tbuckley/cabot-search huggingface dataset:
Effect of body mass index and alcohol consumption on liver disease: analysis of data from two prospective cohort studies
Authors: C. L Hart, D. S Morrison, G D. Batty, R. J Mitchell, G. Davey Smith
Journal: BMJ (2010)

<b>Objective</b> To investigate whether alcohol consumption and raised body mass index (BMI) act together to increase risk of liver disease. <b>Design</b> Analysis of data from prospective cohort studies. <b>Setting</b> Scotland. <b>Participants</b> Data were from two of the Midspan prospective cohort studies (9559 men): “Main” study 1965-8, participants from workplaces across central belt of Scotland, population of island of Tiree, and mainland relatives, and “Collaborative” study, 1970-3, participants from 27 workplaces in Glasgow, Clydebank, and Grangemouth. Follow-up was to 31 December 2007 (median 29 years, range 0.13-42). We divided participants into nine groups based on measures of body mass index (BMI) (underweight/normal weight &lt;25, overweight 25 to &lt;30, and obese ≥30) and alcohol consumption (none, 1-14, and ≥15 units per week). <b>Main outcome measures</b> Liver disease morbidity and mortality. <b>Results</b> 80 (0.8%) men died with liver disease as the main cause and 146 (1.5%) with liver disease as any cause. In the Collaborative study, 196 men (3.3%) had liver disease defined by a death, admission, or cancer registration. BMI and alcohol consumption were strongly associated with liver disease mortality in analyses adjusted for other confounders (P=0.001 and P&lt;0.0001 respectively). Drinkers of 15 or more units per week in any BMI category and obese drinkers had raised relative rates for all definitions of liver disease, compared with underweight/normal weight non-drinkers. Drinkers of 15 or more units per week had adjusted relative rates for liver disease mortality of 3.16 (95% confidence interval 1.28 to 7.8) for underweight/normal weight men, 7.01 (3.02 to 16.3) for overweight, and 18.9 (6.84 to 52.4) for obese men. The relative rate for obese men who consumed 1-14 units per week was 5.3 (1.36 to 20.7). The relative excess risk due to interaction between BMI and alcohol consumption was 5.58 (1.09 to 10.1); synergy index=2.89 (1.29 to 6.47). <b>Conclusions</b> Raised BMI and alcohol consumption are both related to liver disease, with evidence of a supra-additive interaction between the two. The occurrence of both factors in the same populations should inform health promotion and public health policies.
Butyrate and trichostatin A effects on the proliferation/differentiation of human intestinal epithelial cells: induction of cyclin D3 and p21 expression
Authors: S Siavoshian
Journal: Gut (2000)

<h3>BACKGROUND</h3> Sodium butyrate, a product of colonic bacterial fermentation, is able to inhibit cell proliferation and to stimulate cell differentiation of colonic epithelial cell lines. It has been proposed that these cellular effects could be linked to its ability to cause hyperacetylation of histone through the inhibition of histone deacetylase. <h3>AIM</h3> To analyse the molecular mechanisms of butyrate action on cell proliferation/differentiation and to compare them with those of trichostatin A, a well known inhibitor of histone deacetylase. <h3>METHODS</h3> HT-29 cells were grown in the absence or presence of butyrate or trichostatin A. Cell proliferation and cell cycle distribution were studied after DNA staining by crystal violet and propidium iodide respectively. Cell cycle regulatory proteins were studied by western blot and reverse transcription-polymerase chain reaction. Cell differentiation was followed by measuring brush border enzyme activities. Histone acetylation was studied by acid/urea/Triton acrylamide gel electrophoresis. <h3>RESULTS</h3> Butyrate blocked cells mainly in the G<sub>1</sub> phase of the cell cycle, whereas trichostatin A was inhibitory in both G<sub>1</sub> and G<sub>2</sub> phases. Butyrate inhibited the mRNA expression of cyclin D1 without affecting its protein expression and stimulated the protein expression of cyclin D3 without affecting its mRNA expression. Trichostatin A showed similar effects on cyclin D1 and D3. Butyrate and trichostatin A stimulated p21 expression both at the mRNA and protein levels, whereas their effects on the expression of cyclin dependent kinases were slightly different. Moreover, butyrate strongly stimulated the activity of alkaline phosphatase and dipeptidyl peptidase IV, whereas trichostatin A had no effect. Finally, a six hour exposure to butyrate or trichostatin A induced histone H4 hyperacetylation. At 15 and 24 hours, histone H4 remained hyperacetylated in the presence of butyrate, whereas it returned to control levels in the presence of trichostatin A. <h3>CONCLUSIONS</h3> The data may explain how butyrate acts on cell proliferation/differentiation, and they show that trichostatin A does not reproduce every effect of butyrate, mainly because of its shorter half life.
Comment on “Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells”
Authors: Bilada Bilican, Andrea Serio, Sami J. Barmada, Agnes Lumi Nishimura, Gareth J. Sullivan, Monica Carrasco, Hemali P. Phatnani, Clare A. Puddifoot, David Story, Judy Fletcher, In-Hyun Park, Brad A. Friedman, George Q. Daley, David J. A. Wyllie, Giles E. Hardingham, Ian Wilmut, Steven Finkbeiner, Tom Maniatis, Christopher E. Shaw, Siddharthan Chandran
Journal: Science Translational Medicine (2013)

Egawa et al. recently showed the value of patient-specific induced pluripotent stem cells (iPSCs) for modeling amyotrophic lateral sclerosis in vitro. Their study and our work highlight the need for complementary assays to detect small, but potentially important, phenotypic differences between control iPSC lines and those carrying disease mutations.
Inhibition of pancreatic secretion in man by cigarette smoking
Authors: T. E. Bynum, T. E. Solomon, L. R. Johnson, E. D. Jacobson
Journal: Gut (1972)

Cigarette smoking has been linked to an elevated incidence of duodenal ulcer disease in smokers, although the mechanism is unclear. In 23 young normal subjects single or double secretin tests were performed during non-smoking and smoking periods. Cigarette smoking inhibited the secretion of pancreatic juice and bicarbonate in light smokers (< one pack/day for < three years). Heavy smokers (> one pack/day for > three years) exhibited depressed pancreatic secretory rates during non-smoking periods. Inhibition of pancreatic alkaline secretion by cigarette smoking could be the link between the habit and duodenal ulcer disease.
Antioxidant intake, GSTM1 polymorphism and pulmonary function in healthy young adults
Authors: J. Tujague
Journal: European Respiratory Journal (2006)

Dietary antioxidants may protect lung tissue against reactive oxygen species-induced injury, adverse respiratory effects and reduced pulmonary function. Genetic variability in antioxidant enzymes also determines response to oxidative stress in the lung. The current authors evaluated whether lung function levels are associated with dietary intake of antioxidants and the glutathione <i>S</i>-transferase M1 (GSTM1) polymorphism. The current study cohort consisted of healthy, nonsmoking freshmen students who were lifetime residents in the Los Angeles or the San Francisco Bay areas (CA, USA). Participants completed comprehensive residential history, health history and food frequency questionnaires. Blood for genotyping was collected and forced expiratory volume measurements were obtained. Dietary vitamin C, magnesium and daily fruit servings were associated positively with forced expiratory volume in one second in males and with maximum mid-expiratory flow, forced expiratory flow after 75% of expelled volume, and the ratio of maximum mid-expiratory flow to forced vital capacity in females. In multivariable regression, vitamin C (or fruit for male students) and magnesium showed a consistent, positive association with lung function. Among healthy female adolescents, dietary intake of vitamin C is associated with increased levels of lung function. The current study does not support a role for the glutathione <i>S</i>-transferase M1-null genotype as an independent risk factor for decrements in lung function.
A Novel Inhibitor of the Na<sup>+</sup>/ H<sup>+</sup> Exchanger Type 3 Activates the Central Respiratory CO<sub>2</sub> Response and Lowers the Apneic Threshold
Authors: HEIDRUN KIWULL-SCHÖNE, MARTIN WIEMANN, STILLA FREDE, DIETER BINGMANN, KLAUS J. WIRTH, UWE HEINELT, HANS-JOCHEN LANG, PETER KIWULL
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Cultured CO2-sensitive neurons from the ventrolateral medulla of newborn rats enhanced their bioelectric activity upon intracellular acidification induced by inhibition of the Na+/H+ exchanger type 3 (NHE3). Now we detected NHE3 also in the medulla oblongata of adult rabbits. Therefore, this animal model was employed to determine whether NHE3 inhibition also affects central respiratory chemosensitivity in vivo. Seven anesthetized (pentobarbital), vagotomized, paralyzed rabbits were artificially ventilated with O2-enriched air. From the phrenic nerve compound discharge, integrated burst amplitude (IPNA), respiratory rate (fR), and phrenic minute activity (IPNA. fR) were taken as measures of central respiratory rhythm and drive. Effects of potent NHE3 inhibition with the novel brain permeant substance S8218 were studied by comparing respiratory characteristics before and after up to 9.2 +/- 1.1 mg/kg cumulative drug application, yielding average plasma concentrations of 0.9 +/- 0.2 microg/ml. In response to S8218, the baseline level of IPNA. fR was significantly enhanced by an average of 51.0 +/- 6.4% (n = 27, p < 0.0001). The influence of NHE3 inhibition on the respiratory CO2 response was studied at plasma concentrations of S8218 maintained in the range of 0.3 microg/ml (10(-6) M). Although the metabolic acid-base status thereby remained widely unchanged, the group mean apneic threshold PaCO2 was significantly lowered by 0.45 +/- 0.11 kPa (n = 7, p < 0.01), whereby in four of seven animals even strong hyperventilation failed to suppress phrenic nerve rhythmicity completely. Likewise, S8218 significantly augmented IPNA. fR, in the range of PaCO2 between 1 and 6 kPa above threshold, by an average of 38.0 +/- 8.5% (n = 35, p < 0.0001). These in vivo results are compatible with the effects of NHE3 inhibition on chemosensitive brainstem neurons in vitro. Moreover, rhythmogenesis is supported through NHE3 inhibition by lowering the threshold PCO2 for central apnea.
Effect of non-invasive mechanical ventilation on sleep and nocturnal ventilation in patients with chronic respiratory failure
Authors: B. Schonhofer
Journal: Thorax (2000)

Chronic respiratory failure (CRF) is associated with nocturnal hypoventilation. Due to the interaction of sleep and breathing, sleep quality is reduced during nocturnal hypoventilation. Non-invasive mechanical ventilation (NMV), usually performed overnight, relieves symptoms of hypoventilation and improves daytime blood gas tensions in patients with CRF. The time course of the long term effect of NMV on sleep and breathing during both spontaneous ventilation (withdrawing the intervention) and NMV was investigated in patients with CRF due to thoracic restriction.Fifteen consecutive patients (13 women) of mean (SD) age 57.9 (12.0) years with CRF due to thoracic restriction were included in the study. During the one year observation period four polysomnographic studies were performed: three during spontaneous breathing without NMV-before initiation of NMV (T0) and after withdrawing NMV for one night at six months (T6) and 12 months (T12-)-and the fourth during NMV after 12 months (T12+). Daytime blood gas tensions and lung function were also measured.Spontaneous ventilation (in terms of mean oxygen saturation) progressively improved (from T0 to T12-) during both REM sleep (24.8%, 95% CI 12.9 to 36.9) and NREM sleep (21.5%, 95% CI 12.4 to 30.6). Sleep quality during spontaneous ventilation also improved in terms of increased total sleep time (26. 8%, 95% CI 11.6 to 42.0) and sleep efficiency (17.5%, 95% CI 5.4 to 29.6) and decreased awakenings (54.0%, 95% CI 70.3 to 37.7). Accordingly, REM and NREM sleep stages 3 and 4 significantly improved. However, the most significant improvements in both nocturnal ventilation and sleep quality were seen during NMV at 12 months.After long term NMV both spontaneous ventilation during sleep and sleep quality in patients with CRF due to thoracic restriction showed evidence of progressive improvement compared with baseline after withdrawal of NMV for a single night at six and 12 months. However, the greatest improvements in nocturnal ventilation and sleep were achieved during NMV at 12 months.
Requirement for Rac1 in a K-ras–Induced Lung Cancer in the Mouse
Authors: Joseph L. Kissil, Marita J. Walmsley, Linda Hanlon, Kevin M. Haigis, Carla F. Bender Kim, Alejandro Sweet-Cordero, Matthew S. Eckman, David A. Tuveson, Anthony J. Capobianco, Victor L.J. Tybulewicz, Tyler Jacks
Journal: Cancer Research (2007)

Abstract Given the prevalence of Ras mutations in human cancer, it is critical to understand the effector pathways downstream of oncogenic Ras leading to transformation. To directly assess the requirement for Rac1 in K-ras–induced tumorigenesis, we employed a model of lung cancer in which an oncogenic allele of K-ras could be activated by Cre-mediated recombination in the presence or absence of conditional deletion of Rac1. We show that Rac1 function is required for tumorigenesis in this model. Furthermore, although Rac1 deletion alone was compatible with cell viability and proliferation, when combined with K-ras activation in primary epithelial cells, loss of Rac1 caused a profound reduction in proliferation. These data show a specific requirement for Rac1 function in cells expressing oncogenic K-ras. [Cancer Res 2007;67(17):8089–94]
Feasibility and Short-Term Efficacy of Percutaneous Mitral Annular Reduction for the Therapy of Heart Failure-Induced Mitral Regurgitation
Authors: David M. Kaye, Melissa Byrne, Clif Alferness, John Power
Journal: Circulation (2003)

Mitral regurgitation (MR) frequently accompanies congestive heart failure (CHF) and is associated with poorer prognosis and more significantly impaired symptomatic status. Although surgical mitral valve annuloplasty has the potential to offer benefit, concerns about the combined surgical risk and possible effects on ventricular performance have limited progress. We evaluated the feasibility and short-term efficacy of a novel device placed in the coronary sinus to reduce MR in the setting of CHF.CHF and MR were induced in 9 adult sheep by rapid ventricular pacing for 5 to 8 weeks. A mitral annular constraint device was implanted percutaneously through the right internal jugular vein in the coronary sinus and great cardiac vein to create a short-term stable reduction (24.9+/-2.5%) in the mitral annular septal-lateral dimension as assessed echocardiographically. Right and left heart pressures and cardiac output were determined before and 15 minutes after device implantation. MR extent was examined echocardiographically and expressed as a ratio of left atrial area (MR/LAA). After device placement, MR was substantially reduced from an MR/LAA of 42+6% to 4+/-3% (P<0.01). In association, mean pulmonary wedge pressure was significantly reduced (26+/-3 to 18+/-3 mm Hg; P<0.01) and mean cardiac output significantly increased (3.4+/-0.3 to 4.3+/-0.4 L/min; P=0.01).In this model of CHF, percutaneous placement of a mitral annular constraint device in the coronary sinus resulted in the short-term elimination or minimization of MR and was accompanied in the short term by favorable hemodynamic effects.
Integrative Cancer Epidemiology—The Next Generation
Authors: Margaret R. Spitz, Neil E. Caporaso, Thomas A. Sellers
Journal: Cancer Discovery (2012)

Abstract Summary: We outline an integrative approach to extend the boundaries of molecular cancer epidemiology by integrating modern and rapidly evolving “omics” technologies into state-of-the-art molecular epidemiology. In this way, one can comprehensively explore the mechanistic underpinnings of epidemiologic observations in cancer risk and outcome. We highlight the exciting opportunities to collaborate across large observational studies and to forge new interdisciplinary collaborative ventures. Cancer Discov; 2(12); 1087–90. ©2012 AACR.
ER and PI3K Independently Modulate Endocrine Resistance in ER-Positive Breast Cancer
Authors: Brian A. Van Tine, Robert J. Crowder, Matthew J. Ellis
Journal: Cancer Discovery (2011)

Abstract Endocrine therapy–resistant estrogen receptor–positive (ER+) breast cancer is the most common cause of breast cancer death. Miller and colleagues demonstrate that ligand-independent ER activity promotes the growth of breast cancer cells through CDK4/E2F. As an independent event, the phosphatidylinositol 3-kinase (PI3K) pathway is also upregulated in endocrine therapy-resistant cells. Promising preclinical evidence by several groups for the combination of an inhibitor of ligand-independent ER, fulvestrant, with PI3K inhibition, has led to the activation of trials evaluating this concept. Cancer Discovery; 1(4): 287–8. ©2011 AACR. Commentary on Miller et al., p. 338.
Genetic-induced Variations in the GAD65 T-cell Repertoire Governs Efficacy of Anti-CD3/GAD65 Combination Therapy in New-onset Type 1 Diabetes
Authors: Damien Bresson, Matthew Fradkin, Yulia Manenkova, Diane Rottembourg, Matthias von Herrath
Journal: Molecular Therapy (2009)

To enhance efficacy of forthcoming type 1 diabetes (T1D) clinical trials, combination therapies (CTs) are envisaged. In this study, we showed that efficacy of a CT, using anti-CD3 antibody and glutamic acid decarboxylase of 65 kd (GAD65)-expressing plasmid, to reverse new-onset T1D was dependent upon the genetic background. Synergism between both treatments was only observed in the RIP-LCMV-GP but not in the nonobese diabetic (NOD) or RIP-LCMV-NOD models. Efficacy was associated with an expansion of bystander suppressor regulatory T cells (Tregs) recognizing the C-terminal region of GAD65 and secreting interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta), and interferon-gamma (IFN-gamma). In addition, we found that frequency and epitope specificity of GAD65-reactive CD4(+) T cells during antigen priming at diabetes onset and Tregs detected after CT correlated. Consequently, NOD mice harbored significantly lower levels of GAD65-reactive CD4(+) T cells than RIP-LCMV-GP before and after treatment. Our results demonstrate that antigen-specific T cells available at treatment may differ between various major histocompatibility complex (MHC) and genetic backgrounds. These cells play a major role in shaping T-cell responses following antigen-specific immune intervention and determine whether a beneficial Tregs response is generated. Our findings hold important implications to understand and predict the success of antigen-based clinical trials, where responsiveness to immunotherapy might vary from patient to patient.
UK government consults on primary care
Authors: Adrian O'Dowd
Journal: BMJ (2005)

The views of thousands of people on primary care are to be gathered by the Department of Health later this summer in a consultation exercise. These views will help to inform a white paper, to be published at the turn of the year.

Patricia Hewitt, the health secretary, said that this would be a “major public engagement exercise” to help shape the future of all NHS services provided outside hospitals, including GPs' surgeries, walk-in centres, and social and community care.

Doctors and other staff groups will be invited to …
Administration of abciximab to patients receiving tirofiban or eptifibatide: effect on platelet function
Authors: Eli I Lev, Julio I Osende, Merwin F Richard, Jonathan A Robbins, Jenny A Delfin, Oswaldo Rodriguez, Samin K Sharma, Tim Jayasundera, Juan J Badimon, Jonathan D Marmur
Journal: Journal of the American College of Cardiology (2001)
Roles of NMDA NR2B Subtype Receptor in Prefrontal Long-Term Potentiation and Contextual Fear Memory
Authors: Ming-Gao Zhao, Hiroki Toyoda, Yong-Seok Lee, Long-Jun Wu, Shanelle W. Ko, Xue-Han Zhang, Yongheng Jia, Fanny Shum, Hui Xu, Bao-Ming Li, Bong-Kiun Kaang, Min Zhuo
Journal: Neuron (2005)
A Randomized Controlled Trial Comparing the Effects of Counseling and Alarm Device on HAART Adherence and Virologic Outcomes
Authors: Michael H. Chung, Barbra A. Richardson, Kenneth Tapia, Sarah Benki-Nugent, James N. Kiarie, Jane M. Simoni, Julie Overbaugh, Mena Attwa, Grace C. John-Stewart
Journal: PLoS Medicine (2011)

Michael Chung and colleagues show that intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure, whereas use of an alarm device had no effect.
Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial
Authors: Georgina V Long, Daniil Stroyakovskiy, Helen Gogas, Evgeny Levchenko, Filippo de Braud, James Larkin, Claus Garbe, Thomas Jouary, Axel Hauschild, Jean-Jacques Grob, Vanna Chiarion-Sileni, Celeste Lebbe, Mario Mandalà, Michael Millward, Ana Arance, Igor Bondarenko, John B A G Haanen, Johan Hansson, Jochen Utikal, Virginia Ferraresi, Nadezhda Kovalenko, Peter Mohr, Volodymr Probachai, Dirk Schadendorf, Paul Nathan, Caroline Robert, Antoni Ribas, Douglas J DeMarini, Jhangir G Irani, Suzanne Swann, Jeffrey J Legos, Fan Jin, Bijoyesh Mookerjee, Keith Flaherty
Journal: The Lancet (2015)
Effect of the Sampling System on the Shape of Indicator Dilution Curves
Authors: WILLIAM W. LACY, RICHARD W. EMANUEL, ELLIOT V. NEWMAN
Journal: Circulation Research (1957)

This paper describes the distorting effects produced by various sizes of polyethylene tubing and various flow rates on a square wave input of dye concentration. The importance of an accurate sampling system when recording dilution curves for analysis of their shape is emphasized and the distortion caused by inadequate sampling systems is demonstrated in vivo.
An evolving picture
Authors: F D Richard Hobbs
Journal: BMJ (2004)

It is pleasing to see such a flurry of responses on bmj.com espousing the importance of incremental problem solving and of clinical acumen. This interactive case was never likely to be “typical.” As Abdullah Mohammmed comments, “the initial clinical findings seem contradictory.”1 This is so often the case with medicine, and observing symptoms and signs over time remains an essential diagnostic tool, especially in primary care. Most correspondents were …