tbuckley/cabot-search huggingface dataset:
Genetics of ACPA-positive rheumatoid arthritis: the beginning of the end?
Authors: R. R. P. de Vries, D. van der Woude, J. J. Houwing, R. E. M. Toes
Journal: Annals of the Rheumatic Diseases (2011)

Heritability is a measure for the contribution of genetic variation to the variation in liability to disease and for rheumatoid arthritis (RA) had previously been estimated to be about 60%. This has been recently confirmed and could show that the heritability of anti-citrullinated protein autoantibody (ACPA)-positive and ACPA-negative RA is similar. Apart from gender, the main known genetic factor is HLA, and its contribution to genetic variation has previously been estimated as 37% but recent studies indicate that this figure may be too high. HLA-linked genes, and in particular the HLA-DRB1 SE alleles, predispose much more strongly to ACPA-positive than to ACPA-negative RA. The same is true for the protective effect of DERAA-positive DRB1 alleles. It has been calculated that the contribution of the protective and predisposing HLA alleles to genetic variance is about 40% for ACPA-positive and 2% for ACPA-negative RA. A meta-analysis indicated that the protective effect may be confined to the HLA-DRB1*1301 allele. The search for non-HLA genes contributing to the genetic variation in RA susceptibility has implicated about 30 other loci/genes. The OR of the associations with these non-HLA polymorphisms is considerably lower than the ORs of sex and HLA as is their contribution to the genetic variation—namely, altogether only about 5%. This means that known genetic factors do not explain much more than 50% of the genetic variance of ACPA-positive RA. Until recently, the only established non-genetic factor contributing to RA susceptibility was smoking. It has recently been shown that non-inherited maternal HLA-DRB1 DERAA-positive antigens (NIMA) should be added to the environmental factors affecting RA susceptibility.
Hepatic and extrahepatic hepatitis C virus replication in relation to response to interferon therapy
Authors: Mohamed G. Saleh, Christopher J. Tibbs, John Koskinas, Leila M. M. B. Pereira, Adrian B. Bomford, Bernard C. Portmann, Ian G. McFarlane, Roger Williams
Journal: Hepatology (1994)

Response to a 1-yr course of interferon-alpha 2b was assessed in 18 patients with chronic hepatitis C virus infection in relation to clinical, biochemical and histological parameters and to the presence or absence of hepatitis C virus RNA and the presumed replicative form of the virus (negative-strand hepatitis C virus RNA) in serum, liver and peripheral blood mononuclear cells. The findings were compared with those in seven untreated patients studied over the same period. At the start of the study, positive-strand hepatitis C virus RNA was found in sera of all 25 patients, in livers of 24 and in peripheral-blood mononuclear cells of 19 of 22 tested; negative strand was found in livers of 11 and in peripheral-blood mononuclear cells of 15 of 22. Negative-strand hepatitis C virus RNA was not found in the serum of any patient at any stage. All of the five treated patients considered to show complete response during the study period cleared hepatic hepatitis C virus RNA, and four also became seronegative, but three had evidence suggestive of viral replication in their peripheral-blood mononuclear cells; two of these last patients subsequently relapsed. Loss of hepatic hepatitis C virus RNA was the only significant difference between these five and the seven partial and six nonresponders, but it is uncertain whether the observed changes were due specifically to interferon-induced modulation of virus expression because similar (apparently spontaneous) changes were seen in four of the untreated patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Measuring Community Similarity with Phylogenetic Networks
Authors: Donovan H. Parks, Robert G. Beiko
Journal: Molecular Biology and Evolution (2012)

Environmental drivers of biodiversity can be identified by relating patterns of community similarity to ecological factors. Community variation has traditionally been assessed by considering changes in species composition and more recently by incorporating phylogenetic information to account for the relative similarity of taxa. Here, we describe how an important class of measures including Bray–Curtis, Canberra, and UniFrac can be extended to allow community variation to be computed on a phylogenetic network. We focus on phylogenetic split systems, networks that are produced by the widely used median network and neighbor-net methods, which can represent incongruence in the evolutionary history of a set of taxa. Calculating β diversity over a split system provides a measure of community similarity averaged over uncertainty or conflict in the available phylogenetic signal. Our freely available software, Network Diversity, provides 11 qualitative (presence–absence, unweighted) and 14 quantitative (weighted) network-based measures of community similarity that model different aspects of community richness and evenness. We demonstrate the broad applicability of network-based diversity approaches by applying them to three distinct data sets: pneumococcal isolates from distinct geographic regions, human mitochondrial DNA data from the Indonesian island of Nias, and proteorhodopsin sequences from the Sargasso and Mediterranean Seas. Our results show that major expected patterns of variation for these data sets are recovered using network-based measures, which indicates that these patterns are robust to phylogenetic uncertainty and conflict. Nonetheless, network-based measures of community similarity can differ substantially from measures ignoring phylogenetic relationships or from tree-based measures when incongruent signals are present in the underlying data. Network-based measures provide a methodology for assessing the robustness of β-diversity results in light of incongruent phylogenetic signal and allow β diversity to be calculated over widely used network structures such as median networks.
Preoperative Brain Injury in Transposition of the Great Arteries Is Associated With Oxygenation and Time to Surgery, Not Balloon Atrial Septostomy
Authors: Christopher J. Petit, Jonathan J. Rome, Gil Wernovsky, Stefanie E. Mason, David M. Shera, Susan C. Nicolson, Lisa M. Montenegro, Sarah Tabbutt, Robert A. Zimmerman, Daniel J. Licht
Journal: Circulation (2009)

Background— Preoperative brain injury is an increasingly recognized phenomenon in neonates with complex congenital heart disease. Recently, reports have been published that associate preoperative brain injury in neonates with transposition of the great arteries with the performance of balloon atrial septostomy (BAS), a procedure that improves systemic oxygenation preoperatively. It is unclear whether BAS is the cause of brain injury or is a confounder, because neonates who require BAS are typically more hypoxemic. We sought to determine the relationship between preoperative brain injury in neonates with transposition of the great arteries and the performance of BAS. We hypothesized that brain injury results from hypoxic injury, not from the BAS itself. Methods and Results— Infants with transposition of the great arteries (n=26) were retrospectively included from a larger cohort of infants with congenital heart disease who underwent preoperative brain MRI as part of 2 separate prospective studies. Data collected included all preoperative pulse oximetry recordings, all values from preoperative arterial blood gas measurements, and BAS procedure data. MRI scans were performed on the day of surgery, before the surgical repair. Of the 26 neonates, 14 underwent BAS. No stroke was seen in the entire cohort, whereas 10 (38%) of 26 patients were found to have hypoxic brain injury in the form of periventricular leukomalacia. Periventricular leukomalacia was not associated with BAS; however, neonates with periventricular leukomalacia had lower preoperative oxygenation ( P =0.026) and a longer time to surgery ( P =0.028) than those without periventricular leukomalacia. Conclusions— Preoperative brain injury in neonates with transposition of the great arteries is associated with hypoxemia and longer time to surgery. We found no association between BAS and brain injury.
The Influence of Demography and Weak Selection on the McDonald-Kreitman Test: An Empirical Study in Drosophila
Authors: J. Parsch, Z. Zhang, J. F. Baines
Journal: Molecular Biology and Evolution (2008)

The McDonald-Kreitman (MK) test, which compares the ratio of polymorphism to divergence at nonsynonymous and synonymous sites, is frequently used to detect adaptive evolution in protein-coding sequences. Because the two classes of sites share a common evolutionary history, the MK test is thought to be robust to most demographic factors. However, weak selection on nonsynonymous sites can bias the MK test, especially when a species' effective population size has not been constant. Here, we present an empirical analysis of the influence of demography on the MK test by comparing test results for a common set of 136 genes, including a set of sex-biased genes that shows a strong signal of adaptive evolution, in two Drosophila melanogaster populations: an ancestral population from Africa and a derived population from Europe. The latter has undergone a relatively recent bottleneck, which has reduced its effective population size. We find that the MK test has less power to detect positive selection in the European population for two reasons. First, the overall reduced level of standing variation decreases the statistical power of the test. Second, the segregation of slightly deleterious nonsynonymous mutations biases the MK test away from detecting positive selection. The latter effect is stronger for X-linked genes, which have experienced the greatest reduction in effective population size outside of Africa, and also leads to the underestimation of rates of adaptive protein evolution by multilocus implementations of the MK test. Interestingly, a subset of autosomal female-biased genes shows an increased signal of adaptive evolution in the European population. This is inconsistent with currently accepted demographic scenarios and may reflect female-specific changes in selective constraint following the colonization of non-African habitats.
Gαq-containing G proteins regulate B cell selection and survival and are required to prevent B cell–dependent autoimmunity
Authors: Ravi S. Misra, Guixiu Shi, Miguel E. Moreno-Garcia, Anil Thankappan, Michael Tighe, Betty Mousseau, Kim Kusser, Shirly Becker-Herman, Kelly L. Hudkins, Robert Dunn, Marilyn R. Kehry, Thi-Sau Migone, Ann Marshak-Rothstein, Melvin Simon, Troy D. Randall, Charles E. Alpers, Denny Liggitt, David J. Rawlings, Frances E. Lund
Journal: The Journal of Experimental Medicine (2010)

Survival of mature B cells is regulated by B cell receptor and BAFFR-dependent signals. We show that B cells from mice lacking the Gαq subunit of trimeric G proteins (Gnaq−/− mice) have an intrinsic survival advantage over normal B cells, even in the absence of BAFF. Gnaq−/− B cells develop normally in the bone marrow but inappropriately survive peripheral tolerance checkpoints, leading to the accumulation of transitional, marginal zone, and follicular B cells, many of which are autoreactive. Gnaq−/− chimeric mice rapidly develop arthritis as well as other manifestations of systemic autoimmune disease. Importantly, we demonstrate that the development of the autoreactive B cell compartment is the result of an intrinsic defect in Gnaq−/− B cells, resulting in the aberrant activation of the prosurvival factor Akt. Together, these data show for the first time that signaling through trimeric G proteins is critically important for maintaining control of peripheral B cell tolerance induction and repressing autoimmunity.
Mucosal Immune Responses Predict Clinical Outcomes during Influenza Infection Independently of Age and Viral Load
Authors: Christine M. Oshansky, Andrew J. Gartland, Sook-San Wong, Trushar Jeevan, David Wang, Philippa L. Roddam, Miguela A. Caniza, Tomer Hertz, John P. DeVincenzo, Richard J. Webby, Paul G. Thomas
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Children are an at-risk population for developing complications following influenza infection, but immunologic correlates of disease severity are not understood. We hypothesized that innate cellular immune responses at the site of infection would correlate with disease outcome.To test the immunologic basis of severe illness during natural influenza virus infection of children and adults at the site of infection.An observational cohort study with longitudinal sampling of peripheral and mucosal sites in 84 naturally influenza-infected individuals, including infants. Cellular responses, viral loads, and cytokines were quantified from nasal lavages and blood, and correlated to clinical severity.We show for the first time that although viral loads in children and adults were similar, innate responses in the airways were stronger in children and varied considerably between plasma and site of infection. Adjusting for age and viral load, an innate immune profile characterized by increased nasal lavage monocyte chemotactic protein-3, IFN-α2, and plasma IL-10 levels at enrollment predicted progression to severe disease. Increased plasma IL-10, monocyte chemotactic protein-3, and IL-6 levels predicted hospitalization. This inflammatory cytokine production correlated significantly with monocyte localization from the blood to the site of infection, with conventional monocytes positively correlating with inflammation. Increased frequencies of CD14(lo) monocytes were in the airways of participants with lower inflammatory cytokine levels.An innate profile was identified that correlated with disease progression independent of viral dynamics and age. The airways and blood displayed dramatically different immune profiles emphasizing the importance of cellular migration and localized immune phenotypes.
Phase 2 Study of ABT-510 in Patients with Previously Untreated Advanced Renal Cell Carcinoma
Authors: Scot Ebbinghaus, Maha Hussain, Nizar Tannir, Michael Gordon, Apurva A. Desai, Raymond A. Knight, Rod A. Humerickhouse, Jiang Qian, Gary B. Gordon, Robert Figlin
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Angiogenesis is a characteristic of renal cell carcinoma. ABT-510 is an angiogenesis inhibitor that mimics the antiangiogenic properties of thrombospondin-1. This study was designed to assess the safety and efficacy of ABT-510 in patients with advanced renal cell carcinoma. Experimental Design: Patients with previously untreated metastatic or unresectable renal cell carcinoma were randomized to treatment with one of two doses of ABT-510, self-administered s.c. twice daily in 28-day treatment periods without intervening rest periods. End points were progression-free survival (PFS), objective response rate, overall survival, and toxicity. Results: The objective response rate was 4% in the 10 mg twice daily group, and there were two unconfirmed PRs in the 100 mg twice daily group. Respective median PFS was 4.2 and 3.3 months, with a 6-month PFS of 39% and 32%. Median overall survival was 27.8 months (10 mg twice daily) and 26.1 months (100 mg twice daily). The most frequent adverse events were injection site reactions (84%), fatigue (50%), headache (20%), and nausea (19%). The incidence of treatment-related, grade 3/4 adverse events was low and included three bleeding episodes (gastrointestinal hemorrhage, intracranial hemorrhage, and hemoptysis) and one thrombotic event (deep vein thrombosis). No deaths were attributed to ABT-510. Conclusions: There was little evidence of clinical activity for ABT-510, and further evaluation as a single agent for treating advanced renal cell carcinoma is not warranted. The evidence of a favorable safety profile may justify further evaluation in combination therapy.
Inducible Intrapulmonary Arteriovenous Shunt in a Patient with Beriberi Heart
Authors: Shintaro Nakano, Yasumori Sujino, Jun Tanno, Miyuki Ariyama, Toshihiro Muramatsu, Takaaki Senbonmatsu, Shigeyuki Nishimura, Yuichi Tamura, Keiichi Fukuda
Journal: American Journal of Respiratory and Critical Care Medicine (2013)
Effect of Endothelial Shear Stress on the Progression of Coronary Artery Disease, Vascular Remodeling, and In-Stent Restenosis in Humans
Authors: Peter H. Stone, Ahmet U. Coskun, Scott Kinlay, Maureen E. Clark, Milan Sonka, Andreas Wahle, Olusegun J. Ilegbusi, Yerem Yeghiazarians, Jeffrey J. Popma, John Orav, Richard E. Kuntz, Charles L. Feldman
Journal: Circulation (2003)

Native atherosclerosis and in-stent restenosis are focal and evolve independently. The endothelium controls local arterial responses by transduction of shear stress. Characterization of endothelial shear stress (ESS) may allow for prediction of progression of atherosclerosis and in-stent restenosis.By using intracoronary ultrasound, biplane coronary angiography, and measurement of coronary blood flow, we represented the artery in accurate 3D space and determined detailed characteristics of ESS and arterial wall/plaque morphology. Patients who underwent stent implantation and who had another artery with luminal obstruction <50% underwent intravascular profiling initially and after 6-month follow-up. Twelve arteries in 8 patients were studied: 6 native and 6 stented arteries. In native arteries, regions of abnormally low baseline ESS exhibited a significant increase in plaque thickness and enlargement of the outer vessel wall, such that lumen radius remained unchanged (outward remodeling). Regions of physiological ESS showed little change. Regions with increased ESS exhibited outward remodeling with normalization of ESS. In stented arteries, there was an increase in intima-medial thickness, a decrease in lumen radius, and an increase in ESS at all levels of baseline ESS.The present study represents the first experience in humans relating ESS to subsequent outcomes in native and stented arteries. Regions of low ESS develop progressive atherosclerosis and outward remodeling, areas of physiological ESS remain quiescent, and areas of increased ESS exhibit outward remodeling. ESS may have a limited role in in-stent restenosis. This technology can predict areas of minor plaque likely to exhibit progression of atherosclerosis.
Signals that go with the flow
Authors: Charles Nicholson
Journal: Trends in Neurosciences (1999)

Cerebrospinal fluid (CSF) is to the brain what the Great Lakes and waterways are to North America: a system of interconnected fluid spaces that influence the local climate and the environment of the territory that encloses them, while providing a conduit for traffic in goods and services. It is this latter aspect (signaling from the CSF to the brain and vice versa) that was the topic of a one-day meeting organized by Rae Silver (New York, NY, USA) and Mike Lehman (Cincinnati, OH, USA) * Workshop on the CSF as a communication pathway of the brain. Held in Los Angeles, USA; 7 November 1998. *Workshop on the CSF as a communication pathway of the brain. Held in Los Angeles, USA; 7 November 1998..
A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy
Authors: M.S. Aapro, S.M. Grunberg, G.M. Manikhas, G. Olivares, T. Suarez, S.A. Tjulandin, L.F. Bertoli, F. Yunus, B. Morrica, F. Lordick, A. Macciocchi
Journal: Annals of Oncology (2006)
Activated B cells express receptors for, and proliferate in response to, pure interleukin 2.
Authors: R H Zubler, J W Lowenthal, F Erard, N Hashimoto, R Devos, H R MacDonald
Journal: The Journal of Experimental Medicine (1984)

In this study we investigated whether interleukin 2 (IL-2) acts on B cell proliferation and whether activated B cells express IL-2 receptors. First, the functional activity of immunoaffinity-purified or recombinant human IL-2 was studied in a B blast assay using positively selected murine surface Ig-positive cells that had been activated by lipopolysaccharide (LPS) plus anti-Ig antibodies (anti-Ig). In this assay, T cells were not detected by fluorescence-activated cell sorter analysis. It was found that both IL-2 preparations led to optimal B cell proliferation compared with supernatants obtained from murine or human spleen cells or murine cloned T helper cells. Second, we observed that the IL-2 requirement in this assay was about the same as in a proliferation assay using lectin-activated polyclonal murine Lyt-2-positive T cells. Third, analysis of the binding of radiolabeled immunoaffinity-purified IL-2 to B cells indicated that LPS plus anti-Ig-activated B cells expressed a mean of 3,500 IL-2 receptors per cell with an apparent dissociation constant of 150 pM. However, neither nonactivated B cells nor B cells activated by LPS alone exhibited significant specific IL-2 binding. The functional and the receptor data are consistent with the conclusion that IL-2 is a growth factor not only for T cells but also for B cells.
Restarting Anticoagulant Treatment After Intracranial Hemorrhage in Patients With Atrial Fibrillation and the Impact on Recurrent Stroke, Mortality, and Bleeding
Authors: Peter Brønnum Nielsen, Torben Bjerregaard Larsen, Flemming Skjøth, Anders Gorst-Rasmussen, Lars Hvilsted Rasmussen, Gregory Y.H. Lip
Journal: Circulation (2015)

Background— Intracranial hemorrhage is the most feared complication of oral anticoagulant treatment. The optimal treatment option for patients with atrial fibrillation who survive an intracranial hemorrhage remains unknown. We hypothesized that restarting oral anticoagulant treatment was associated with a lower risk of stroke and mortality in comparison with not restarting. Methods and Results— Linkage of 3 Danish nationwide registries in the period between 1997 and 2013 identified patients with atrial fibrillation on oral anticoagulant treatment with incident intracranial hemorrhage. Patients were stratified by treatment regimens (no treatment, oral anticoagulant treatment, or antiplatelet therapy) after the intracranial hemorrhage. Event rates were assessed 6 weeks after hospital discharge and compared with Cox proportional hazard models. In 1752 patients (1 year of follow-up), the rate of ischemic stroke/systemic embolism and all-cause mortality (per 100 person-years) for patients treated with oral anticoagulants was 13.6, in comparison with 27.3 for nontreated patients and 25.7 for patients receiving antiplatelet therapy. The rate of ischemic stroke/systemic embolism and all-cause mortality (per 100 person-years) for recurrent intracranial hemorrhage, the rate of ischemic stroke/systemic embolism, and all-cause mortality (per 100 person-years) patients treated with oral anticoagulants was 8.0, in comparison with 8.6 for nontreated patients and 5.3 for patients receiving antiplatelet therapy. The adjusted hazard ratio of ischemic stroke/systemic embolism and all-cause mortality was 0.55 (95% confidence interval, 0.39–0.78) in patients on oral anticoagulant treatment in comparison with no treatment. For ischemic stroke/systemic embolism and for all-cause mortality, hazard ratios were 0.59 (95% confidence interval, 0.33–1.03) and 0.55 (95% confidence interval, 0.37–0.82), respectively. Conclusions— Oral anticoagulant treatment was associated with a significant reduction in ischemic stroke/all-cause mortality rates, supporting oral anticoagulant treatment reintroduction after intracranial hemorrhage as feasible. Future trials are encouraged to guide clinical practice in these patients.