</i> inactivation on pancreas development and function. <h3>Design</h3> We deleted <i>Gata6</i> in all epithelial cells in the murine pancreas at the onset of its development. Acinar proliferation, apoptosis, differentiation and exocrine functions were assessed using reverse transcriptase quantitative PCR (RT-qPCR), chromatin immunoprecipitation, immunohistochemistry and enzyme assays. Adipocyte transdifferentiation was assessed using electron microscopy and genetic lineage tracing. <h3>Results</h3> Gata6 is expressed in all epithelial cells in the adult mouse pancreas but it is only essential for exocrine pancreas homeostasis: while dispensable for pancreatic development after e10.5, it is required for complete acinar differentiation, for establishment of polarity and for the maintenance of acinar cells in the adult. Gata6 regulates directly the promoter of genes coding for digestive enzymes and the transcription factors <i>Rbpjl</i> and <i>Mist1</i>. Upon pancreas-selective <i>Gata6</i> inactivation, massive loss of acinar cells and fat replacement take place. This is accompanied by increased acinar apoptosis and proliferation, acinar-to-ductal metaplasia and adipocyte transdifferentiation. By contrast, the endocrine pancreas is spared. <h3>Conclusions</h3> Our data show that Gata6 is required for the complete differentiation of acinar cells through multiple transcriptional regulatory mechanisms. In addition, it is required for the maintenance of the adult acinar cell compartment. Our studies suggest that <i>GATA6</i> alterations may contribute to diseases of the human adult exocrine pancreas.
Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome
Authors: Richard S. Legro, Robert G. Brzyski, Michael P. Diamond, Christos Coutifaris, William D. Schlaff, Peter Casson, Gregory M. Christman, Hao Huang, Qingshang Yan, Ruben Alvero, Daniel J. Haisenleder, Kurt T. Barnhart, G. Wright Bates, Rebecca Usadi, Scott Lucidi, Valerie Baker, J.C. Trussell, Stephen A. Krawetz, Peter Snyder, Dana Ohl, Nanette Santoro, Esther Eisenberg, Heping Zhang
Journal: New England Journal of Medicine (2014)

Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes.
Effects of Oropharyngeal Exercises on Patients with Moderate Obstructive Sleep Apnea Syndrome
Authors: Kátia C. Guimarães, Luciano F. Drager, Pedro R. Genta, Bianca F. Marcondes, Geraldo Lorenzi-Filho
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Upper airway muscle function plays a major role in maintenance of the upper airway patency and contributes to the genesis of obstructive sleep apnea syndrome (OSAS). Preliminary results suggested that oropharyngeal exercises derived from speech therapy may be an effective treatment option for patients with moderate OSAS.To determine the impact of oropharyngeal exercises in patients with moderate OSAS.Thirty-one patients with moderate OSAS were randomized to 3 months of daily ( approximately 30 min) sham therapy (n = 15, control) or a set of oropharyngeal exercises (n = 16), consisting of exercises involving the tongue, soft palate, and lateral pharyngeal wall.Anthropometric measurements, snoring frequency (range 0-4), intensity (1-3), Epworth daytime sleepiness (0-24) and Pittsburgh sleep quality (0-21) questionnaires, and full polysomnography were performed at baseline and at study conclusion. Body mass index and abdominal circumference of the entire group were 30.3 +/- 3.4 kg/m(2) and 101.4 +/- 9.0 cm, respectively, and did not change significantly over the study period. No significant change occurred in the control group in all variables. In contrast, patients randomized to oropharyngeal exercises had a significant decrease (P < 0.05) in neck circumference (39.6 +/- 3.6 vs. 38.5 +/- 4.0 cm), snoring frequency (4 [4-4] vs. 3 [1.5-3.5]), snoring intensity (3 [3-4] vs. 1 [1-2]), daytime sleepiness (14 +/- 5 vs. 8 +/- 6), sleep quality score (10.2 +/- 3.7 vs. 6.9 +/- 2.5), and OSAS severity (apnea-hypopnea index, 22.4 +/- 4.8 vs. 13.7 +/- 8.5 events/h). Changes in neck circumference correlated inversely with changes in apnea-hypopnea index (r = 0.59; P < 0.001).Oropharyngeal exercises significantly reduce OSAS severity and symptoms and represent a promising treatment for moderate OSAS. Clinical trial registered with www.clinicaltrials.gov (NCT 00660777).
Impact of Scotland's Smoke-Free Legislation on Pregnancy Complications: Retrospective Cohort Study
Authors: Daniel F. Mackay, Scott M. Nelson, Sally J. Haw, Jill P. Pell
Journal: PLoS Medicine (2012)

Background Both active smoking and environmental tobacco smoke exposure are associated with pregnancy complications. In March 2006, Scotland implemented legislation prohibiting smoking in all wholly or partially enclosed public spaces. The aim of this study was to determine the impact of this legislation on preterm delivery and small for gestational age. Methods and Findings We conducted logistic regression analyses using national administrative pregnancy data covering the whole of Scotland. Of the two breakpoints tested, 1 January 2006 produced a better fit than the date when the legislation came into force (26 March 2006), suggesting an anticipatory effect. Among the 716,941 eligible women who conceived between August 1995 and February 2009 and subsequently delivered a live-born, singleton infant between 24 and 44 wk gestation, the prevalence of current smoking fell from 25.4% before legislation to 18.8% after legislation (p<0.001). Three months prior to the legislation, there were significant decreases in small for gestational age (−4.52%, 95% CI −8.28, −0.60, p = 0.024), overall preterm delivery (−11.72%, 95% CI −15.87, −7.35, p<0.001), and spontaneous preterm labour (−11.35%, 95% CI −17.20, −5.09, p = 0.001). In sub-group analyses, significant reductions were observed among both current and never smokers. Conclusions Reductions were observed in the risk of preterm delivery and small for gestational age 3 mo prior to the introduction of legislation, although the former reversed partially following the legislation. There is growing evidence of the potential for tobacco control legislation to have a positive impact on health. Please see later in the article for the Editors' Summary
The endothelin receptor antagonist bosentan restores gut oxygen delivery and reverses intestinal mucosal acidosis in porcine endotoxin shock
Authors: A Oldner, M Wanecek, M Goiny, E Weitzberg, A Rudehill, K Alving, A Sollevi
Journal: Gut (1998)

Endothelin-1, the most potent vasoconstrictor known, is produced in septic states and may be involved in the pathophysiology of the deteriorated splanchnic circulation seen in septic shock.To elucidate the capability of bosentan, a non-peptide mixed endothelin receptor antagonist, to attenuate splanchnic blood flow disturbances and counteract intestinal mucosal acidosis in endotoxic shock.In 16 anaesthetised pigs, central and regional haemodynamics were monitored by thermodilution and ultrasonic flow probes, respectively. A tonometer in the ileum was used for measurement of mucosal pH. Onset of endotoxin challenge was followed by bosentan administration (to eight pigs) two hours later.Endotoxin infusion reduced cardiac index and systemic oxygen delivery; bosentan restored these parameters. The reduced mean arterial blood pressure and renal blood flow remained unaffected by bosentan. The profound reduction in gut oxygen delivery in response to endotoxin was completely abolished by bosentan. Bosentan significantly improved the notably deteriorated intestinal mucosal pH and mucosal-arterial PCO2 gap. The mucosal-portal vein PCO2 gap, used to monitor the mucosa in relation to the gut as a whole (including the spleen and pancreas), was also greatly increased by endotoxaemia and significantly reversed by bosentan.Bosentan completely restored the profound endotoxin induced reductions in systemic and gut oxygen delivery with a concomitant reversal of intestinal mucosal acidosis. Results suggest that endothelin is involved in the pronounced perfusion disturbances seen in the gut in endotoxic shock. Bosentan may prove useful in reducing gut ischaemia in septic shock.
Genetic testing services are to be regulated to protect UK patients
Authors: A. O'Dowd
Journal: BMJ (2010)

A crackdown on genetic test services has been unveiled in an attempt to prevent companies giving people misleading impressions about their future health.

The Human Genetics Commission—the United Kingdom’s advisory body on genetics—has published a framework that will force companies to follow principles of consent, data protection, honest marketing, scientific rigour, and balanced interpretation.

The commission said it believed that guidance was necessary given concerns about a growing market for “direct to consumer” services that offer tests for conditions such as Huntington’s disease and breast cancer.

Companies offer to test large numbers of genes …