tbuckley/cabot-search huggingface dataset:
Comparison of the Bromsulphalein Method with Simultaneous Direct Hepatic Blood Flow
Authors: EWALD E. SELKURT
Journal: Circulation Research (1954)

A method has been devised for directly measuring hepatic outflow in dogs so as to permit simultaneous comparison with the indirect method, employing the hepatic removal of Bromsulphalein (BSP). The results show that the indirect method averages 7.3 per cent higher than the direct. This difference is attributed to a small Degrees of extrahepatic removal of the dye.
Phaeochromocytoma Simulating Thyrotoxicosis
Authors: J. V. S. A. Davies
Journal: BMJ (1952)

MEDICAL MEMORANDAseem most likely, with a mesenteric infarct to account for the second-day ileus.Phaeochromocytoma was considered be- cause of the glycosuria and hypertension, but, after perusal of the papers by Crowther (1951) and Swan (1951), was rejected as unlike any previous case so far reported at that time.Unfortunately, the paper of Gilliland and Daniel was not noted until the day of the necropsy, when the similarity in presentation and signs was remarked upon.Presumably haemorrhage into the cystic, friable, necrotic tumour produced the severely shocked state which, with a curious lividity of the skin, persisted throughout the whole illness.The use of anticoagulants must have aided this considerably, as must the bout of hypertension.A trouble- some feature of the case was the diabetes, more and more insulin being required to keep the urine clear of sugar as her blood pressure rose after the original fall.I would like to express my thanks to Dr. J. C.
Identification of novel small molecule inhibitors of adenovirus gene transfer using a high throughput screening approach
Authors: Margaret R. Duffy, Alan L. Parker, Eric R. Kalkman, Katie White, Dmytro Kovalskyy, Sharon M. Kelly, Andrew H. Baker
Journal: Journal of Controlled Release (2013)

Due to many favourable attributes adenoviruses (Ads) are the most extensively used vectors for clinical gene therapy applications. However, following intravascular administration, the safety and efficacy of Ad vectors are hampered by the strong hepatic tropism and induction of a potent immune response. Such effects are determined by a range of complex interactions including those with neutralising antibodies, blood cells and factors, as well as binding to native cellular receptors (coxsackie adenovirus receptor (CAR), integrins). Once in the bloodstream, coagulation factor X (FX) has a pivotal role in determining Ad liver transduction and viral immune recognition. Due to difficulties in generating a vector devoid of multiple receptor binding motifs, we hypothesised that a small molecule inhibitor would be of value. Here, a pharmacological approach was implemented to block adenovirus transduction pathways. We developed a high throughput screening (HTS) platform to identify small molecule inhibitors of FX-mediated Ad5 gene transfer. Using an in vitro fluorescence and cell-based HTS, we evaluated 10,240 small molecules. Following sequential rounds of screening, three compounds, T5424837, T5550585 and T5660138 were identified that ablated FX-mediated Ad5 transduction with low micromolar potency. The candidate molecules possessed common structural features and formed part of the one pharmacophore model. Focused, mini-libraries were generated with structurally related molecules and in vitro screening revealed novel hits with similar or improved efficacy. The compounds did not interfere with Ad5:FX engagement but acted at a subsequent step by blocking efficient intracellular transport of the virus. In vivo , T5660138 and its closely related analogue T5660136 significantly reduced Ad5 liver transgene expression at 48 h post-intravenous administration of a high viral dose (1 × 10 11 vp/mouse). Therefore, this study identifies novel and potent small molecule inhibitors of the Ad5 transduction which may have applications in the Ad gene therapy setting. A high throughput screening strategy was employed to find small molecule compounds that blocked adenovirus transduction pathways in vitro and decreased liver gene transfer in vivo .
Membranous Glomerulonephritis Induced in the Pig by Antibody to Angiotensin-Converting Enzyme
Authors: SHOICHI MARUYAMA, EDWARD CANTU, CESARE DEMARTINO, ADRIAN VLADUTIU, PETER R. B. CALDWELL, CATHERINE Y. WANG, VIVETTE D'AGATI, GABRIEL GODMAN, DAVID M. STERN, GIUSEPPE ANDRES
Journal: Journal of the American Society of Nephrology (1999)

In the course of studies on the humoral consequences of swine to primate xenotransplantation, the investigators induced formation of glomerular subepithelial immune deposits and tubular lesions in pigs injected with heterologous antibody to angiotensin-converting enzyme. This study describes the morphology of the lesions, discusses their mechanism, explains their relevance for understanding the pathogenesis of human idiopathic membranous glomerulonephritis, and proposes future directions for investigations.
Pressure-Derived Fractional Flow Reserve to Assess Serial Epicardial Stenoses
Authors: Bernard De Bruyne, Nico H. J. Pijls, Guy R. Heyndrickx, Dominique Hodeige, Richard Kirkeeide, K. Lance Gould
Journal: Circulation (2000)

Background-Fractional flow reserve (FFR) is an index of stenosis severity validated for isolated stenoses. This study develops the theoretical basis and experimentally validates equations for predicting FFR of sequential stenoses separately. Methods and Results-For 2 stenoses in series, equations were derived to predict FFR (FFR(pred)) of each stenosis separately (ie, as if the other one were removed) from arterial pressure (P(a)), pressure between the 2 stenoses (P(m)), distal coronary pressure (P(d)), and coronary occlusive pressure (P(w)). In 5 dogs with 2 stenoses of varying severity in the left circumflex coronary artery, FFR(pred) was compared with FFR(app) (ratio of the pressure just distal to that just proximal to each stenoses) and to FFR(true) (ratio of the pressures distal to proximal to each stenosis but after removal of the other one) in case of fixed distal and varying proximal stenoses (n=15) and in case of fixed proximal and varying distal stenoses (n=20). The overestimation of FFR(true) by FFR(app) was larger than that of FFR(true) by FFR(pred) (0.070+/-0.007 versus 0.029+/-0.004, P<0.01 for fixed distal stenoses, and 0.114+/-0.01 versus 0.036+/-0. 004, P<0.01 for fixed proximal stenoses). This overestimation of FFR(true) by FFR(app) was larger for fixed proximal than for fixed distal stenoses. Conclusions-The interaction between 2 stenoses is such that FFR of each lesion separately cannot be calculated by the equation for isolated stenoses (P(d)/P(a) during hyperemia) applied to each separately but can be predicted by more complete equations taking into account P(a), P(m), P(d), and P(w).
Pharmacogenomics of anticoagulants: steps toward personal dosage
Authors: Ann K Daly
Journal: Genome Medicine (2009)

Warfarin and other coumarin anticoagulants are widely used clinically, but currently dosing is determined individually on the basis of patient response. There is increasing evidence that genetic factors, together with several non-genetic patient-specific factors, are important determinants of stable dose requirement for these compounds. Genotype for CYP2C9, which encodes the main cytochrome P450 enzyme that metabolizes warfarin, and VKORC1, the gene encoding the warfarin target vitamin K epoxide reductase, together account for approximately 30% of the variability in dose requirement. The past two years have seen several advances in the area of genetic factors affecting coumarin anticoagulant response. In particular, prospective studies have taken place to analyze whether earlier small retrospective studies can be confirmed, and the question of whether genes other than CYP2C9 and VKORC1 are important in determining dose requirement has been examined. So far, no strong evidence that other genes contribute to dose requirement has been found, apart from a minor but novel role for another cytochrome P450 gene, CYP4F2. A recently published whole genome association study confirms that the main genes important in warfarin response are CYP2C9 and VKORC1. Clinical trials comparing genotype-guided and conventional warfarin initiation have suggested that genotyping may be of value, but larger studies are still needed to show clear clinical benefit. Current knowledge of genetic factors affecting other coumarin anticoagulants is more limited and this area requires further study, as does the impact of ethnic variation in genes relevant to coumarin responses. Here we review recent advances in the area of coumarin anticoagulant genetics and its potential clinical application.
Empirical levofloxacin-containing versus clarithromycin-containing sequential therapy for Helicobacter pylori eradication: a randomised trial
Authors: M. Romano, A. Cuomo, A. G. Gravina, A. Miranda, M. R. Iovene, A. Tiso, M. Sica, A. Rocco, R. Salerno, R. Marmo, A. Federico, G. Nardone
Journal: Gut (2010)

<h3>Background and aims</h3> Antimicrobial drug resistance is a major cause of the failure of <i>Helicobacter pylori</i> eradication and is largely responsible for the decline in eradication rate. Quadruple therapy has been suggested as a first-line regimen in areas with clarithromycin resistance rate &gt;15%. This randomised trial aimed at evaluating the efficacy of a levofloxacin-containing sequential regimen in the eradication of <i>H pylori</i>-infected patients in a geographical area with &gt;15% prevalence of clarithromycin resistance versus a clarithromycin-containing sequential therapy. <h3>Methods</h3> 375 patients who were infected with <i>H pylori</i> and naïve to treatment were randomly assigned to one of the following treatments: (1) 5 days omeprazole 20 mg twice daily + amoxicillin 1 g twice daily followed by 5 days omeprazole 20 mg twice daily + clarithromycin 500 mg twice daily + tinidazole 500 mg twice daily; or (2) omeprazole 20 mg twice daily + amoxicillin 1 g twice daily followed by omeprazole 20 mg twice daily + levofloxacin 250 mg twice daily + tinidazole 500 mg twice daily; or (3) omeprazole 20 mg twice daily + amoxicillin 1 g twice daily followed by omeprazole 20 mg twice daily + levofloxacin 500 mg twice daily + tinidazole 500 mg twice daily. Antimicrobial resistance was assessed by the E-test. Efficacy, adverse events and costs were determined for each group. <h3>Results</h3> Eradication rates in the intention-to-treat analyses were 80.8% (95% CI, 72.8% to 87.3%) with clarithromycin sequential therapy, 96.0% (95% CI, 90.9% to 98.7%) with levofloxacin-250 sequential therapy, and 96.8% (95% CI, 92.0% to 99.1%) with levofloxacin-500 sequential therapy. No differences in prevalence of antimicrobial resistance or incidence of adverse events were observed between groups. Levofloxacin-250 therapy was cost-saving compared with clarithromycin sequential therapy. <h3>Conclusion</h3> In an area with &gt;15% prevalence of clarithromycin resistant <i>H pylori</i> strains, a levofloxacin-containing sequential therapy is more effective, equally safe and cost-saving compared to a clarithromycin-containing sequential therapy.
Zonal Heterogeneity in Action of Angiotensin-Converting Enzyme Inhibitor on Renal Microcirculation
Authors: HIROTO MATSUDA, KOICHI HAYASHI, KOKI ARAKAWA, MAREO NAITOH, EIJI KUBOTA, MASANORI HONDA, AKIRA MATSUMOTO, HIROMICHI SUZUKI, TOKUNORI YAMAMOTO, FUMIHIKO KAJIYA, TAKAO SARUTA
Journal: Journal of the American Society of Nephrology (1999)

Abstract. The present study examined the role of intrarenal bradykinin in angiotensin-converting enzyme inhibitor (ACEI)-induced dilation of renal afferent (AFF) and efferent arterioles (EFF) in vivo, and further evaluated whether ACEI-stimulated bradykinin activity differed in superficial (SP) and juxtamedullary nephrons (JM). Arterioles of canine kidneys were visualized with an intravital charge-coupled device camera microscope. E4177 (an angiotensin receptor antagonist, 30 μg/kg) dilated AFF and EFF in SP (15 ± 3% and 19 ± 5%) and JM (15 ± 3% and 18 ± 4%). Subsequently, cilazaprilat (30 μg/kg) caused further dilation of both AFF (29 ± 4%) and EFF (36 ± 4%) in JM, whereas in SP it dilated only EFF (29 ± 3%). Similarly, in the presence of E4177, cilazaprilat caused further increases in sodium excretion. This cilazaprilat-induced vasodilation and natriuresis was abolished by a bradykinin antagonist (Nα-adamantaneacetyl-D-Arg-[Hyp3,Thi5,8,D-Phe7]-bradykinin). In parallel with these results, cilazaprilat increased renal bradykinin content, more greatly in the medulla than in the cortex (5.7 ± 0.4 versus 4.6 ± 0.1 ng/g). Similarly, cilazaprilat elicited greater bradykinin-dependent increases of nitrite/nitrate in the medulla. In conclusion, zonal heterogeneity in renal bradykinin/nitric oxide levels and segmental differences in reactivity to bradykinin contribute to the diverse responsiveness of renal AFF and EFF to ACEI. ACEI-enhanced kinin action would participate in the amelioration of glomerular hemodynamics and renal sodium excretion by ACEI.
Regional Lung Strain and Inflammation
Authors: Giacomo Bellani, Antonio Pesenti, Guido Musch
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

compared with tracking a specific lung ROI from one lung volume to another.This has been validated in healthy animals (2) as well as in humans undergoing radiotherapy treatment planning (3-5).Based on this approach (2), we calculated a correction factor for the parameter (VT CT /EELV) calculated by Bellani and coauthors (1) to the actual volume strain sVol.As is evident from Figure 1, the data of Bellani and colleagues may underestimate the actual volume strain by 2-to 10-fold, depending on the end-inspiratory density of the ROI.It is possible that correcting these data will result in a greater correlation between K i and sVol and strengthen the conclusions of their study.Our method has some limitations (2).If the lung is heterogeneously inflated within this ROI, our approach using mean density will underestimate the maximum strains experienced by the lung.Evolving methods in which continuous image registration tracks regional deformation on a voxel level will eventually permit high-resolution measurement of regional lung expansion and mechanical properties (6-10) and further innovative investigations such as this one.The measurement of regional lung function in human subjects, whether regional metabolic activity or lung deformation, is a challenging frontier for investigators that we believe will provide unique insight into how the interactions between mechanical and biological mechanisms result in the emergence of lung diseases and pathological syndromes.The application of complementary CT and PET imaging modalities (1) is an intriguing example of how the assessment of regional lung function may permit delineation of important pathophysiologic relationships, even in the presence of heterogeneous lung injury.
Testing the Infinitely Many Genes Model for the Evolution of the Bacterial Core Genome and Pangenome
Authors: R. Eric Collins, Paul G. Higgs
Journal: Molecular Biology and Evolution (2012)

When groups of related bacterial genomes are compared, the number of core genes found in all genomes is usually much less than the mean genome size, whereas the size of the pangenome (the set of genes found on at least one of the genomes) is much larger than the mean size of one genome. We analyze 172 complete genomes of Bacilli and compare the properties of the pangenomes and core genomes of monophyletic subsets taken from this group. We then assess the capabilities of several evolutionary models to predict these properties. The infinitely many genes (IMG) model is based on the assumption that each new gene can arise only once. The predictions of the model depend on the shape of the evolutionary tree that underlies the divergence of the genomes. We calculate results for coalescent trees, star trees, and arbitrary phylogenetic trees of predefined fixed branch length. On a star tree, the pangenome size increases linearly with the number of genomes, as has been suggested in some previous studies, whereas on a coalescent tree, it increases logarithmically. The coalescent tree gives a better fit to the data, for all the examples we consider. In some cases, a fixed phylogenetic tree proved better than the coalescent tree at reproducing structure in the gene frequency spectrum, but little improvement was gained in predictions of the core and pangenome sizes. Most of the data are well explained by a model with three classes of gene: an essential class that is found in all genomes, a slow class whose rate of origination and deletion is slow compared with the time of divergence of the genomes, and a fast class showing rapid origination and deletion. Although the majority of genes originating in a genome are in the fast class, these genes are not retained for long periods, and the majority of genes present in a genome are in the slow or essential classes. In general, we show that the IMG model is useful for comparison with experimental genome data both for species level and widely divergent taxonomic groups. Software implementing the described formulae is provided at http://github.com/rec3141/pangenome.
Long-term Survivors of Childhood Ewing Sarcoma: Report From the Childhood Cancer Survivor Study
Authors: J. P. Ginsberg, P. Goodman, W. Leisenring, K. K. Ness, P. A. Meyers, S. L. Wolden, S. M. Smith, M. Stovall, S. Hammond, L. L. Robison, K. C. Oeffinger
Journal: JNCI Journal of the National Cancer Institute (2010)

The survival of Ewing sarcoma (ES) patients has improved since the 1970s but is associated with considerable future health risks. The study population consisted of long-term (≥5-year) survivors of childhood ES diagnosed before age 21 from 1970 to 1986. Cause-specific mortality was evaluated in eligible survivors (n = 568), and subsequent malignant neoplasms, chronic health conditions, infertility, and health status were evaluated in the subset participating in the Childhood Cancer Survivor Study (n = 403). Outcomes were compared with the US population and sibling control subjects (n = 3899). Logistic, Poisson, or Cox proportional hazards models, with adjustments for sex, age, race/ethnicity, and potential intrafamily correlation, were used. Statistical tests were two-sided. Cumulative mortality of ES survivors was 25.0% (95% confidence interval [CI] = 21.1 to 28.9) 25 years after diagnosis. The all-cause standardized mortality ratio was 13.3 (95% CI = 11.2 to 15.8) overall, 23.1 (95% CI = 17.6 to 29.7) for women, and 10.0 (95% CI = 7.9 to 12.5) for men. The nonrecurrence-progression non-external cause standardized mortality ratio (subsequent non-ES malignant neoplasms and cardiac and pulmonary causes potentially attributable to ES treatment) was 8.7 (95% CI = 6.2 to 12.0). Twenty-five years after ES diagnosis, cumulative incidence of subsequent malignant neoplasms, excluding nonmelanoma skin cancers, was 9.0% (95% CI = 5.8 to 12.2). Compared with siblings, survivors had an increased risk of severe, life-threatening, or disabling chronic health conditions (relative risk = 6.0, 95% CI = 4.1 to 9.0). Survivors had lower fertility rates (women: P = .005; men: P < .001) and higher rates of moderate to extreme adverse health status ( P < .001). Long-term survivors of childhood ES exhibit excess mortality and morbidity.
Increased Endothelial Mitogen-Activated Protein Kinase Phosphatase-1 Expression Suppresses Proinflammatory Activation at Sites That Are Resistant to Atherosclerosis
Authors: Mustafa Zakkar, Hera Chaudhury, Gunhild Sandvik, Karine Enesa, Le Anh Luong, Simon Cuhlmann, Justin C. Mason, Rob Krams, Andrew R. Clark, Dorian O. Haskard, Paul C. Evans
Journal: Circulation Research (2008)

Atherosclerosis is a chronic inflammatory disease of arteries. It is triggered by proinflammatory mediators which induce adhesion molecules (eg, vascular cell adhesion molecule [VCAM]-1) in endothelial cells (ECs) by activating p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases by phosphorylation. Blood flow influences atherosclerosis by exerting shear stress (mechanical drag) on the inner surface of arteries, a force that alters endothelial physiology. Regions of the arterial tree exposed to high shear are protected from endothelial activation, inflammation, and atherosclerosis, whereas regions exposed to low or oscillatory shear are susceptible. We examined whether MAP kinase phosphatase (MKP)-1, a negative regulator of p38 and JNK, mediates the antiinflammatory effects of shear stress. We observed that expression of MKP-1 in cultured ECs was elevated by shear stress, whereas the expression of VCAM-1 was reduced. MKP-1 induction was shown to be necessary for the antiinflammatory effects of shear stress because gene silencing of MKP-1 restored VCAM-1 expression in sheared ECs. Immunostaining revealed that MKP-1 is preferentially expressed by ECs in a high-shear, protected region of the mouse aorta and is necessary for suppression of EC activation at this site, because p38 activation and VCAM-1 expression was enhanced by genetic deletion of MKP-1. We conclude that MKP-1 induction is required for the antiinflammatory effects of shear stress. Thus, our findings reveal a novel molecular mechanism contributing to the spatial distribution of vascular inflammation and atherosclerosis.
Silencing Nox4 in the Paraventricular Nucleus Improves Myocardial Infarction–Induced Cardiac Dysfunction by Attenuating Sympathoexcitation and Periinfarct Apoptosis
Authors: David W. Infanger, Xian Cao, Scott D. Butler, Melissa A. Burmeister, Yi Zhou, John A. Stupinski, Ram V. Sharma, Robin L. Davisson
Journal: Circulation Research (2010)

Myocardial infarction (MI)-induced heart failure is characterized by central nervous system-driven sympathoexcitation and deteriorating cardiac function. The paraventricular nucleus (PVN) of the hypothalamus is a key regulator of sympathetic nerve activity and is implicated in heart failure. Redox signaling in the PVN and other central nervous system sites is a primary mechanism of neuro-cardiovascular regulation, and excessive oxidant production by activation of NADPH oxidases (Noxs) is implicated in some neuro-cardiovascular diseases.We tested the hypothesis that Nox-mediated redox signaling in the PVN contributes to MI-induced sympathoexcitation and cardiac dysfunction in mice.Real-time PCR revealed that Nox4 was the most abundantly expressed Nox in PVN under basal conditions. Coronary arterial ligation (MI) caused a selective upregulation of this homolog compared to Nox1 and Nox2. Adenoviral gene transfer of Nox4 (AdsiNox4) to PVN (bilateral) attenuated MI-induced superoxide formation in this brain region (day 14) to the same level as that produced by PVN-targeted gene transfer of cytoplasmic superoxide dismutase (AdCu/ZnSOD). MI mice treated with AdsiNox4 or AdCu/ZnSOD in the PVN showed marked improvement in cardiac function as assessed by echocardiography and left ventricular hemodynamic analysis. This was accompanied by significantly diminished sympathetic outflow and apoptosis in the periinfarct region of the heart.These results suggest that MI causes dysregulation of Nox4-mediated redox signaling in the PVN, which leads to sympathetic overactivation and a decline in cardiac function. Targeted inhibition of oxidant signaling in the PVN could provide a novel treatment for MI-induced heart failure.