tbuckley/cabot-search huggingface dataset:
Letter by Vítek et al Regarding Article, “Niacin Inhibits Vascular Inflammation via the Induction of Heme Oxygenase-1”
Authors: Libor Vítek, Jana Vaníková, Petr Nachtigal
Journal: Circulation (2012)

Inflammation via the Induction of Heme Oxygenase-1"To the Editor:We read with interest a recent article by Dr Wu and colleagues on the anti-inflammatory effects of niacin, mediated by induction of heme oxygenase-1. 1 The authors performed detailed studies on a rabbit model of vascular inflammation, clearly demonstrating that niacin inhibits inflammatory processes in the vascular wall mainly via induction of heme oxygenase-1, an important cytoprotective protein responsible for bilirubin production in the human body.In fact, the authors demonstrated substantial elevation of serum bilirubin levels in response to niacin treatment.In our opinion, 2 aspects of the study deserve additional explanation.First, the concentrations of bilirubin in the rabbit sera were extremely low, almost 3 orders of magnitude lower compared with data by others 2 and below the sensitivity of the majority of analytical methods, including that used by the authors.Second, bilirubin is not the major bile pigment in rabbits.Because rabbits exhibit only Ͻ0.4% of the rat hepatic biliverdin reductase activity, the major biliary bile pigment is biliverdin. 3Moreover, bilirubin infusion to rabbits leads to increased biliary secretion of biliverdin, indicating that bilirubin in rabbits is rapidly oxidized back to biliverdin. 4 Thus, it is our opinion that both pigments in lapine sera, ie, biliverdin plus bilirubin, should be considered when assessing the effects of heme oxygenase-1 induction in rabbits.
Participation of Tyrosine Phosphorylation in Cytoskeletal Reorganization, α <sub>IIb</sub> β <sub>3</sub> Integrin Receptor Activation, and Aspirin-Insensitive Mechanisms of Thrombin-Stimulated Human Platelets
Authors: M. Teresa Santos, Antonio Moscardó, Juana Vallés, Marcial Martínez, Marta Piñón, Justo Aznar, M. Johan Broekman, Aaron J. Marcus
Journal: Circulation (2000)

Background —Fibrinogen binding to the active conformation of the α IIb β 3 integrin receptor (glycoprotein IIb/IIIa) and cytoskeletal reorganization are important events in platelet function. Tyrosine phosphorylation of platelet proteins plays an essential role in platelet signal transduction pathways. We studied the participation of tyrosine kinases on these aspects of platelet reactivity and their importance in cyclooxygenase (COX)-1–independent mechanisms in thrombin-stimulated human platelets. Methods and Results —Using washed platelets from normal donors and tyrphostin-A47 and aspirin as tyrosine kinase and COX-1 inhibitors, respectively, we found that tyrphostin-A47 downregulated (1) the thrombin-activated conformational change of α IIb β 3 , (2) actin polymerization and cytoskeletal reorganization, and (3) the quantity of tyrosine-phospho-rylated proteins associated with the reorganized cytoskeleton. The latter are important components of multimolecular signaling complexes. Concomitantly, platelet aggregation and secretion were significantly reduced. Aspirin did not affect receptor activation or tyrosine phosphorylation but did decrease the initial (30-second) burst of actin polymerization. Importantly, aspirin significantly amplified the inhibitory effect of tyrphostin-A47 on all aspects of platelet reactivity that we evaluated. Conclusions —Tyrosine protein phosphorylation is a regulatory control system of the inside-out mechanism of α IIb β 3 activation and cytoskeletal assembly in thrombin-stimulated human platelets. Inhibition of these aspects of platelet function with tyrphostin-A47 is amplified when platelets are treated with aspirin. Therefore, tyrosine phosphorylation is a major component of early signaling events and of COX-1–independent mechanisms of thrombin-induced platelet reactivity. The study results may indicate a novel target for therapeutic intervention.
Ultrasonography for Diagnosis of Orbital Tumors
Authors: Juris G. Dakters
Journal: JAMA (1968)

The diagnosis of intra-orbital tumors is frequently difficult, and sometimes, in spite of all investigative attempts, the cause of unilateral ocular proptosis is not determined. Also, in cases where the presence of a tumor is strongly suspected, it is occasionally difficult to learn the orbital location of the neoplasm for planning of surgical approach. Ultrasonography of the orbit has been useful for these purposes, and reaching the decision to perform surgical removal is thus simplified. Ultrasonography of the orbit is easily performed and is harmless when done properly.
Heritability and Linkage Analysis of Sensitivity to Cisplatin-Induced Cytotoxicity
Authors: M. Eileen Dolan, Karla G. Newbold, Ramamoorthy Nagasubramanian, Xiaolin Wu, Mark J. Ratain, Edwin H. Cook, Judith A. Badner
Journal: Cancer Research (2004)

Little is known about the genetic determinants explaining variation in sensitivity to chemotherapeutic cytotoxicity. We characterized the degree of cisplatin sensitivity, using lymphoblastoid cell lines derived from 10 Centre d'Etude du Polymorphisme Humain pedigrees. We estimated the heritability for susceptibility to cisplatin-induced cytotoxicity to be approximately 0.47; therefore, sensitivity to the cytotoxic effects of cisplatin is under appreciable genetic influence. Linkage analysis was performed, and the strongest signal (lod score, 2.16; empirical P = 0.0005) was found on chromosome 1 at 44 cM. Susceptibility to cisplatin-induced cytotoxicity is likely due to multiple loci, with low locus-specific heritability contributing to the trait. These data show the power of using large pedigrees that have been extensively genotyped for evaluating the genetic contribution to sensitivity to cell growth inhibition by anticancer agents.
Progress in modelling acute lung injury in a pre-clinical mouse model
Authors: Michael A. Matthay, James P. Howard
Journal: European Respiratory Journal (2012)

Animal models of acute lung injury (ALI) have contributed significantly to our understanding of the pathogenesis and pathophysiology of the clinical syndrome of ALI and acute respiratory distress syndrome (ARDS) [1]. Investigators have used a wide variety of small- and large-animal models in order to understand the mechanisms of injury to both the lung endothelial and epithelial barriers, as well as to test novel therapeutic strategies [2–4]. All animal models are limited in their ability to model the complex clinical syndrome of ALI/ARDS because they cannot replicate several of the confounding factors, including the effects of age, chronic medical diseases such as liver and renal insufficiency, and the impact of genetic and environmental factors that may contribute to the clinical syndrome of ALI/ARDS [3]. Nevertheless, animal models have made important contributions to understanding several of the mechanisms responsible for the development of lung injury [4, 5].

In this issue of the European Respiratory Journal , Patel et al. [6] report a mouse model of ALI that reproduces several features of the pathophysiology of ALI. …
S1 guideline for diagnostic evaluation in androgenetic alopecia in men, women and adolescents
Authors: U. Blume-Peytavi, A. Blumeyer, A. Tosti, A. Finner, V. Marmol, M. Trakatelli, P. Reygagne, A. Messenger
Journal: British Journal of Dermatology (2010)

Androgenetic alopecia (AGA) is the most common hair loss disorder, affecting both men and women. Due to the frequency and the often significant impairment of life perceived by the affected patients, competent advice, diagnosis and treatment is particularly important. As evidence-based guidelines on hair disorders are rare, a European consensus group was constituted to develop guidelines for the diagnostic evaluation and treatment of AGA. This S1 guideline for diagnostic evaluation of AGA in men, women and adolescents reviews the definition of AGA and presents expert opinion-based recommendations for sex-dependent steps in the diagnostic procedure.
Clinical Ethics Consultants: Advocates for Both Patients and Clinicians
Authors: Alexander A. Kon
Journal: The American Journal of Bioethics (2012)

Click to increase image sizeClick to decrease image size Acknowledgments This article is not subject to US Copyright Law.The views expressed are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. government.
STUDIES ON THROMBIN-INDUCED PLATELET AGGLUTINATION
Authors: Richard W. Shermer, Reginald G. Mason, Robert H. Wagner, Kenneth M. Brinkhous
Journal: The Journal of Experimental Medicine (1961)

A one-stage macroscopic test for platelet agglutination was used to study the effect of thrombin and thrombin-cation mixtures on washed platelets. Conclusions regarding platelet agglutination are as follows: (a) Canine, bovine, or human thrombin alone does not cause agglutination of canine or human platelets. (b) Thrombin with calcium or magnesium causes rapid platelet agglutination. Both calcium and magnesium are active at physiologic concentrations. Divalent manganese or cadmium ions can be substituted for calcium or magnesium. (c) The agglutination reaction is affected but little by the species of origin of thrombin or platelets, or by variations in ionic strength or pH over a broad range. (d) Temperature at which the reaction is carried out is critical; optimal temperature for the test is 28 degrees C. (e) Agglutination is inhibited by high ionic strength, by pH values outside the range 6.4-8.6, and by temperatures outside the range 25-28 degrees C. High concentrations of calcium have a specific inhibitory effect. (f) Platelet agglutination time is as sensitive an index of thrombin concentration as is the fibrinogen clotting time. A comparison is made between divalent cations which influence platelet agglutination induced by thrombin, TAg', and TAg. A similar comparison is made of cations influencing the action of thrombin on the "substrates," fibrinogen, TAMe, and platelets.
<i>TERC</i>polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres
Authors: A M Jones, A D Beggs, L Carvajal-Carmona, S Farrington, A Tenesa, M Walker, K Howarth, S Ballereau, S V Hodgson, A Zauber, M Bertagnolli, R Midgley, H Campbell, D Kerr, M G Dunlop, I P M Tomlinson
Journal: Gut (2011)

<h3>Background and aims</h3> Shorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC. <h3>Methods</h3> In a large sample, the study investigated whether candidate single nucleotide polymorphisms (SNP) in 'telomere biology' genes were associated with telomere length in leucocytes. SNP associated with an increased risk of CRC were searched for separately. <h3>Results</h3> Carriers of the common allele at SNP rs10936599, near the telomerase RNA component (TERC) locus, had significantly longer telomeres. It was independently found that the same rs10936599 allele was associated with increased risk of both CRC and colorectal adenomas. Neither telomere length nor CRC risk was associated with variation near telomerase reverse transcriptase or other telomere biology genes. In silico analysis showed that SNP rs2293607 was strongly correlated with rs10936599, mapped within <i>TERC</i> transcripts, had a predicted effect on messenger RNA folding and lay at a reported transcription factor binding site. <i>TERC</i> mRNA were expressed, differing only at the alleles of rs2293607, in CRC cell line HCT116. The long-telomere/CRC-risk allele was associated with higher levels of <i>TERC</i> mRNA and the formation of longer telomeres. <h3>Conclusions</h3> Common genetic variation at <i>TERC</i> is associated with both longer telomeres and an increased risk of CRC, a potential mechanism being reduced levels of cell senescence or death. This finding is somewhat paradoxical, given retrospective studies reporting that CRC cases have shorter telomeres than controls. One possibility is that that association actually results from poorer survival in patients with longer telomeres.
Eosinophil activation and preschool viral wheeze
Authors: A Oommen
Journal: Thorax (2003)

<b>Background:</b> A study was undertaken to ascertain whether systemic eosinophil activation is associated with preschool viral wheeze (PVW). <b>Methods:</b> Urinary eosinophil protein X (uEPX) and serum total IgE (IgE) levels were measured in children admitted to hospital with PVW, and uEPX was measured 6 weeks after discharge. Two years after admission, current wheeze in children aged ⩾5 years was determined by questionnaire. Controls were recruited from children undergoing elective surgery (normal controls) and from those with skin prick test reactivity to foods (atopic controls). <b>Results:</b> There was no difference in uEPX levels between normal controls (n=15) and atopic controls (n=8). uEPX levels were increased in children with acute PVW (n=84; p&lt;0.001 <i>v</i> normal controls, p&lt;0.01 <i>v</i> atopic controls) and fell on convalescence (n=20, 95% CI −217 to −31 µg/mmol creatinine, p&lt;0.05). In children with acute PVW there was no association between uEPX and serum IgE levels or markers of clinical severity. Respiratory questionnaires were returned for 25/55 eligible children. There was no difference in uEPX level during acute PVW when stratified by “current wheeze” (n=18) or “no wheeze” (n=7) 2 years later. <b>Conclusions:</b> Systemic eosinophil activation is associated with PVW but is not associated with serum IgE, clinical severity, or persistence of wheeze into the early school age period.
The development of cytogenetically normal, abnormal and mosaic embryos: a theoretical model
Authors: F. J. Los
Journal: Human Reproduction Update (2004)

Assisted reproduction and preimplantation genetic diagnosis (PGD) involve various complicated techniques, each of them with its own problems. However, the greatest problem with PGD for chromosome abnormalities is not of a technical nature but is a biological phenomenon: chromosomal mosaicism in the cleavage stage embryo. Here, we present a hypothetical, quantitative model for the development of chromosomally normal, abnormal and mosaic embryos. The arising of mosaicism in 2-8-cell embryos was described by a binomial probability model on the occurrence of mitotic events inducing chromosomal changes in the blastomeres. This model converted the 'mean' rate of mosaicism found in cross-sectional studies (60%) into an equal rate of mosaic embryos at arrival at the 8-cell stage (59.8%). The disappearance of > 90% of the mosaic embryos or the mosaicism itself from surviving embryos during the morula stage was explained by mitotic arrest of most of the mitotically changed cells under increasing cell cycle control. In our model, 25.9 and 14.3% of the embryos at the 8-cell stage are normal and abnormal respectively. The remaining 59.8% of the embryo shows mosaicism: 34.6% of abnormal/normal cells and 25.2% of abnormal/abnormal cells. The high proportion of abnormal and mosaic embryos together explains the high rate of abnormal laboratory findings in PGD for chromosomal abnormalities and aneuploidy screening. The poor representation of a 1- or 2-cell biopsy for the 7- or 6-cell post-biopsy embryo in the case of mosaicism explains the high rate of false-negative and false-positive results.
NF- B activation is required for adaptive cardiac hypertrophy
Authors: L. Zelarayan, A. Renger, C. Noack, M.-P. Zafiriou, C. Gehrke, R. van der Nagel, R. Dietz, L. de Windt, M. W. Bergmann
Journal: Cardiovascular Research (2009)

We have previously shown that cardiac-specific inhibition of NF-κB attenuates angiotensin II (AngII)-induced left ventricular (LV) hypertrophy in vivo. We now tested whether NF-κB inhibition is able to block LV remodelling upon chronic pressure overload and chronic AngII stimulation. Cardiac-restricted NF-κB inhibition was achieved by expression of a stabilized IκBα mutant (IκBαΔN) in cells with an active α-myosin heavy chain (αMHC) promoter employing the Cre/lox technique. Upon low-gradient trans-aortic constriction (TAC, gradient 21 ± 3 mmHg), hypertrophy was induced in both male and female control mice after 4 weeks. At this time, LV hypertrophy was blocked in transgenic (TG) male but not female mice with NF-κB inhibition. Amelioration of LV hypertrophy was associated with activation of NF-κB by dihydrotestosterone in isolated neonatal cardiomyocytes. LV remodelling was not attenuated by NF-κB inhibition after 8 weeks TAC, demonstrated by decreased fractional shortening (FS) in both control and TG mice irrespective of gender. Similar results were obtained when TAC was performed with higher gradients (48 ± 4 mmHg). In TG mice, FS dropped to similar low levels over the same time course [FS sham, 29 ± 1% (mean ± SEM); FS control + 14 days TAC, 13 ± 3%; FS TG + 14 days TAC, 9 ± 5%]. Similarly, LV remodelling was accelerated by NF-κB inhibition in an AngII-dependent genetic heart failure model (AT1-RαMHC) associated with significantly increased cardiac fibrosis in double AT1-RαMHC/TG mice. NF-κB inhibition attenuates cardiac hypertrophy in a gender-specific manner but does not alter the course of stress-induced LV remodelling, indicating NF-κB to be required for adaptive cardiac hypertrophy.
Addiction to Elevated Insulin-like Growth Factor I Receptor and Initial Modulation of the AKT Pathway Define the Responsiveness of Rhabdomyosarcoma to the Targeting Antibody
Authors: Liang Cao, Yunkai Yu, Isaac Darko, Duane Currier, Linnia H. Mayeenuddin, Xiaolin Wan, Chand Khanna, Lee J. Helman
Journal: Cancer Research (2008)

Insulin-like growth factor I receptor (IGF-IR) and its ligands are overexpressed by tumors, mediating proliferation and protecting against stress-induced apoptosis. Accordingly, there has been a considerable amount of interest in developing therapeutic agents against IGF-IR. IGF-IR is believed to be ubiquitously expressed without detectable mutation or amplification in cancer. We explored the determinants of cellular response to a humanized anti-IGF-IR antibody. Our results showed a large variation in IGF-IR levels in rhabdomyosarcoma tumor specimens that were comparable with those in rhabdomyosarcoma cell lines. In vitro analysis revealed a direct and very significant correlation between elevated IGF-IR levels and antiproliferative effects of the antibody and defined a receptor number that would predict sensitivity. Our data further suggested a strong dependence on IGF-IR for AKT signaling in cells with elevated IGF-IR. The sensitivity of the high IGF-IR-expressing cells was blocked with a constitutively active AKT. The extracellular signal-regulated kinase pathway was not affected by the antibody. In vivo studies showed that anti-IGF-IR had single-agent antitumor activity; furthermore, predictions of responses based on IGF-IR levels were accurate. In vivo biomarker analysis suggested that h7C10 down-regulated both IGF-IR and p-AKT initially, concordant with antitumor activity. Subsequent progression of tumors was associated with reactivation of p-AKT despite sustained suppression of IGF-IR. These results identified the first predictive biomarker for anti-IGF-IR therapies in cancer.
Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology
Authors: C. Feliciani, P. Joly, M.F. Jonkman, G. Zambruno, D. Zillikens, D. Ioannides, C. Kowalewski, H. Jedlickova, S. Kárpáti, B. Marinovic, D. Mimouni, S. Uzun, S. Yayli, M. Hertl, L. Borradori
Journal: British Journal of Dermatology (2015)

Bullous pemphigoid is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or generalized bullous lesions. In up to 20% of affected patients, bullae may be completely absent, and only excoriations, prurigo‐like lesions, eczematous lesions, urticated lesions and/or infiltrated plaques are observed. The disease is significantly associated with neurological disorders. The morbidity of bullous pemphigoid and its impact on quality of life are significant. So far, a limited number of national treatment guidelines have been proposed, but no common European consensus has emerged. Our consensus for the treatment of bullous pemphigoid has been developed under the guidance of the European Dermatology Forum in collaboration with the European Academy of Dermatology and Venereology. It summarizes evidence‐based and expert‐based recommendations.
Nosocomial Legionnaires' Disease in Columbus, Ohio
Authors: JAMES S. MARKS
Journal: Annals of Internal Medicine (1979)

Three patients with severe pneumonia at a community hospital in Columbus, Ohio, were found to have Legionnaires' disease in late August 1977. A subsequent serologic survey of patients with pneumonia at this hospital identified three additional cases. Among patients with pneumonia, hospital exposure in the 2 weeks before onset of illness was significantly associated with Legionnaires' disease (P = 0.003). Serosurveys of hospital employees with a recent history of upper respiratory illness, healthy employees, and workers at the hospital construction site showed that one of 101, one of 107, and none of 114, respectively, has a single reciprocal titer of greater than or equal to 256 to the Legionnaires' disease (LD) bacterium. Serosurveys of patients with pneumonia at three control hospitals identified five additional patients with Legionnaires' disease, three of them with pneumonia that was apparently hospital acquired in a single renal transplant unit. A fourth patient from that unit without clinical illness had a fourfold rise in titer to LD bacterium.
Maternal but Not Paternal Association of Ambulatory Blood Pressure With Albumin Excretion in Young Offspring With Type 1 Diabetes
Authors: M. Loredana Marcovecchio, Paivi H. Tossavainen, Carlo L. Acerini, Timothy G. Barrett, Julie Edge, Andrew Neil, Julian Shield, Barry Widmer, R. Neil Dalton, David B. Dunger
Journal: Diabetes Care (2009)

OBJECTIVE Familial predisposition to hypertension has been associated with the development of diabetic nephropathy in adults, but there are limited data in adolescents. Our aim was to assess whether parental ambulatory blood pressure (ABP) was associated with ABP and albumin excretion in young offspring with type 1 diabetes. RESEARCH DESIGN AND METHODS Twenty-four-hour ABP monitoring was performed in 509 young offspring (mean ± SD age 15.8 ± 2.3 years) with type 1 diabetes, 311 fathers, and 444 mothers. Systolic (SBP) and diastolic blood pressure (DBP) measurements during 24 h, daytime, and nighttime were calculated. Three early morning urinary albumin-to-creatinine ratios (ACRs), A1C, and anthropometric parameters were available for the offspring. RESULTS All paternal ABP parameters, except for nighttime SBP, were independently related to the offspring's ABP (24-h SBP β = 0.18, 24-h DBP β = 0.22, daytime SBP β = 0.25, daytime DBP β = 0.23, and nighttime DBP β = 0.18; all P &amp;lt; 0.01). Maternal 24-h DBP (β = 0.19, P = 0.004), daytime DBP (β = 0.09, P = 0.04), and nighttime SBP (β = 0.24 P = 0.001) were related to the corresponding ABP parameter in the offspring. Significant associations were found between the offspring's logACR and maternal ABP. The association with 24-h DBP (β = 0.16, P = 0.02), daytime DBP (β = 0.16 P = 0.02), and nighttime DBP (β = 0.15 P = 0.03) persisted even after adjustment for the offspring's ABP. Mothers of offspring with microalbuminuria had higher ABP than mothers of offspring without microalbuminuria (all P &amp;lt; 0.05). CONCLUSIONS In this cohort, parental ABP significantly influenced offspring blood pressure, therefore confirming familial influences on this trait. In addition, maternal ABP, particularly DBP, was closely related to ACR in the offspring, suggesting a dominant effect of maternal genes or an effect of the intrauterine environment on microalbuminuria risk.