tbuckley/cabot-search huggingface dataset:
P184 Applying the GOLD 2011 Classification to a Real-World COPD Population in Germany
Authors: C Vogelmeier, M Small, S Broomfield, J Vestbo
Journal: Thorax (2012)

<h3>Objectives</h3> The GOLD 2011 Strategy now recommends assessment based on exacerbation history and symptoms in addition to airflow limitation. Our goal was to better understand this classification system by analysing the distribution of patients across the 4 groups, their treatment and comorbidities in a real-world population. <h3>Methods</h3> GOLD 2011 criteria were applied to a German COPD population sampled from the Adelphi Respiratory Disease Specific Programme undertaken in 2011. Patients were recruited from consulting primary and specialist physicians. Chi-squared tests were performed. <h3>Results</h3> 507 patients had a FEV1 value and/or exacerbation history and COPD Assessment Test (CAT) score. 10.5% of patients scored 0–9 using CAT, resulting in an uneven distribution of patients in groups A-D, 7.7, 49.9, 2.8 and 39.6% respectively. Using mMRC the distribution of patients in groups A-D was 35.1, 20.9, 19.1, and 24.9%. Inhaled corticosteroid (ICS) therapy was prescribed to 51.3, 57.9 and 42.7% of group A, B and D patients, respectively. Cardiovascular disease (51.3, 68.0, 75.2% [p=0.02]), diabetes (6.5, 17.8, 18.9% [p=0.20]) and obesity (0, 12.6, 16.8% [p=0.04]) increased across groups A, B and D respectively. Due to low numbers, group C was excluded from the comparison analysis. <h3>Conclusion</h3> 2.8% of patients qualified as high risk/low symptoms suggesting this patient type is rare based on a CAT evaluation, using mMRC this proportion was 19.1%. An education gap exists regarding the appropriate use of ICS given the high proportion of treated low risk patients. CV and metabolic comorbidities are more prevalent with increasing risk/symptoms so a holistic approach may be necessary, especially for group D patients.
What Is a “Mood Stabilizer”? An Evidence-Based Response
Authors: Mark S. Bauer, Landis Mitchner
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: The term "mood stabilizer" is widely used in the context of treating bipolar disorder, but the U.S. Food and Drug Administration (FDA) does not officially recognize the term, and no consensus definition is accepted among investigators. The authors propose a "two-by-two" definition by which an agent is considered a mood stabilizer if it has efficacy in treating acute manic and depressive symptoms and in prophylaxis of manic and depressive symptoms in bipolar disorder. They review the literature on the efficacy of agents in any of these four roles to determine which if any agents meet this definition of mood stabilizer. METHOD: The authors conducted a comprehensive review of English-language literature describing peer-reviewed, U.S. Agency for Healthcare Research and Quality class A controlled trials in order to identify agents with efficacy in any of the four roles included in their definition of a mood stabilizer. The trials were classified as positive or negative on the basis of primary outcome variables. An "FDA-like" criterion of at least two positive placebo-controlled trials was required to consider an agent efficacious. The authors also conducted a sensitivity analysis by raising and relaxing the criteria for including trials in the review. RESULTS: The authors identified 551 candidate articles, yielding 111 class A trials, including 81 monotherapy trials with 95 independent analyses published through June 2002. Lithium, valproate, and olanzapine had unequivocal evidence for efficacy in acute manic episodes, lithium in acute depressive episodes and in prophylaxis of mania and depression, and lamotrigine in prophylaxis (relapse polarity unspecified). Thus, only lithium fulfilled the a priori definition of a mood stabilizer. Relaxing the quality criterion did not change this finding, while raising the threshold resulted in no agents fulfilling the definition. CONCLUSIONS: When all four treatment roles are considered, the evidence supported a role for lithium as first-line agent for treatment of bipolar disorder. The analysis also highlights unmet needs and promising agents and provides a yardstick for evaluating new treatment strategies.
Chordate Hox and ParaHox Gene Clusters Differ Dramatically in Their Repetitive Element Content
Authors: P. W. Osborne, D. E.K. Ferrier
Journal: Molecular Biology and Evolution (2009)

The ParaHox and Hox gene clusters control aspects of animal anterior–posterior development and are related as paralogous evolutionary sisters. Despite this relationship, it is not clear if the clusters operate in similar ways, with similar constraints. To compare clusters, we examined the transposable-element (TE) content of amphioxus and mammalian ParaHox and Hox clusters. Chordate Hox clusters are known to be largely devoid of TEs, possibly due to gene regulation and constraints on clustering in these animals. Here, we describe several novel amphioxus TEs and show that the amphioxus ParaHox cluster is a hotspot for TE insertion. TE contents of mammalian ParaHox loci are at background levels, in stark contrast to chordate Hox clusters. This marks a significant difference between Hox and ParaHox clusters. The presence of so many potentially disruptive elements implies selection constrains these ParaHox clusters as they have not dispersed despite 500 My of evolution for each lineage.
Acute myocardial infarction: diagnostic and prognostic applications of two-dimensional echocardiography.
Authors: R A Kloner, A F Parisi
Journal: Circulation (1987)

Now that we are entering an era when thrombolytic therapy and early invasive interventions appear to offer significant myocardium-sparing effects, it is important to attempt to exploit techniques that bear directly on the issue of anatomy to obtain an objective measure of infarct size and prognosis. Traditional tests for AMI were developed as diagnostic measures and cannot be expected to measure up to issues raised by modern therapy. Despite its pitfalls, echocardiography can be applied prognostically during the first few hours of AMI evolution to far more patients than can any other imaging technique. We believe that an adequate echocardiographic examination can be an important adjunct that should be used in the early risk assessment of any patient with AMI. Those patients with the greatest potential reversible myocardial damage are clearly the best candidates for aggressive interventions, particularly thrombolysis. For patients with small or no detectable regional wall motion abnormalities, a more conservative initial approach is in order.
Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma
Authors: Xiaoguang Li, Wenbo Yao, Ya Yuan, Peizhan Chen, Bin Li, Jingquan Li, Ruiai Chu, Haiyun Song, Dong Xie, Xiaoqing Jiang, Hui Wang
Journal: Gut (2015)

<h3>Objective</h3> Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited effective treatment options. An alternative strategy is to target cells, such as tumour-infiltrating macrophages, in the HCC tumour microenvironment. The CCL2/CCR2 axis is required for recruitment of monocytes/macrophages and is implicated in various aspects of liver pathology, including HCC. We investigated the feasibility of CCL2/CCR2 as a therapeutic target against HCC. <h3>Design</h3> CCL2 expression was analysed in two independent HCC cohorts. Growth of three murine HCC cells was evaluated in an orthotopic model, a postsurgical recurrence model and a subcutaneous model in mice after blocking CCL2/CCR2 axis by a novel CCR2 antagonist or knocking out of host CCR2. In vivo macrophage or T cell depletion and in vitro cell coculture were further conducted to investigate CCL2/CCR2-mediated crosstalk between tumour-associated macrophages (TAMs) and tumour cells. <h3>Result</h3> CCL2 is overexpressed in human liver cancers and is prognostic for patients with HCC. Blockade of CCL2/CCR2 signalling with knockout of CCR2 or with a CCR2 antagonist inhibits malignant growth and metastasis, reduces postsurgical recurrence, and enhances survival. Further, therapeutic blocking of the CCL2/CCR2 axis inhibits the recruitment of inflammatory monocytes, infiltration and M2-polarisation of TAMs, resulting in reversal of the immunosuppression status of the tumour microenvironment and activation of an antitumorous CD8<sup>+</sup> T cell response. <h3>Conclusions</h3> In patients with liver cancer, CCL2 is highly expressed and is a prognostic factor. Blockade of CCL2/CCR2 signalling suppresses murine liver tumour growth via activating T cell antitumour immune response. The results demonstrate the translational potential of CCL2/CCR2 blockade for treatment of HCCs.
Syndrome of Short P-R Interval with Abnormal QRS Complexes and Paroxysmal Tachycardia (Wolff-Parkinson-White Syndrome)
Authors: LOUIS WOLFF
Journal: Circulation (1954)

The syndrome of short P-R interval with abnormal QRS complexes and paroxysmal tachycardia occurs in otherwise healthy individuals in all age groups. Its interest and importance are related to our knowledge and concepts of the cardiac mechanism, the prevalence and clinical manifestations of paroxysmal tachycardia, the masking of the electrocardiographic signs of heart disease, and the serious consequences involved in making an incorrect diagnosis of heart disease. A single mechanism is in all probability responsible for the abnormal electrocardiogram and the paroxysmal tachycardia. Premature activation of a small fraction of ventricular musculature shortens the P-R interval and lengthens the QRS interval, thus accounting for the electrocardiographic peculiarities of the syndrome. Whether an anomaly of impulse formation or an anomaly of conduction is responsible for pre-excitation is not known, and the propensity to paroxysmal tachycardia can be explained on either basis. There is no evidence that hitherto unknown phenomena are responsible for the syndrome. The disorder is probably congenital in nature. A noteworthy feature is the spontaneous or induced shift, back and forth, from the abnormal to the normal type of electrocardiogram. Many drugs and procedures are available for this purpose. This is of immeasurable help in establishing the diagnosis of the Wolff-Parkinson-White syndrome in doubtful cases, and in unmasking the many abnormalities which anomalous excitation conceals. Diagnostic errors are common, and the reasons for these have been discussed. Myocardial infarction, mitral stenosis, congenital heart disease, right and left ventricular hypertrophy, myocarditis, and bundle-branch block are the mistaken diagnoses most commonly made. Myocardial infarction, right and left ventricular hypertrophy, and right bundle branch block are the conditions most commonly concealed by the anomalous electrocardiogram. The most important problems still requiring elucidation are those related to etiology, and to the mechanisms responsible for the abnormal electrocardiogram and paroxysmal rapid heart action.
Impact of genetic engineering on the understanding of spermatogenesis
Authors: D. Escalier
Journal: Human Reproduction Update (2001)

To date, about 100 genes have been found, by genetic engineering, to be implicated in spermatogenesis. Primordial germ cells, spermatogonia, spermatocytes I and elongating spermatids are particularly sensitive. Transgenic and knockout mice permit an approach to be made to the question of genetic factors involved in DNA damage repair, thermal injury, sperm chromatin compaction and sex-specific recombination. Knockout mice reveal unexpected functional redundancies of testis-specific genes. This review considers how functional divergences can exist among homologous genes from different species, and to what extent the phenotypes of knockout mice can be similar to those from spontaneous mutations. Additional anomalies in reproductive function have frequently been found in these mice, as were found factors leading to tumour susceptibility and/or various diseases. Finally, knockout mice remind us that, in nearly all cases, hemizygous individuals retain a fertility and a wild-type sperm phenotype, although half of the spermatozoa share a genetic defect. The findings strongly emphasize the importance of understanding epidemiology in male infertility, to identify hereditary forms of impaired spermatogenesis, and to create DNA and pathological germ cell banks.
Retraction of: FAK mediates the activation of cardiac fibroblasts induced by mechanical stress through regulation of the mTOR complex
Authors: A. P. Dalla Costa, C. F. M. Z. Clemente, H. F. Carvalho, J. B. Carvalheira, W. Nadruz, K. G. Franchini
Journal: Cardiovascular Research (2014)

Cardiovasc Res (2010); 86 (3): 421–431. doi:10.1093/cvr/cvp416

The study by Dalla Costa et al. reported an analysis of the role of focal adhesion kinase in …
Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF-beta production.
Authors: G Messer, U Spengler, M C Jung, G Honold, K Blömer, G R Pape, G Riethmüller, E H Weiss
Journal: The Journal of Experimental Medicine (1991)

Since a dysregulated synthesis of tumor necrosis factor alpha (TNF-alpha) may be involved in the pathogenesis of autoimmune diseases, it was of interest to precisely locate the recently reported NcoI restriction fragment length polymorphism (RFLP) of the TNF-alpha region. However, by mapping of 56.8 kb of overlapping cosmid clones and direct sequencing, we could localize the polymorphic NcoI restriction site within the first intron of the TNF-beta gene and not in the TNF-alpha gene. To study whether regulatory mechanisms are affected by this polymorphism, we analyzed the TNF-alpha/TNF-beta production of phytohemagglutinin-stimulated peripheral blood mononuclear cells of individuals homozygous for the TNF-beta NcoI RFLP by ELISA and concomitant Northern blot analysis. On days 2-4 after stimulation with mitogen, the TNFB*1 allele corresponding to a 5.3-kb NcoI fragment presented with a significantly higher TNF-beta response. A mRNA analysis demonstrated that higher protein levels of TNF-beta correlate also with increased amounts of TNF-beta transcripts. No allelic association was found in respect to TNF-alpha production. To further investigate a possible allelic influence on transcription, we determined the DNA sequence of 2 kb of the 5' portion of our cloned TNFB*2 allele and compared it with the available TNF-beta sequences. By computer-aided recognition motif search of DNA binding factors, we report putative binding sites conserved between mouse and man in the 5' flanking region as well as in intron 1 of the TNF-beta gene, found also in other cytokine promoter sequences. In addition, by polymerase chain reaction amplification and sequencing of 740 bp of the 5' part of TNF-beta of individuals typed homozygously for the NcoI RFLP, we could show that amino acid position 26 is conserved as asparagine in the TNFB*1 and as threonine in the TNFB*2 sequence. A previously reported, EcoRI RFLP in the 3' untranslated region of TNF-beta does not segregate with either of the two alleles. Thus, four TNFB alleles can be defined at the DNA level.
Calcium current in single cells isolated from normal and hypertrophied rat heart. Effects of beta-adrenergic stimulation.
Authors: F Scamps, E Mayoux, D Charlemagne, G Vassort
Journal: Circulation Research (1990)

The L-type calcium current was investigated in normal and hypertrophied rat ventricular myocytes as a possible cause of the action potential lengthening that has been reported during hypertrophy. Regulation of the calcium current (ICa) by a beta-adrenergic agonist (isoproterenol) was also analyzed since beta-agonist-induced positive inotropy is less marked in hypertrophied heart. Left ventricular hypertrophy was induced by stenosis of the abdominal aorta. For recording ICa, the whole-cell patch-clamp technique was used. Potassium currents were suppressed by replacing K+ ions with Cs+ ions in both the extracellular and intracellular media, and sodium current was blocked by 50 microM tetrodotoxin. The Ca2+ current was larger in hypertrophied cells (2.2 +/- 0.6 nA [n= 31]) than in normal cells (1.2 +/- 0.5 nA [n = 33]). However, if one relates ICa amplitude to the cell membrane area, as estimated by membrane capacitance measurement, no significant difference was observed in current density (8.5 +/- 2.5 pA/pF [n = 31] and 8.3 +/- 2.1 pA/pF [n = 33] in hypertrophied and in normal cells, respectively). In both cell types, ICa displayed the same voltage and time dependence. When expressed as a percentage, the maximal increase in ICa amplitude that was obtained with 100 nM isoproterenol was less in hypertrophied cells (+78%) than in normal cells (+120%). The sensitivity of ICa to beta-adrenergic stimulation was not modified: EC50 was 3.8 nM for hypertrophied cells and 4.8 nM for normal cells. Forskolin and cyclic AMP were as effective in both cell types. Stimulation of ICa by beta-adrenergic agonist was decreased in agreement with a reduced number of binding sites of beta-agonists and/or an altered coupling of the G-proteins.
Vasodilator Action of Guanethidine
Authors: Francois M. Abboud, John W. Eckstein
Journal: Circulation Research (1962)

The cardiovascular effects of intravenous guanethidine were measured in animals treated with reserpine. The action of intraarterial guanethidine was studied also in perfused forelegs of dogs. The following conclusions were reached: 1. There was no significant increase in cardiac output, heart rate, or systemic arterial pressure following intravenous guanethidine in treated animals; only sustained vasodilatation was observed. 2. The vasodilatation was caused by a local action of the drug on vascular smooth muscle. The dilatation became more pronounced following depletion of catecholamines with reserpine and repeated administration of guanethidine. 3. The dilatation did not appear to be mediated through the release of catecholamines, histamine, or acetylcholine. It may have resulted, at least in part, from stimulation of beta adrenergic receptors or other "dilator receptors" which are blocked by dichloroisoproterenol.
The Functional A Allele Was Resurrected via Recombination in the Human ABO Blood Group Gene
Authors: Takashi Kitano, Antoine Blancher, Naruya Saitou
Journal: Molecular Biology and Evolution (2012)

Functional A and B alleles are distinguished at two critical sites in exon 7 of the human ABO blood group gene. The most frequent nonfunctional O alleles have one-base deletion in exon 6 producing a frameshift, and it has the A type signature in two critical sites in exon 7. Previous studies indicated that B and O alleles were derived from A allele in human lineage. In this study, we conducted a phylogenetic network analysis using six representative haplotypes: A101, A201, B101, O01, O02, and O09. The result indicated that the A allele, possibly once extinct in the human lineage a long time ago, was resurrected by a recombination between B and O alleles less than 300,000 years ago.
Levoamphetamine and Dextroamphetamine: Differential Effect on Aggression and Hyperkinesis in Children and Dogs
Authors: L. EUGENE ARNOLD, VLADIMIR KIRILCUK, SAMUEL A. CORSON, ELIZABETH O'L. CORSON
Journal: American Journal of Psychiatry (1973)

In laboratory experiments with hyperkinetic, untrainable dogs and in a comparison of levoamphetamine, dextroamphetamine, and placebo in children, levoamphetamine and dextroamphetamine were found to be approximately equal in calming an aggressive, hostile dog and in benefiting "unsocialized-aggressive" children: dextroamphetamine was more effective than levoamphetamine in calming "nervousness" and hyperactivity in dogs and in overanxious-hyperkinetic children. These data suggest that in the hyperkinetic syndrome, aggression and hostility may be benefited equally by levoamphetamine or dextroamphetamine via a dopaminergic mechanism, while anxiety and overactivity may be benefited significantly only by the dextro isomer via a norepinephrinergic mechanism.
Variations in Cause and Management of Atrial Fibrillation in a Prospective Registry of 15 400 Emergency Department Patients in 46 Countries
Authors: Jonas Oldgren, Jeff S. Healey, Michael Ezekowitz, Patrick Commerford, Alvaro Avezum, Prem Pais, Jun Zhu, Petr Jansky, Alben Sigamani, Carlos A. Morillo, Lisheng Liu, Albertino Damasceno, Alex Grinvalds, Juliet Nakamya, Paul A. Reilly, Katalin Keltai, Isabelle C. Van Gelder, Afzal Hussein Yusufali, Eiichi Watanabe, Lars Wallentin, Stuart J. Connolly, Salim Yusuf
Journal: Circulation (2014)

Background— Atrial fibrillation (AF) is the most common sustained arrhythmia; however, little is known about patients in a primary care setting from high-, middle-, and low-income countries. Methods and Results— This prospective registry enrolled patients presenting to an emergency department with AF at 164 sites in 46 countries representing all inhabited continents. Patient characteristics were compared among 9 major geographic regions. Between September 2008 and April 2011, 15 400 patients were enrolled. The average age was 65.9, standard deviation 14.8 years, ranging from 57.2, standard deviation 18.8 years in Africa, to 70.1, standard deviation 13.4 years in North America, P &lt;0.001. Hypertension was globally the most common risk factor for AF, ranging in prevalence from 41.6% in India to 80.7% in Eastern Europe, P &lt;0.001. Rheumatic heart disease was present in only 2.2% of North American patients, in comparison with 21.5% in Africa and 31.5% in India, P &lt;0.001. The use of oral anticoagulation among patients with a CHADS 2 score of ≥2 was greatest in North America (65.7%) but was only 11.2% in China, P &lt;0.001. The mean time in the therapeutic range was 62.4% in Western Europe, 50.9% in North America, but only between 32% and 40% in India, China, Southeast Asia, and Africa, P &lt;0.001. Conclusions— There is a large global variation in age, risk factors, concomitant diseases, and treatment of AF among regions. Improving outcomes globally requires an understanding of this variation and the conduct of research focused on AF associated with different underlying conditions and treatment of AF and predisposing conditions in different socioeconomic settings.