tbuckley/cabot-search huggingface dataset:
Anti-tumour necrosis factor agents reduce non-steroidal anti-inflammatory drug-induced small bowel injury in rheumatoid arthritis patients
Authors: Toshio Watanabe, Tetsuya Tanigawa, Masatsugu Shiba, Yuji Nadatani, Yasuaki Nagami, Satoshi Sugimori, Hirokazu Yamagami, Kenji Watanabe, Kazunari Tominaga, Yasuhiro Fujiwara, Tatsuya Koike, Tetsuo Arakawa
Journal: Gut (2013)

<h3>Objective</h3> The role of tumour necrosis factor α (TNFα) in the pathogenesis of non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal damage remains unclear. We evaluated the preventive effect of anti-TNF therapy against NSAID-induced enteropathy in rheumatoid arthritis (RA) patients. <h3>Design</h3> Capsule endoscopy was performed in 95 consecutive RA patients who received NSAID for more than 3 months, with or without anti-TNF therapy over a period of 3 months. The findings were scored from 0 to 4: 0, normal; 1, red spots; 2, one to four erosions; 3, more than four erosions; and 4, large erosions/ulcers. The relationship between the use of anti-TNF therapy and the risk of severe damage (scores 3 or 4) or the most severe damage (score 4) was assessed using multiple logistic regression analysis. Furthermore, a propensity score matching analysis was performed to reduce the effects of TNF selection bias. <h3>Results</h3> By stratifying the patients on the basis of anti-TNF therapy, we obtained crude OR of 0.23 for severe damage (95% CI 0.09 to 0.65) and 0.37 for the most severe damage (95% CI 0.16 to 0.86). This protective effect of anti-TNF therapy remained robust to adjustments for baseline characteristics, with the adjusted OR for severe damage and the most severe damage ranging from 0.23 to 0.26 and 0.06 to 0.41, respectively. Propensity score matching yielded similar results and showed the protective effects of anti-TNF therapy against severe and most severe damage. <h3>Conclusions</h3> Anti-TNF therapy may protect against NSAID-induced small intestinal damage in RA patients.
Distinct and overlapping control of 5-methylcytosine and 5-hydroxymethylcytosine by the TET proteins in human cancer cells
Authors: Emily L Putiri, Rochelle L Tiedemann, Joyce J Thompson, Chunsheng Liu, Thai Ho, Jeong-Hyeon Choi, Keith D Robertson
Journal: Genome biology (2014)

The TET family of dioxygenases catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), but their involvement in establishing normal 5mC patterns during mammalian development and their contributions to aberrant control of 5mC during cellular transformation remain largely unknown. We depleted TET1, TET2, and TET3 in a pluripotent embryonic carcinoma cell model and examined the impact on genome-wide 5mC, 5hmC, and transcriptional patterns.TET1 depletion yields widespread reduction of 5hmC, while depletion of TET2 and TET3 reduces 5hmC at a subset of TET1 targets suggesting functional co-dependence. TET2 or TET3 depletion also causes increased 5hmC, suggesting these proteins play a major role in 5hmC removal. All TETs prevent hypermethylation throughout the genome, a finding dramatically illustrated in CpG island shores, where TET depletion results in prolific hypermethylation. Surprisingly, TETs also promote methylation, as hypomethylation was associated with 5hmC reduction. TET function is highly specific to chromatin environment: 5hmC maintenance by all TETs occurs at polycomb-marked chromatin and genes expressed at moderate levels; 5hmC removal by TET2 is associated with highly transcribed genes enriched for H3K4me3 and H3K36me3. Importantly, genes prone to hypermethylation in cancer become depleted of 5hmC with TET deficiency, suggesting that TETs normally promote 5hmC at these loci. Finally, all three TETs, but especially TET2, are required for 5hmC enrichment at enhancers, a condition necessary for expression of adjacent genes.These results provide novel insight into the division of labor among TET proteins and reveal important connections between TET activity, the chromatin landscape, and gene expression.
PSYCHOLOGY AND THE PRACTICE OF MEDICINE
Authors: J. C. McClure
Journal: BMJ (1930)

} responsible, in a 'cpmmunitv's life, not only for oui' own welfare but also for tht of otlier people.No person's lE DICINE.'psychology is properly developed unless emotions, and their -By niatural expressions, are controlled within safe social limits, and a sense of duty to other people is properly developed.
Neuroprotection and progenitor cell renewal in the injured adult murine retina requires healing monocyte-derived macrophages
Authors: Anat London, Elena Itskovich, Inbal Benhar, Vyacheslav Kalchenko, Matthias Mack, Steffen Jung, Michal Schwartz
Journal: The Journal of Experimental Medicine (2011)

The death of retinal ganglion cells (RGCs) is a hallmark of many retinal neuropathies. Neuroprotection, axonal regeneration, and cell renewal are vital for the integrity of the visual system after insult but are scarce in the adult mammalian retina. We hypothesized that monocyte-derived macrophages, known to promote healing in peripheral tissues, are required after an insult to the visual system, where their role has been largely overlooked. We found that after glutamate eye intoxication, monocyte-derived macrophages infiltrated the damaged retina of mice. Inhibition of this infiltration resulted in reduced survival of RGCs and diminished numbers of proliferating retinal progenitor cells (RPCs) in the ciliary body. Enhancement of the circulating monocyte pool led to increased RGC survival and RPC renewal. The infiltrating monocyte-derived macrophages skewed the milieu of the injured retina toward an antiinflammatory and neuroprotective one and down-regulated accumulation of other immune cells, thereby resolving local inflammation. The beneficial effect on RGC survival depended on expression of interleukin 10 and major histocompatibility complex class II molecules by monocyte-derived macrophages. Thus, we attribute to infiltrating monocyte-derived macrophages a novel role in neuroprotection and progenitor cell renewal in the injured retina, with far-reaching potential implications to retinal neuropathies and other neurodegenerative disorders.
Novel Clinically Relevant Genes in Gastrointestinal Stromal Tumors Identified by Exome Sequencing
Authors: Sebastian F. Schoppmann, Ursula Vinatzer, Niko Popitsch, Martina Mittlböck, Sandra Liebmann-Reindl, Gerd Jomrich, Berthold Streubel, Peter Birner
Journal: Clinical Cancer Research (2013)

Chromosomal gains and losses resulting in altered gene dosage are known to be recurrent in gastrointestinal stromal tumors (GIST). The aim of our study was the identification of clinical relevant genes in these candidate regions.A cohort of 174 GIST was investigated using DNA array (n = 29), FISH (n = 125), exome sequencing (n = 13), and immunohistochemistry (n = 145).Array analysis revealed recurrent copy number variations (CNVs) of chromosomal arms 1p, 1q, 3p, 4q, 5q, 7p, 11q, 12p, 13q, 14q, 15q, and 22q. FISH studies of these CNVs showed that relative loss of 1p was associated with shorter disease-free survival (DFS). Analysis of exome sequencing concentrating on target regions showing recurrent CNVs revealed a median number of 3,404 (range 1,641-13,602) variants (SNPs, insertions, deletions) in each tumor minus paired blood sample; variants in at least three samples were observed in 37 genes. After further analysis, target genes were reduced to 10 in addition to KIT and PDGFRA. Immunohistochemical investigation showed that expression of SYNE2 and DIAPH1 was associated with shorter DFS, expression of RAD54L2 with shorter and expression of KIT with longer overall survival.Using a novel approach combining DNA arrays, exome sequencing, and immunohistochemistry, we were able to identify 10 target genes in GIST, of which three showed hithero unknown clinical relevance. Because the identified target genes SYNE2, MAPK8IP2, and DIAPH1 have been shown to be involved in MAP kinase signaling, our data further indicate the important role of this pathway in GIST.
Violence in E-Rated Video Games
Authors: Kimberly M. Thompson
Journal: JAMA (2001)

ContextChildren's exposure to violence, alcohol, tobacco and other substances, and sexual messages in the media are a source of public health concern; however, content in video games commonly played by children has not been quantified.ObjectivesTo quantify and characterize the depiction of violence, alcohol, tobacco and other substances, and sex in video games rated E (for "Everyone"), analogous to the G rating of films, which suggests suitability for all audiences.DesignWe created a database of all existing E-rated video games available for rent or sale in the United States by April 1, 2001, to identify the distribution of games by genre and to characterize the distribution of content descriptors associated with these games. We played and assessed the content of a convenience sample of 55 E-rated video games released for major home video game consoles between 1985 and 2000.Main Outcome MeasuresGame genre; duration of violence; number of fatalities; types of weapons used; whether injuring characters or destroying objects is rewarded or is required to advance in the game; depiction of alcohol, tobacco and other substances; and sexual content.ResultsBased on analysis of the 672 current E-rated video games played on home consoles, 77% were in sports, racing, or action genres and 57% did not receive any content descriptors. We found that 35 of the 55 games we played (64%) involved intentional violence for an average of 30.7% of game play (range, 1.5%-91.2%), and we noted significant differences in the amount of violence among game genres. Injuring characters was rewarded or required for advancement in 33 games (60%). The presence of any content descriptor for violence (n = 23 games) was significantly correlated with the presence of intentional violence in the game (at a 5% significance level based on a 2-sided Wilcoxon rank-sum test, t53 = 2.59). Notably, 14 of 32 games (44%) that did not receive a content descriptor for violence contained acts of violence. Action and shooting games led to the largest numbers of deaths from violent acts, and we found a significant correlation between the proportion of violent game play and the number of deaths per minute of play. We noted potentially objectionable sexual content in 2 games and the presence of alcohol in 1 game.ConclusionsContent analysis suggests a significant amount of violence in some E-rated video games. The content descriptors provide some information to parents and should be used along with the rating, but the game's genre also appears to play a role in the amount of violent play. Physicians and parents should understand that popular E-rated video games may be a source of exposure to violence and other unexpected content for children and that games may reward the players for violent actions.
Long-Term Outcome in Elderly Patients With Chronic Angina Managed Invasively Versus by Optimized Medical Therapy
Authors: Matthias Pfisterer
Journal: Circulation (2004)

There are no prospective trial data on long-term outcomes in 80-year-old patients with chronic angina with regard to antiischemic therapy.To assess long-term survival and quality of life (QoL) in patients from the Trial of Invasive versus Medical Therapy in the Elderly (TIME), all 276 1-year survivors (of a total 301 patients) were contacted after a median of 3.1 years (range, 1.1 to 5.9 years). At baseline, patients were 80+/-4 years old, 42% were women, and they were designated as being in angina class 3.2+/-0.7, despite their taking 2.5+/-0.7 antiischemic drugs. Patients were randomized to an invasive (n=153) or an optimized medical (n=148) strategy. Survival of invasive-strategy versus medical-strategy patients was 91.5% versus 95.9% after 6 months, 89.5% versus 93.9% after 1 year, and 70.6% versus 73.0% after 4.1 years (P=NS). Mortality was independently increased in patients >or=80 years of age, with prior heart failure, ejection fraction <or=0.45, and >or=2 comorbidities, and without revascularization within the first year. Revascularization within the first year improved survival in invasive-strategy (P=0.07) and medical-strategy (P<0.001) patients. The early benefit of both treatments in angina relief and QoL was maintained long term, but freedom from major events remained higher in invasive-strategy versus medical-strategy patients (39% versus 20%, P<0.0001).Long-term survival was similar for patients assigned to invasive and medical treatment. The benefits of both treatments in angina relief and improvement in QoL were maintained, but nonfatal events occurred more frequently in patients assigned to medical treatment. Irrespective of whether patients were catheterized initially or only after drug therapy failure, their survival rates were better if they were revascularized within the first year.
SOME EFFECTS OF FORMALDEHYDE ON HORSE ANTIPNEUMOCOCCUS SERUM AND DIPHTHERIA ANTITOXIN, AND THEIR SIGNIFICANCE FOR THE THEORY OF ANTIGEN-ANTIBODY AGGREGATION
Authors: Harry Eagle
Journal: The Journal of Experimental Medicine (1938)

Small amounts of formaldehyde inhibited the precipitating activity of horse diphtheria antitoxin with toxin and of horse antipneumococcus serum with the homologous capsular carbohydrate. Approximately 1 part of commercial formaldehyde to 1000 parts of serum, acting for 24 hours, inhibited the flocculating activity completely. In both cases, the combining affinity of the treated antibody for the corresponding antigen was not demonstrably affected, as determined both by in vitro experiments and by animal protection. More intensive treatment of the antipneumococcus serum caused an apparent loss of its bacterial agglutinating activity, but on centrifugation the organisms cohered: combination had occurred, and only the spontaneous aggregation was prevented. These effects are the same as those previously described for diazo compounds, and have been qualitatively reproduced with acetaldehyde, benzaldehyde and butyraldehyde. The quantitative relationships suggest that only a few groups in the antibody molecule need be modified by formaldehyde in order to prevent aggregation; and it is probable that these are some of the free NH(2) groups of the antibody protein. In marked contrast, the combining affinity of both antipneumococcus antibody and diphtheria antitoxin for the corresponding antigens was only slightly affected by amounts of formaldehyde which sufficed to block the free NH(2) groups rapidly and almost completely. Similarly, this amount of treatment did not affect the reactivity of these two antisera acting as antigen with a rabbit antiserum versus horse serum. The integrity of the NH(2) groups is apparently not essential for the activity of these sera acting either as antigen or as antibody; and the slow disappearance of their activity in concentrated HCOH is apparently to be ascribed to some secondary reaction other than the simple addition of HCOH to free NH(2) groups. The present experiments do not support the theory that antigen-antibody aggregates are lattice-like structures built up from elementary antigen-antibody compounds because of residual specific combining groups. The aggregating activity of both antipneumococcus serum and diphtheria antitoxin was completely inhibited by procedures which did not demonstrably affect their combining power with antigen. This suggests that the aggregation of antigen-antibody compounds is a secondary, non-specific reaction. It is perhaps significant that the amount of formaldehyde which just sufficed to prevent aggregation also caused a marked increase in the solubility of the pneumococcus antibody, which could then no longer be precipitated at serum pH by dilution with water or by dialysis. This strongly suggests that the loss of precipitating activity is actually due to the increased solubility of the antibody and supports the hypothesis that the primary cause of specific antigen-antibody aggregation is the relative insolubility of the bound antibody.
Efficacy and Safety of Brexpiprazole for the Treatment of Acute Schizophrenia: A 6-Week Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Christoph U. Correll, Aleksandar Skuban, John Ouyang, Mary Hobart, Stephanie Pfister, Robert D. McQuade, Margaretta Nyilas, William H. Carson, Raymond Sanchez, Hans Eriksson
Journal: American Journal of Psychiatry (2015)

The efficacy, safety, and tolerability of brexpiprazole and placebo were compared in adults with acute schizophrenia.This was a multicenter, randomized, double-blind, placebo-controlled study. Patients with schizophrenia experiencing an acute exacerbation were randomly assigned to daily brexpiprazole at a dosage of 0.25, 2, or 4 mg or placebo (1:2:2:2) for 6 weeks. Outcomes included change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score (primary endpoint measure), Clinical Global Impressions Scale (CGI) severity score (key secondary endpoint measure), and other efficacy and tolerability measures.The baseline overall mean PANSS total score was 95.2, and the CGI severity score was 4.9. Study completion rates were 62.2%, 68.1%, and 67.2% for patients in the 0.25-, 2-, and 4-mg brexpiprazole groups, respectively, versus 59.2% in the placebo group. At week 6, compared with placebo, brexpiprazole dosages of 2 and 4 mg produced statistically significantly greater reductions in PANSS total score (treatment differences: -8.72 and -7.64, respectively) and CGI severity score (treatment differences: -0.33 and -0.38). The most common treatment-emergent adverse event for brexpiprazole was akathisia (2 mg: 4.4%; 4 mg: 7.2%; placebo: 2.2%). Weight gain with brexpiprazole was moderate (1.45 and 1.28 kg for 2 and 4 mg, respectively, versus 0.42 kg for placebo at week 6). There were no clinically or statistically significant changes from baseline in lipid and glucose levels and extrapyramidal symptom ratings.Brexpiprazole at dosages of 2 and 4 mg/day demonstrated statistically significant efficacy compared with placebo and good tolerability for patients with an acute schizophrenia exacerbation.
A Milestone in Medical History
Authors: J. A. Moody
Journal: BMJ (1954)

Twenty years previous to the foundation of this Branch the Provincial Medical and Surgical Association had just been formed, and the medical profession had under- gone in that time great and striking changes in its social and educational aspects and in its general tone, the well- informed practitioner tending to displace the apothe- cary, and the level in the standard of treatment in all
Concentrated Ambient Particles Alter Myocardial Blood Flow during Acute Ischemia in Conscious Canines
Authors: Carlo R. Bartoli, Gregory A. Wellenius, Brent A. Coull, Ichiro Akiyama, Edgar A. Diaz, Joy Lawrence, Kazunori Okabe, Richard L. Verrier, John J. Godleski
Journal: Environmental Health Perspectives (2008)

Experimental and observational studies have demonstrated that short-term exposure to ambient particulate matter (PM) exacerbates myocardial ischemia.We conducted this study to investigate the effects of concentrated ambient particles (CAPs) on myocardial blood flow during myocardial ischemia in chronically instrumented conscious canines.Eleven canines were instrumented with a balloon occluder around the left anterior descending coronary artery and catheters for determination of myocardial blood flow using fluorescent microspheres. Telemetric electrocardiographic and blood pressure monitoring was available for four of these animals. After recovery, we exposed animals by inhalation to 5 hr of either filtered air or CAPs (mean concentration+/-SD, 349.0+/-282.6 microg/m3) in a crossover protocol. We determined myocardial blood flow during a 5-min coronary artery occlusion immediately after each exposure. Data were analyzed using mixed models for repeated measures. The primary analysis was based on four canines that completed the protocol.CAPs exposure decreased total myocardial blood flow during coronary artery occlusion by 0.12 mL/min/g (p<0.001) and was accompanied by a 13% (p<0.001) increase in coronary vascular resistance. Rate-pressure product, an index of myocardial oxygen demand, did not differ by exposure (p=0.90). CAPs effects on myocardial blood flow were significantly more pronounced in myocardium within or near the ischemic zone versus more remote myocardium (p interaction<0.001).These results suggest that PM exacerbates myocardial ischemia by increased coronary vascular resistance and decreased myocardial perfusion. Further studies are needed to elucidate the mechanism of these effects.
Soluble M6P/IGF2R Released by TACE Controls Angiogenesis via Blocking Plasminogen Activation
Authors: Vladimir Leksa, Robert Loewe, Brigitte Binder, Herbert B. Schiller, Paul Eckerstorfer, Florian Forster, Ana Soler-Cardona, Gabriela Ondrovičová, Eva Kutejová, Eva Steinhuber, Johannes Breuss, Johannes Drach, Peter Petzelbauer, Bernd R. Binder, Hannes Stockinger
Journal: Circulation Research (2011)

The urokinase plasminogen activator (uPA) system is among the most crucial pericellular proteolytic systems associated with the processes of angiogenesis. We previously identified an important regulator of the uPA system in the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R).Here, we wanted to clarify whether and how did the soluble form of M6P/IGF2R (sM6P/IGF2R) contribute to modulation of the uPA system.By using specific inhibitors and RNA interference, we show that the tumor necrosis factor α convertase (TACE, ADAM-17) mediates the release of the ectodomain of M6P/IGF2R from human endothelial cells. We demonstrate further that sM6P/IGF2R binds plasminogen (Plg) and thereby prevents Plg from binding to the cell surface and uPA, ultimately inhibiting in this manner Plg activation. Furthermore, peptide 18-36 derived from the Plg-binding site of M6P/IGF2R mimics sM6P/IGF2R in the inhibition of Plg activation and blocks cancer cell invasion in vitro, endothelial cell invasion in vivo, and tumor growth in vivo.The interaction of sM6P/IGF2R with Plg may be an important regulatory mechanism to inhibit migration of cells using the uPA/uPAR system.
Explaining the Increase of Diabetes Prevalence and Plasma Glucose in Mauritius
Authors: Dianna J. Magliano, Stefan Söderberg, Paul Z. Zimmet, Lei Chen, Noorjehan Joonas, Sudhir Kowlessur, Jose Larhubarbe, Dhanunjaye Gaoneadry, Vassen Pauvaday, Jaakko Tuomilehto, K. George M.M. Alberti, Jonathan E. Shaw
Journal: Diabetes Care (2011)

Secular trends in the epidemiology of diabetes are best described by studying the same population over time, but few such studies exist. Using surveys from Mauritius in 1987 and 2009, we examined 1) the change in the prevalence of diabetes, 2) the extent to which changes in traditional diabetes risk factors explained the increase, and 3) the change in the distribution of plasma glucose levels over time.Independent population-based surveys were undertaken in Mauritius in 1987 and 2009 using similar methodology in adults aged 20-74 years. Physical measurements and fasting blood samples were taken, and an oral glucose tolerance test was performed at both surveys.The age-standardized prevalence of diabetes in 2009 was 22.3% (95% CI 20.0-24.6) among men and 20.2% (18.3-22.3) among women, representing an increase since 1987 of 64 and 62% among men and women, respectively. Concurrent changes in the distribution of age, ethnicity, waist circumference, BMI, physical activity, smoking, family history of diabetes, and hypertension explained more of the increase in the prevalence of diabetes in men than in women. Increases in plasma glucose (especially fasting glucose) were seen across the population but were greater at the upper levels.In Mauritius, there has been a marked increase in diabetes prevalence over 22 years. This mainly results from changes in traditional risk factors, leading to population-wide increases in plasma glucose levels. Interventions to control this escalation of diabetes should focus on population-wide strategies.