Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Altered Thymic Function during Interferon Therapy in HCV-Infected Patients

Interferon alpha (IFNα) therapy, despite good efficacy in curing HCV infection, leads to major side effects, in particular inducement of a strong peripheral T-cell lymphocytopenia. We here analyze the early consequences of IFNα therapy on both thymic function and peripheral T-cell homeostasis in patients in the acute or chronic phase of HCV-infection as well as in HIV/HCV co-infected patients. The evolution of T-cell subsets and T-cell homeostasis were estimated by flow cytometry while thymic function was measured through quantification of T-cell receptor excision circles (TREC) and estimation of intrathymic precursor T-cell proliferation during the first four months following the initiation of IFNα therapy. Beginning with the first month of therapy, a profound lymphocytopenia was observed for all T-cell subsets, including naïve T-cells and recent thymic emigrants (RTE), associated with inhibition of intrathymic precursor T-cell proliferation. Interleukin (IL)-7 plasma concentration rapidly dropped while lymphocytopenia progressed. This was neither a consequence of higher consumption of the cytokine nor due to its neutralization by soluble CD127. Decrease in IL-7 plasma concentration under IFNα therapy correlated with the decline in HCV viral load, thymic activity and RTE concentration in blood. These data demonstrate that IFNα-based therapy rapidly impacts on thymopoiesis and, consequently, perturbs T-cell homeostasis. Such a side effect might be detrimental for the continuation of IFNα therapy and may lead to an increased level of infectious risk, in particular in HIV/HCV co-infected patients. Altogether, this study suggests the therapeutic potential of IL-7 in the maintenance of peripheral T-cell homeostasis in IFNα-treated patients

Albumin and multiple sclerosis

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Leakage of the blood–brain barrier (BBB) is a common pathological feature in multiple sclerosis (MS). Following a breach of the BBB, albumin, the most abundant protein in plasma, gains access to CNS tissue where it is exposed to an inflammatory milieu and tissue damage, e.g., demyelination. Once in the CNS, albumin can participate in protective mechanisms. For example, due to its high concentration and molecular properties, albumin becomes a target for oxidation and nitration reactions. Furthermore, albumin binds metals and heme thereby limiting their ability to produce reactive oxygen and reactive nitrogen species. Albumin also has the potential to worsen disease. Similar to pathogenic processes that occur during epilepsy, extravasated albumin could induce the expression of proinflammatory cytokines and affect the ability of astrocytes to maintain potassium homeostasis thereby possibly making neurons more vulnerable to glutamate exicitotoxicity, which is thought to be a pathogenic mechanism in MS. The albumin quotient, albumin in cerebrospinal fluid (CSF)/albumin in serum, is used as a measure of blood-CSF barrier dysfunction in MS, but it may be inaccurate since albumin levels in the CSF can be influenced by multiple factors including: 1) albumin becomes proteolytically cleaved during disease, 2) extravasated albumin is taken up by macrophages, microglia, and astrocytes, and 3) the location of BBB damage affects the entry of extravasated albumin into ventricular CSF. A discussion of the roles that albumin performs during MS is put forth

Proceedings of the Fourth Caldwell Conference, St. Catherines Island, Georgia, March 27-29, 2009.

391 p. : ill. (chiefly col.), maps (chiefly col.) ; 26 cm. "Issued March 23, 2011."This edited volume addresses the geoarchaeology of St. Catherines Island (Georgia). The field of geoarchaeology has typically been defined as either geology pursued within an archaeological framework or (sometimes the reverse) as archaeology framed with the help of geological methodology. Either way, the formalized objectives of geoarchaeology define a broad range of pursuits, from placing archaeological sites into relative and absolute temporal context through the application of stratigraphic principles and absolute dating techniques, to understanding the natural processes of site formation, to reconstructing the landscapes that existed around a site or group of sites at the time of occupation. The editors of this volume have generally followed the lead of G.R. Rapp and C.L. Hill (2006, Geoarchaeology : the earth-science approach to archaeological interpretation) by stressing the importance of multiple viewpoints and methodologies in applying geoscience techniques to evaluate the archaeological record. In the broadest sense, then, Geoarchaeology of St. Catherines Island applies multiple earth science concepts, techniques, or knowledge bases to the known archaeological record and the processes that created that record. This volume consists of 16 papers presenting the newest research on the stratigraphic and geomorphological evolution of the St. Catherines Island landscape. Of particular interest are presentations addressing the relative timing and nature of sedimentation, paleobiology, sea level change, stream capture, hydrology, and erosional patterning evident on St. Catherines Island (and to some degree the rest of the Georgia Bight). These papers were initially presented at the Fourth Caldwell Conference, cosponsored by the American Museum of Natural History and the St. Catherines Island Foundation, held on St. Catherines Island (Georgia), March 27-29, 2009. Table of contents: Why this archaeologist cares about geoarchaeology : some pasts and futures of St. Catherines Island / David Hurst Thomas -- Evolution of late Pleistocene-Holocene climates and environments of St. Catherines Island and the Georgia Bight / Fredrick J. Rich, Anthony Vega, and Frank J. Vento -- Geoarchaeological research at St. Catherines Island : defining the geological foundation / Gale A. Bishop, Brian K. Meyer, R. Kelly Vance, and Fredrick J. Rich -- Development of a late Pleistocene-Holocene genetic stratigraphic framework for St. Catherines Island : archaeological implications / Frank J. Vento and Patty A. Stahlman -- Ichnological diagnosis of ancient storm-washover fans, Yellow Banks Bluff, St. Catherines Island / Anthony J. Martin and Andrew K. Rindsberg -- Quaternary vegetation and depositional history of St. Catherines Island / Fredrick J. Rich and Robert K. Booth -- Recent shoreline erosion and vertical accretion patterns, St. Catherines Island / Donald B. Potter Jr. -- Role of storm events in beach ridge formation, St. Catherines Island / Harold B. Rollins, Kathi Beratan, and James E. Pottinger -- Drainage changes at Ossabaw, St. Catherines, and Sapelo sounds and their influence on island morphology and spit building on St. Catherines Island / Timothy M. Chowns -- Vibracores and vibracore transects : constraining the geological and cultural history of St. Catherines Island / Gale A. Bishop, David Hurst Thomas, Matthew C. Sanger, Brian K. Meyer, R. Kelly Vance, Robert K. Booth, Fredrick J. Rich, Donald B. Potter, and Timothy Keith-Lucas -- Application of ground penetrating radar to investigations of the stratigraphy, structure, and hydrology of St. Catherines Island / R. Kelly Vance, Gale A. Bishop, Fredrick J. Rich, Brian K. Meyer, and Eleanor J. Camann -- Postsettlement dispersal and dynamic repopulation of estuarine habitats by adult Mercenaria mercenaria, St. Catherines Island / Robert S. Prezant, Harold B. Rollins, and Ronald B. Toll -- The foundation for sea turtle geoarchaeology and zooarchaeology : morphology of recent and ancient sea turtle nests, St. Catherines Island, Georgia, and Cretaceous Fox Hills Sandstone, Elbert County, Colorado / Gale A. Bishop, Fredric L. Pirkle, Brian K. Meyer, and William A. Pirkle -- Sea turtle habitat deterioration on St. Catherines Island : defining the modern transgression / Gale A. Bishop and Brian K. Meyer -- Modeling indigenous hunting and harvesting of sea turtles and their eggs on the Georgia Coast / Gale A. Bishop, David Hurst Thomas, and Brian K. Meyer -- Geomorphology, sea level, and marine resources : St. Catherines Island / Harold B. Rollins and David Hurst Thomas -- Appendix 1. Noncultural radiocarbon record from St. Catherines Island : a compendium -- Appendix 2. Vibracore record from St. Catherines Island : a compendium.Conference sponsored by the American Museum of Natural History and the St. Catherines Island Foundation

Effects of oxygen, growth state, and senescence on the antioxidant responses of WI-38 fibroblasts

Mitotically active, growth-arrested cells and proliferatively senescent cultures of human fetal lung fibroblasts (WI-38) were exposed to six different oxygen tensions for various lengths of time and then analyzed to determine the responses of their antioxidant defense system. Glutathione (GSH) concentration increased as a function of ambient oxygen tension in early passage cultures; the effect was larger in exponentially growing cultures than in those in a state of contact-inhibited growth arrest, but was absent in senescent cells. Conversely, the activity of glutathione disulfide reductase was greater in growth-arrested cultures than in mitotically active cells irrespective of oxygen tension. Glucose-6-phosphate dehydrogenase was lowest in log-phase cells exposed to different oxygen tensions for 24 h and in senescent cells. Both hypoxia and hyperoxia depressed selenium-dependent glutathione peroxidase activity in early passage cultures, while the activity of the enzyme progressively declined with increasing oxygen in senescent cells. The GSH S-transferase activity was unresponsive to changes in ambient oxygen tension in either young or senescent cultures. Manganese-containing superoxide dismutase (MnSOD) activity was unaffected by oxygen tension, but was elevated in young confluent cultures as compared with cultures in log-phase growth. MnSOD activity was significantly higher in senescent cultures than in early passage cultures and was also responsive to increased oxygen tension in senescent cultures. Copper–zinc-containing superoxide dismutases activity was not affected by oxygen tension or the passage of time, but it declined in senescent cultures

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Moral and ethical judgement in the academic training: a pilot study on students of Economics.

Moral reasoning is central in all professionalisms and it is crucial in those professions where economical and financial aspects can be used to “help” or not the others. The present pilot study aims at investigating possible differences in moral judgement between students of Economics at their first year and students at the end of university training. This population will be compared to a similar group of students of the School of Psychology. Results show that gender and academic seniority can directly drive moral decision making, while the fact to be enrolled in different academic courses (i.e. Economics Vs Psychology) can probably only indirectly modulate this behavior. Some explanations to these phenomena have been put forward and discussed in a critical way