tbuckley/cabot-search huggingface dataset:
Repeated Replication and a Prospective Meta-Analysis of the Association Between Chromosome 9p21.3 and Coronary Artery Disease
Authors: Heribert Schunkert, Anika Götz, Peter Braund, Ralph McGinnis, David-Alexandre Tregouet, Massimo Mangino, Patrick Linsel-Nitschke, Francois Cambien, Christian Hengstenberg, Klaus Stark, Stefan Blankenberg, Laurence Tiret, Pierre Ducimetiere, Andrew Keniry, Mohammed J.R. Ghori, Stefan Schreiber, Nour Eddine El Mokhtari, Alistair S. Hall, Richard J. Dixon, Alison H. Goodall, Henrike Liptau, Helen Pollard, Daniel F. Schwarz, Ludwig A. Hothorn, H. -Erich Wichmann, Inke R. König, Marcus Fischer, Christa Meisinger, Willem Ouwehand, Panos Deloukas, John R. Thompson, Jeanette Erdmann, Andreas Ziegler, Nilesh J. Samani
Journal: Circulation (2008)

Recently, genome-wide association studies identified variants on chromosome 9p21.3 as affecting the risk of coronary artery disease (CAD). We investigated the association of this locus with CAD in 7 case-control studies and undertook a meta-analysis.A single-nucleotide polymorphism (SNP), rs1333049, representing the 9p21.3 locus, was genotyped in 7 case-control studies involving a total of 4645 patients with myocardial infarction or CAD and 5177 controls. The mode of inheritance was determined. In addition, in 5 of the 7 studies, we genotyped 3 additional SNPs to assess a risk-associated haplotype (ACAC). Finally, a meta-analysis of the present data and previously published samples was conducted. A limited fine mapping of the locus was performed. The risk allele (C) of the lead SNP, rs1333049, was uniformly associated with CAD in each study (P<0.05). In a pooled analysis, the odds ratio per copy of the risk allele was 1.29 (95% confidence interval, 1.22 to 1.37; P=0.0001). Haplotype analysis further suggested that this effect was not homogeneous across the haplotypic background (test for interaction, P=0.0079). An autosomal-additive mode of inheritance best explained the underlying association. The meta-analysis of the rs1333049 SNP in 12,004 cases and 28,949 controls increased the overall level of evidence for association with CAD to P=6.04x10(-10) (odds ratio, 1.24; 95% confidence interval, 1.20 to 1.29). Genotyping of 31 additional SNPs in the region identified several with a highly significant association with CAD, but none had predictive information beyond that of the rs1333049 SNP.This broad replication provides unprecedented evidence for association between genetic variants at chromosome 9p21.3 and risk of CAD.
Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida
Authors: N.M.J. van der Put, F.J.M. Trijbels, L.P. van den Heuvel, H.J. Blom, R.P.M. Steegers-Theunissen, T.K.A.B. Eskes, E.C.M. Mariman, M. den Heyer, P. Frosst, R. Rozen
Journal: The Lancet (1995)
'Secrets From Sweden'
Authors: Herman A. Hein
Journal: JAMA (1982)

SWEDEN has reported remarkably low perinatal mortality rates for many years. The Swedes' apparent superiority in perinatal health has generally been ascribed to their relatively advantaged economic status and healthy, homogeneous "stock." However, little attention has been directed to the Swedish system of providing perinatal health care. Immigration to Sweden in recent years has been substantial, and during the period 1973 to 1976, 8.8% of all births in Sweden occurred to immigrant mothers. These women constituted 6.8% of all women of reproductive age during the years noted.<sup>1</sup>Since, in Sweden, immigrants are less advantaged with regard to income, occupation, and living quarters,<sup>2</sup>one might suspect that these conditions would lead to higher perinatal mortality. Interestingly, the immigrant mothers experienced a slightly lower perinatal mortality than their Swedish counterparts.<sup>1</sup> One conceivable explanation is that foreign mothers constitute a favorably selected group and that this counterbalances the socioeconomic factors
Evaluation of autologous plasma skin test in patients with chronic idiopathic urticaria
Authors: H. Yıldız, O. Karabudak, B. Doğan, Y. Harmanyeri
Journal: British Journal of Dermatology (2011)

The pathophysiological mechanism of chronic urticaria is still poorly understood and its aetiology is considered to have an autoreactive basis. Autologous serum skin tests (ASSTs) and autologous plasma skin tests (APSTs) comprise the simplest ways for diagnosing autoreactive urticaria (with autoantibodies, histamine-releasing factor and coagulation factors, especially thrombin) in a clinical setting. However, there are still some questions about the specificity of these tests.To evaluate the role of autoreactivity in the pathogenesis of chronic urticaria by means of measuring plasma prothrombin fragments 1 + 2, which are used as markers of thrombin, and to compare the APST with the ASST.Forty-two patients (19 men and 23 women; mean age 35·7 years, range 28-76) and 35 healthy volunteers (19 men and 16 women; mean age 30·3 years, range 20-80) were included in the study. APST, negative (ASST, sodium citrate, saline) and positive (histamine) control tests were performed in the patient and control groups. The levels of plasma prothrombin fragments 1 + 2 were also assessed.When the APST was evaluated without negative controls, it was positive in 67% of patients. However, the APST was positive in 0% when it was evaluated with negative controls. Levels of prothrombin fragments 1 + 2 were found to be elevated in patients with chronic idiopathic urticaria.We suggest that as negative control tests were not performed along with the APST in previous studies, the APST showed a high rate of positivity. Thus, the use of APST for evaluating autoreactivity in clinical practice is not superior to the use of ASST and further studies should be conducted.
Epidermal Growth Factor Receptor (EGFR) Is Overexpressed in Anaplastic Thyroid Cancer, and the EGFR Inhibitor Gefitinib Inhibits the Growth of Anaplastic Thyroid Cancer
Authors: Bradley A. Schiff, Andrea B. McMurphy, Samar A. Jasser, Maher N. Younes, Dao Doan, Orhan G. Yigitbasi, Seungwon Kim, Ge Zhou, Mahitosh Mandal, Benjamin N. Bekele, F. Christopher Holsinger, Steven I. Sherman, Sai-Ching Yeung, Adel K. El-Naggar, Jeffrey N. Myers
Journal: Clinical Cancer Research (2004)

Abstract Purpose: No effective treatment options currently are available to patients with anaplastic thyroid cancer (ATC), resulting in high mortality rates. Epidermal growth factor (EGF) has been shown to play a role in the pathogenesis of many types of cancer, and its receptor (EGFR) provides an attractive target for molecular therapy. Experimental Design: The expression of EGFR was determined in ATC in vitro and in vivo and in human tissue arrays of ATC. We assessed the potential of the EGFR inhibitor gefitinib (“Iressa,” ZD1839) to inhibit EGFR activation in vitro and in vivo, inhibit ATC cellular proliferation, induce apoptosis, and reduce the growth of ATC cells in vivo when administered alone and in combination with paclitaxel. Results: EGFR was overexpressed in ATC cell lines in vitro and in vivo and in human ATC specimens. Activation of EGFR by EGF was blocked by the addition of gefitinib. In vitro studies showed that gefitinib greatly inhibited cellular proliferation and induced apoptosis in ATC cell lines and slowed tumor growth in a nude mouse model of thyroid carcinoma cells injected subcutaneously. Conclusions: ATC cells consistently overexpress EGFR, rendering this receptor a potential target for molecular therapy. Gefitinib effectively blocks activation of EGFR by EGF, inhibits ATC cellular proliferation, and induces apoptosis in vitro. Our in vivo results show that gefitinib has significant antitumor activity against ATC in a subcutaneous nude mouse tumor model and therefore is a potential candidate for human clinical trials.
Platelets from spontaneously hypertensive rats exhibit decreased expression of inhibitory guanine nucleotide regulatory protein. Relation with adenylyl cyclase activity.
Authors: M B Anand-Srivastava
Journal: Circulation Research (1993)

We have recently demonstrated an enhanced expression of inhibitory guanine nucleotide regulatory protein (Gi) in the heart and aorta from spontaneously hypertensive rats (SHR) as compared with control Wistar-Kyoto (WKY) rats; this enhanced Gi expression was associated with an increased inhibition of adenylyl cyclase by inhibitory hormones and decreased stimulation of adenylyl cyclase by stimulatory hormones. In the present studies, we have determined the levels of stimulatory and inhibitory guanine nucleotide regulatory proteins (Gs and Gi, respectively) in platelets from SHR by cholera toxin- and pertussis toxin-catalyzed ADP-ribosylations, respectively, as well as by immunoblotting techniques using specific antibodies for Gs and Gi. Cholera toxin catalyzed the ADP-ribosylation of a single protein of M(r) 45,000 in rat platelets from SHR and WKY rats, and the labeling of this band was not altered in SHR as compared with WKY rats. Pertussis toxin, on the other hand, catalyzed the ADP-ribosylation of a single protein band of M(r) 41,000 in platelets from SHR and WKY rats, and unlike the response in heart and aorta, the labeling of this band was significantly decreased in SHR as compared with WKY rats. Furthermore, immunoblotting experiments using AS/7 antibody, which is specific for Gi alpha-1 and Gi alpha-2, showed a decrease in Gi alpha-2 in platelets from SHR as compared with WKY rats. In addition, the inhibitory effects of angiotensin II and atrial natriuretic factor on adenylyl cyclase and cAMP levels were completely abolished in SHR platelets, whereas the stimulatory effects of GTP, N-ethylcarboxamide adenosine, prostaglandin E1, and forskolin on adenylyl cyclase and cAMP levels were enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)
Rhythm Control in Atrial Fibrillation — One Setback after Another
Authors: Michael E. Cain, Anne B. Curtis
Journal: New England Journal of Medicine (2008)

Atrial fibrillation, the most common sustained arrhythmia observed in hospitalized patients, is associated with substantial morbidity, and its occurrence approximately doubles the rate of death as compared with that of patients in whom sinus rhythm is maintained. The global effect of atrial fibrillation on public health is so great that international professional organizations have integrated the results of seminal studies to progressively formulate data-driven management guidelines.1 Patients with heart failure are at increased risk for atrial fibrillation and constitute an important subgroup of all patients with this arrhythmia. Data from trials involving patients with atrial fibrillation have shown that a . . .
A Critical Role for OX40 in T Cell–mediated Immunopathology during Lung Viral Infection
Authors: Ian R. Humphreys, Gerhard Walzl, Lorna Edwards, Aaron Rae, Sue Hill, Tracy Hussell
Journal: The Journal of Experimental Medicine (2003)

Respiratory infections are the third leading cause of death worldwide. Illness is caused by pathogen replication and disruption of airway homeostasis by excessive expansion of cell numbers. One strategy to prevent lung immune–mediated damage involves reducing the cellular burden. To date, antiinflammatory strategies have affected both antigen-specific and naive immune repertoires. Here we report a novel form of immune intervention that specifically targets recently activated T cells alone. OX40 (CD134) is absent on naive T cells but up-regulated 1–2 d after antigen activation. OX40–immunoglobulin fusion proteins block the interaction of OX40 with its ligand on antigen-presenting cells and eliminate weight loss and cachexia without preventing virus clearance. Reduced proliferation and enhanced apoptosis of lung cells accompanied the improved clinical phenotype. Manipulation of this late costimulatory pathway has clear therapeutic potential for the treatment of dysregulated lung immune responses.
US accrediting agency tightens rules for continuing medical education
Authors: Janice Hopkins Tanne
Journal: BMJ (2004)

The Accreditation Council for Continuing Medical Education, which accredits the continuing medical education (CME) courses required of most US physicians, has announced changes to limit the influence of the pharmaceutical industry. The council's seven members, including the American Medical Association, approved the changes, which affect the council's nearly 700 accredited providers of education.

The changes have come about, in part, because leading doctors who speak on the courses often have ties to pharmaceutical firms. Previously experts exposed their industry ties, but were free to speak about off label or investigational uses of drugs—uses not approved by the Food and Drug Administration. Although speakers may still discuss such uses, they must confine their discussions to evidence based …
Benzodiazepine receptor antagonist (flumazenil) does not affect sleep-related breathing disorders
Authors: B Schonhofer, D Kohler
Journal: European Respiratory Journal (1996)

Benzodiazepine drugs may impair breathing during sleep, leading to the development of sleep-disordered breathing or, in subjects with sleep apnoea, an increase in the severity of pre-existing apnoeas. Flumazenil is a selective benzodiazepine-antagonist. We hypothesized that endogenous ligands of benzodiazepine receptors might contribute to the pathogenesis of obstructive sleep apnoea syndrome (OSAS) and that the intensity of OSAS could, therefore, be reduced by flumazenil. Ten male patients (mean age 55 yrs, mean body mass index 42.4 kg.m-2, mean apnoea index (AI) 53.5 and mean respiratory disturbance index (RDI) 74.2) were investigated. None of the patients had been treated for OSAS prior to the study. The study design was randomized, single-blind, placebo-controlled and cross-over. On the first or second study night, patients were randomly assigned to receive i.v. flumazenil (2 mg) or placebo (0.9% NaCl) between 01:00 and 01:30 h. Comparing the polysomnographic results of the placebo night and the flumazenil night in all 10 patients, no significant differences were found regarding obstructive events or sleep architecture. Accordingly, the data concerning sleep-disordered breathing and sleep stages during the 30 min period prior to and the 30 min period following the administration of flumazenil did not differ. It is concluded that endogenous ligands of the benzodiazepine receptor play no role in the pathogenesis of obstructive sleep apnoea syndrome, since respiratory and sleep data are not altered by flumazenil. Therefore, attempts to treat obstructive sleep apnoea syndrome with flumazenil do not seem to be warranted.
Is Primary Prevention of Rheumatic Fever the Missing Link in the Control of Rheumatic Heart Disease in Africa?
Authors: Ganesan Karthikeyan, Bongani M. Mayosi
Journal: Circulation (2009)

Rheumatic fever and rheumatic heart disease continue to be major public health problems in the developing world, particularly in the countries of sub-Saharan Africa. Because of its cost effectiveness, secondary prophylaxis is advocated as the principal means of disease prevention and control. However, in developing countries, valvular damage, due to earlier, unrecognized episodes of rheumatic fever, has already occurred by the time secondary prophylaxis is instituted. Secondary prophylaxis cannot reduce the incidence of new cases of rheumatic fever and has not been shown to alter the natural history of rheumatic valvular disease. Experience from several regions of the world suggests that incorporation of a strategy of primary antibiotic prophylaxis into a comprehensive program for disease control can reduce the incidence of rheumatic fever and rheumatic heart disease. In this article, we argue that a strategy of primary antibiotic prophylaxis, with appropriate modifications, can be successfully implemented in resource-poor settings across the world and should be a key component of any rheumatic heart disease control program. This, we believe, is essential for reducing the global burden of rheumatic heart disease.
Effects of moguisteine, a peripheral nonnarcotic antitussive agent, on airway inflammation in guinea-pigs in vivo
Authors: L Gallico, N Oggioni, C Dalla Rosa, R Ceserani, S Tognella
Journal: European Respiratory Journal (1996)

Cough is a common symptom of respiratory diseases associated with irritation or inflammation of the airways, and symptomatic antitussive drugs are frequently prescribed to control an abnormal cough reflex. Our aim was to evaluate the effects of moguisteine, a novel, peripheral, nonnarcotic antitussive agent, on airway inflammation induced in guinea-pigs with a variety of stimuli. These stimuli included exposure to tobacco smoke for 10 min, to elicit airway hyperreactivity, eosinophil recruitment in bronchoalveolar lavage (BAL), airway epithelial damage and plasma exudation; graded platelet-activating factor (PAF) infusion (600 ng.kg-1 over one h), to induce airway hyperreactivity; 2% ovalbumin (OA) aerosol challenge in 1% OA-sensitized animals, to induce late-phase (17 and 72 h) airway leucocyte accumulation. We also assessed the activity of moguisteine on plasma leakage induced by capsaicin, on bronchoconstriction induced by acetylcholine (ACh), histamine (H) and PAF, and on leukotriene mediated allergic bronchospasm in OA-sensitized guinea-pig. Moguisteine (p.o. and i.m.) and dexamethasone (p.o. and i.m.) dose-dependently reduced tobacco smoke-induced bronchial hyperreactivity. Moguisteine and dexamethasone abolished eosinophil recruitment in BAL, prevented the sloughing of the epithelium and significantly reduced airway microvascular leakage. Both agents were also highly effective in reducing bronchial hyperreactivity elicited by PAF infusion. In addition, moguisteine was active in inhibiting airway neutrophil and eosinophil accumulation in BAL observed 17 and 72 h after OA challenge in sensitized guinea-pigs. In contrast to dexamethasone, moguisteine did not prevent capsaicin-induced plasma leakage. It was also ineffective against bronchoconstriction as induced by ACh, H, and PAF and failed to inhibit leukotriene-dependent bronchospasm. Our data suggest that moguisteine represents an antitussive compound endowed with interesting airway anti-inflammatory properties in guinea-pigs in vivo. Its mechanism of action remains to be elucidated.
The Threshold Level of Adenomatous Polyposis Coli Protein for Mouse Intestinal Tumorigenesis
Authors: Qin Li, Tomo-o Ishikawa, Masanobu Oshima, Makoto M. Taketo
Journal: Cancer Research (2005)

Abstract The adenomatous polyposis coli (APC) gene, whose mutations are responsible for familial adenomatous polyposis, is a major negative controller of the Wnt/β-catenin pathway. To investigate the dose-dependent effects of APC protein in suppressing intestinal tumorigenesis, we constructed mutant mice carrying hypomorphic Apc alleles ApcneoR and ApcneoF whose expression levels were reduced to 20% and 10% of the wild type, respectively. Although both hypomorphic heterozygotes developed intestinal polyps, tumor multiplicities were much lower than that in ApcΔ716 mice, heterozygotes of an Apc null allele. Like in ApcΔ716 mice, loss of the wild-type Apc allele was confirmed for all polyps examined in the ApcneoR and ApcneoF mice. In the embryonic stem cells homozygous for these hypomorphic Apc alleles, the level of the APC protein was inversely correlated with both the β-catenin accumulation and β-catenin/T-cell factor transcriptional activity. These results suggest that the reduced APC protein level increases intestinal polyp multiplicity through quantitative stimulation of the β-catenin/T-cell factor transcription. We further estimated the threshold of APC protein level that forms one polyp per mouse as ∼15% of the wild type. These results also suggest therapeutic implications concerning Wnt signaling inhibitors.
Thoracic injuries in professional rugby players: mechanisms of injury and imaging characteristics
Authors: Daichi Hayashi, Frank W Roemer, Ryan Kohler, Ali Guermazi, Chris Gebers, Richard De Villiers
Journal: British Journal of Sports Medicine (2013)

Professional rugby players are prone to traumatic thoracic injuries due to the use of minimal protective gear to cover the torso. In the 2007 Rugby World Cup, thoracic injuries occurred at a rate of 8.3 cases/1000 player-hours. CT and MRI play an important role in the diagnosis of these injuries. Vital internal organs, such as the heart, lungs, trachea, liver and large blood vessels lie within close proximity to the bony structures and what seems to be a simple rib fracture or clavicular dislocation can have potentially life-threatening complications that are not detected by conventional radiography. Cross-sectional imaging helps to determine the choice of treatment. Ultrasound offers a quick and dynamic imaging examination and allows high-resolution assessment of superficial tissues that complements conventional imaging. In this review article, we (1) presented data on incidence of thoracic injuries in professional rugby players; (2) described the anatomy of the joints comprising the thoracic cage and major muscles attached to the rib cage; (3) discussed indications and relevance for MRI and presented an optimised MRI protocol for assessment of suspected thoracic injury; and (4) illustrated various types of thoracic injuries seen in professional rugby players, including sternal contusion, retrosternal haematoma, manubriosternal disruption, sternoclavicular dislocation, rib fractures and injuries of the pectoralis major muscle.
TCT.1, a target molecule for gamma/delta T cells, is encoded by an immunoglobulin superfamily gene (Blast-1) located in the CD1 region of human chromosome 1.
Authors: P Del Porto, F Mami-Chouaib, J M Bruneau, S Jitsukawa, J Dumas, M Harnois, T Hercend
Journal: The Journal of Experimental Medicine (1991)

We have recently generated a series of gamma/delta T cell clones able to kill, after in vitro immunization, an Epstein-Barr Virus-transformed B cell line (designated E418) in a non-major histocompatibility complex-requiring fashion. A monoclonal antibody, termed anti-10H3, produced against E418 was selected by its ability to block these cytotoxic interactions. Further analysis indicated that the inhibitory effects of anti-10H3 were highly selective (i.e., no blocking activity with multiple control clones used as effector cells; no alteration of the natural killer-like function mediated by the relevant gamma/delta clones against 10H3+ tumor cells such as Rex). The molecule immunoprecipitated by anti-10H3, termed TCT.1, was characterized as a 43-kD protein broadly distributed in the hematopoietic system. The TCT.1 molecule has been further studied here by protein microsequencing. Results show that the TCT.1-derived peptide sequences are virtually identical to corresponding regions of Blast-1, a previously described surface protein with unknown function. The likely identity of the two molecules has been strengthened by analyzing the susceptibility of TCT.1 to phosphatidylinositol-specific phospholipase C digestion in light of the known anchorage of Blast-1 to the cell membrane through a glycosyl-phosphatidylinositol-containing lipid. The TCT.1/Blast-1-encoding gene is well characterized; it belongs to the immunoglobulin gene superfamily and it is located in the same band of chromosome 1 as the CD1 gene cluster. Together, these data further support the view that proteins distinct from the conventional class I/II histocompatibility molecules are involved in specific T cell recognition.
Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24
Authors: Stefanie Birnbaum, Kerstin U Ludwig, Heiko Reutter, Stefan Herms, Michael Steffens, Michele Rubini, Carlotta Baluardo, Melissa Ferrian, Nilma Almeida de Assis, Margrieta A Alblas, Sandra Barth, Jan Freudenberg, Carola Lauster, Gül Schmidt, Martin Scheer, Bert Braumann, Stefaan J Bergé, Rudolf H Reich, Franziska Schiefke, Alexander Hemprich, Simone Pötzsch, Regine P Steegers-Theunissen, Bernd Pötzsch, Susanne Moebus, Bernhard Horsthemke, Franz-Josef Kramer, Thomas F Wienker, Peter A Mossey, Peter Propping, Sven Cichon, Per Hoffmann, Michael Knapp, Markus M Nöthen, Elisabeth Mangold
Journal: Nature Genetics (2009)