tbuckley/cabot-search huggingface dataset:
MECHANISMS OF ENDOTOXIN TOLERANCE
Authors: Sheldon E. Greisman, Frank A. Carozza, J. Dixon Hills
Journal: The Journal of Experimental Medicine (1963)

Pyrogenic tolerance following 7 daily intravenous injections of 2.0 microg/kg E. coli endotoxin in albino rabbits was associated with significant increases in RES phagocytic activity as measured with colloidal carbon. Nevertheless, 4 hours after RES blockade with thorotrast (3 ml/kg), the tolerant rabbits exhibited significantly lower fever indices following intravenous endotoxin challenge than did non-tolerant control animals despite comparably depressed capacities to clear carbon from the blood. Moreover, plasma from rabbits tolerant to endotoxin induced significant tolerance in normal rabbits prepared by thorotrast blockade without enhancing the depressed carbon clearance. This passive protection extended to heterologous endotoxins. Analysis of the data indicates that RES blockade does not abolish tolerance; rather blockade resets the reactivity to endotoxin in the normal and tolerant animal, rendering both exquisitely reactive, but permitting retention of the major portion of tolerance. Apparently the tolerant animal possesses a dual endotoxin defense system. One system is abolished by thorotrast; the other is in part humoral, accounts for the greater portion of tolerance, and is thorotrast-resistant. The nature of the humoral component is not defined but is consistent with that of an opsonin with high endotoxin specificity.
Donor CMV serostatus has no impact on CMV viremia or disease when prophylactic granulocyte transfusions are given following allogeneic peripheral blood stem cell transplantation
Authors: Ravi Vij, John F. DiPersio, Partha Venkatraman, Kathryn Trinkaus, Lawrence T. Goodnough, Randy A. Brown, Hanna J. Khoury, Steven M. Devine, Aarti Oza, Shalini Shenoy, William Blum, Douglas Adkins
Journal: Blood (2003)
Clinical Features of Metastatic Bone Disease and Risk of Skeletal Morbidity
Authors: Robert E. Coleman
Journal: Clinical Cancer Research (2006)

Abstract The skeleton is the most common organ to be affected by metastatic cancer and the site of disease that produces the greatest morbidity. Skeletal morbidity includes pain that requires radiotherapy, hypercalcemia, pathologic fracture, and spinal cord or nerve root compression. From randomized trials in advanced cancer, it can be seen that one of these major skeletal events occurs on average every 3 to 6 months. Additionally, metastatic disease may remain confined to the skeleton with the decline in quality of life and eventual death almost entirely due to skeletal complications and their treatment. The prognosis of metastatic bone disease is dependent on the primary site, with breast and prostate cancers associated with a survival measured in years compared with lung cancer, where the average survival is only a matter of months. Additionally, the presence of extraosseous disease and the extent and tempo of the bone disease are powerful predictors of outcome. The latter is best estimated by measurement of bone-specific markers, and recent studies have shown a strong correlation between the rate of bone resorption and clinical outcome, both in terms of skeletal morbidity and progression of the underlying disease or death. Our improved understanding of prognostic and predictive factors may enable delivery of a more personalized treatment for the individual patient and a more cost-effective use of health care resources.
Report on the Accreditation Process
Authors: William E. Jacott
Journal: JAMA (1988)

THE AMERICAN Medical Association (AMA) has participated in the accreditation of educational programs since the first publication of an "ideal standard" for undergraduate medical education in 1905. This report is to inform the House of Delegates of the current status of accreditation activities in undergraduate, graduate, and continuing medical education. Accreditation is a process by which an academic program or institution voluntarily seeks recognition by an accrediting agency. The accrediting agency establishes valid standards, or<i>Essentials</i>, necessary for the basic quality of an academic program or institution. When requested, the accrediting agency evaluates the program or institution and, if there is substantial compliance with the<i>Essentials</i>, grants accreditation for a specified number of years. Accreditation as applied to medical education serves several purposes. It encourages improvement in the quality of each level of medical education. Its fundamental purpose is to assure participants in an educational endeavor that the program or
Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell–associated antigens
Authors: Yasunobu Miyake, Kenichi Asano, Hitomi Kaise, Miho Uemura, Manabu Nakayama, Masato Tanaka
Journal: Journal of Clinical Investigation (2007)

Injection of apoptotic cells can induce suppression of immune responses to cell-associated antigens. Here, we show that intravenous injection of apoptotic cells expressing a fragment of myelin oligodendrocyte glycoprotein (MOG) reduced MOG-specific T cell response and prevented the development of EAE. Since injected apoptotic cells accumulated initially in the splenic marginal zone (MZ), the role of macrophages in the MZ in immune suppression was examined using transgenic mice in which these cells could be transiently deleted by diphtheria toxin (DT) injection. DT-treated mice became susceptible to EAE even though MOG-expressing apoptotic cells were preinjected. Deletion of the macrophages caused delayed clearance of injected dying cells in the MZ. In wild-type mice, injected apoptotic cells were selectively engulfed by CD8 alpha(+) DCs, which are responsible for suppression of immune responses to cell-associated antigens. In contrast, deletion of macrophages in the MZ caused aberrant phagocytosis of injected dying cells by CD8 alpha(-)CD11b(+) DCs. These results indicate that macrophages in the MZ regulate not only efficient clearance of apoptotic cells but also selective engulfment of dying cells by CD8 alpha(+) DCs and that functional failure of these unique macrophages impairs suppression of immune responses to cell-associated antigens.
Redistribution of collateral blood flow from necrotic to surviving myocardium following coronary occlusion in the dog.
Authors: H O Hirzel, G R Nelson, E H Sonnenblick, E S Kirk
Journal: Circulation Research (1976)

Early changes in collateral blood flow after acute coronary occlusion may be critical for survival of ischemic myocardium. We used 15-mum radioactive microspheres to study myocardial blood flow in thoracotomized dogs 10 minutes and 24 hours after occlusion of the left anterior descending coronary artery (LAD). The ischemic area was delineated by dye injected into the distal artery, and indentification of potentially ischemic samples was confirmed by a newly developed technique in which microspheres were excluded from the normally perfused LAD. Layers were separated into necrotic or normal as defined by gross inspection and confirmed by histological examination and creatine phosphokinase assay. Infarction always involved endocardial layers and extended toward the epicardium. Average myocardial blood flow in 48 necrotic samples from 16 dogs either remained low (less than 0.05 ml/min g-1) or declined, falling from 0.11 +/-0.02(SE) at 10 minutes to 0.05 +/-0.01 ml/min g-1 at 24 hours (P less than 0.001). In contrast, in the 32 normal-appearing samples which were ischemic at 10 minutes, flow increased from 0.24 +/-0.03 to 0.39 +/-0.04 ml/min g-1 (P less than 0.001). Flow in control myocardium was 1.43 +/-0.12 and 1.04 +/-0.07 ml/min g-1, respectively. Peripheral mean coronary arterial pressure increased from 26 +/- 3 to 35 +/- 3 mm Hg, largely because of enlargement of collateral vessels; collateral conductance calculated from retrograde flow in 14 dogs increased from 0.023 +/- 0.005 after occlusion to 0.051 +/- 0.009 ml/min mm Hg-1 24 hours later (P less than 0.001). Thus, coronary collateral blood flow is redistributed from necrotic endocardial layers to surviving epicardial ones. In combination with a developing collateral supply this process may be essential for sparing myocardium after coronary occlusion.
THE DEVELOPMENT OF THE CHRONIC NEPHRITIS INDUCED IN THE DOG BY URANIUM NITRATE. A FUNCTIONAL AND PATHOLOGICAL STUDY WITH OBSERVATIONS ON THE FORMATION OF URINE BY THE ALTERED KIDNEYS
Authors: William deB. MacNider
Journal: The Journal of Experimental Medicine (1929)

1. A chronic nephritis was produced in the dog which involves all of the histological elements of the kidney by the use of one subcutaneous injection of 4 mg. of uranium nitrate per kilo. In such animals the sequence of the histological changes in the kidneys in correlation with their functional expression has been studied in dogs from the commencement of the; injury until the chronic nehritis has existed for 5 years and 2 months. 2. As early as the 2nd day following the development of an acute nephritis, the animals became polyuric with an albuminous urine containing granular casts. There was a marked reduction in the elimination of phenolsulphonephthalein, or it failed to appear in the urine in a 2 hour period. The reserve alkali of the blood was reduced to as low as 7.8 and a retention occurred in urea nitrogen, non-protein nitrogen and creatinine. At such periods of renal functional depression there was slight evidence of structural glomerular injury but marked evidence of proximal convoluted tubule degeneration and necrosis.
Imatinib Mesylate Resistance Through BCR-ABL Independence in Chronic Myelogenous Leukemia
Authors: Nicholas J. Donato, Ji Y. Wu, Jonathan Stapley, Hui Lin, Ralph Arlinghaus, Bharat Aggarwal, Shishir Shishodin, Maher Albitar, Kimberly Hayes, Hagop Kantarjian, Moshe Talpaz
Journal: Cancer Research (2004)

Imatinib mesylate (IM) binds to the BCR-ABL protein, inhibiting its kinase activity and effectively controlling diseases driven by this kinase. IM resistance has been associated with kinase mutations or increased BCR-ABL expression. However, disease progression may be mediated by other mechanisms that render tumor cells independent of BCR-ABL. To demonstrate this potential, IM-resistant cells were found in chronic myelogenous leukemia patients with continuous BCR-ABL gene expression but undetectable BCR-ABL protein expression. These cells were unresponsive to IM and acquired BCR-ABL-independent signaling characteristics. IM resistance in some patients may be mediated through loss of kinase target dependence.
The novel BH3 α-helix mimetic JY-1-106 induces apoptosis in a subset of cancer cells (lung cancer, colon cancer and mesothelioma) by disrupting Bcl-xL and Mcl-1 protein–protein interactions with Bak
Authors: Xiaobo Cao, Jeremy L Yap, M Karen Newell-Rogers, Chander Peddaboina, Weihua Jiang, Harry T Papaconstantinou, Dan Jupitor, Arun Rai, Kwan-Young Jung, Richard P Tubin, Wenbo Yu, Kenno Vanommeslaeghe, Paul T Wilder, Alexander D MacKerell, Steven Fletcher, Roy W Smythe
Journal: Molecular Cancer (2013)

Abstract Background It has been shown in many solid tumors that the overexpression of the pro-survival Bcl-2 family members Bcl-2/Bcl-xL and Mcl-1 confers resistance to a variety of chemotherapeutic agents. We designed the BH3 α-helix mimetic JY-1-106 to engage the hydrophobic BH3-binding grooves on the surfaces of both Bcl-xL and Mcl-1. Methods JY-1-106–protein complexes were studied using molecular dynamics (MD) simulations and the SILCS methodology. We have evaluated the in vitro effects of JY-1-106 by using a fluorescence polarization (FP) assay, an XTT assay, apoptosis assays, and immunoprecipitation and western-blot assays. A preclinical human cancer xenograft model was used to test the efficacy of JY-1-106 in vivo. Results MD and SILCS simulations of the JY-1-106–protein complexes indicated the importance of the aliphatic side chains of JY-1-106 to binding and successfully predicted the improved affinity of the ligand for Bcl-xL over Mcl-1. Ligand binding affinities were measured via an FP assay using a fluorescently labeled Bak-BH3 peptide in vitro . Apoptosis induction via JY-1-106 was evidenced by TUNEL assay and PARP cleavage as well as by Bax–Bax dimerization. Release of multi-domain Bak from its inhibitory binding to Bcl-2/Bcl-xL and Mcl-1 using JY-1-106 was detected via immunoprecipitation (IP) western blotting. At the cellular level, we compared the growth proliferation IC 50 s of JY-1-106 and ABT-737 in multiple cancer cell lines with various Bcl-xL and Mcl-1 expression levels. JY-1-106 effectively induced cell death regardless of the Mcl-1 expression level in ABT-737 resistant solid tumor cells, whilst toxicity toward normal human endothelial cells was limited. Furthermore, synergistic effects were observed in A549 cells using a combination of JY-1-106 and multiple chemotherapeutic agents. We also observed that JY-1-106 was a very effective agent in inducing apoptosis in metabolically stressed tumors. Finally, JY-1-106 was evaluated in a tumor-bearing nude mouse model, and was found to effectively repress tumor growth. Strong TUNEL signals in the tumor cells demonstrated the effectiveness of JY-1-106 in this animal model. No significant side effects were observed in mouse organs after multiple injections. Conclusions Taken together, these observations demonstrate that JY-1-106 is an effective pan-Bcl-2 inhibitor with very promising clinical potential.
Midregional Fragment of Proadrenomedullin, New-Onset Albuminuria, and Cardiovascular and All-Cause Mortality in Patients With Type 2 Diabetes (ZODIAC-30)
Authors: Gijs W.D. Landman, Peter R. van Dijk, Iefke Drion, Kornelis J.J. van Hateren, Joachim Struck, Klaas H. Groenier, Rijk O.B. Gans, Henk J.G. Bilo, Stephan J.L. Bakker, Nanne Kleefstra
Journal: Diabetes Care (2013)

The midregional fragment of proadrenomedullin (MR-proADM) is a marker of endothelial dysfunction and has been associated with a variety of diseases. Our aim was to investigate whether MR-proADM is associated with new-onset albuminuria and cardiovascular (CV) and all-cause mortality in patients with type 2 diabetes treated in primary care.Patients with type 2 diabetes participating in the observational Zwolle Outpatient Diabetes Project Integrating Available Care (ZODIAC) study were included. Cox regression analyses were used to assess the relation of baseline MR-proADM with new-onset albuminuria and CV and all-cause mortality. Risk prediction capabilities of MR-proADM for new-onset albuminuria and CV and all-cause mortality were assessed with Harrell's C and the integrated discrimination improvement.In 1,243 patients (mean age 67 [±12] years), the median follow-up was 5.6 years (interquartile range 3.1-10.1); 388 (31%) patients died, with 168 (12%) CV deaths. Log2 MR-proADM was associated with CV (hazard ratio 1.96 [95% CI 1.27-3.01]) and all-cause mortality (1.78 [1.34-2.36]) after adjusting for age, sex, BMI, smoking, systolic blood pressure, cholesterol-to-HDL ratio, duration of diabetes, HbA1c, ACE inhibitor/angiotensin receptor blocker, history of CV diseases, log serum creatinine, and log albumin-to-creatinine ratio. MR-proADM slightly improved mortality risk prediction. The age- and sex-adjusted, but not multivariate-adjusted, MR-proADM levels were associated with new-onset albuminuria.MR-proADM was associated with CV and all-cause mortality in patients with type 2 diabetes after a median follow-up of 5.6 years. There was no independent relationship with new-onset albuminuria. In the availability of an extensive set of risk factors, there was little added effect of MR-proADM in risk prediction of CV and all-cause mortality.
Fractional Flow Reserve Compared With Intravascular Ultrasound Guidance for Optimizing Stent Deployment
Authors: William F. Fearon, Jorge Luna, Habib Samady, Eric R. Powers, Ted Feldman, Nabil Dib, E. Murat Tuzcu, Michael W. Cleman, Tony M. Chou, David J. Cohen, Michael Ragosta, Atsushi Takagi, Allen Jeremias, Peter J. Fitzgerald, Alan C. Yeung, Morton J. Kern, Paul G. Yock
Journal: Circulation (2001)

Background Determination of fractional flow reserve (FFR) has been proposed as a means to assess stent deployment. In this prospective, multicenter trial, we evaluate the use of FFR to optimize stenting by comparing it with standard intravascular ultrasound (IVUS) criteria. Methods and Results Eighty-four stable patients with isolated coronary lesions underwent coronary stent deployment starting at 10 atm and increased serially by 2 atm until the FFR was ≥0.94 or 16 atm was achieved. IVUS was then performed. FFR was measured with a coronary pressure wire with intracoronary adenosine to induce hyperemia. The diagnostic characteristics of an FFR &lt;0.94 to predict suboptimal stent expansion by IVUS, defined in both absolute and relative terms, were calculated. Over a range of IVUS criteria, the highest sensitivity, specificity, and predictive accuracy of FFR were 80%, 30%, and 42%, respectively. Receiver operator characteristic analysis defined an optimal FFR cut point at ≥0.96; at this threshold, the sensitivity, specificity, and predictive accuracy of FFR were 75%, 58%, and 62%, respectively ( P =0.03 for comparison of predictive accuracy, P =0.01 for concordance between FFR and IVUS). The negative predictive value was 88%. Significantly better diagnostic performance was achieved in a subgroup that received higher doses (&gt;30 μg) of intracoronary adenosine during pressure measurements, suggesting that FFR might be overestimated in the other group. Conclusions A fractional flow reserve &lt;0.96, measured after stent deployment, predicts a suboptimal result based on validated intravascular ultrasound criteria; however, an FFR ≥0.96 does not reliably predict an optimal stent result. Higher doses of intracoronary adenosine than previously used to measure FFR improve these results.
Decreased computed tomographic lung density during exacerbation of asthma
Authors: F. Mitsunobu, K. Ashida, Y. Hosaki, H. Tsugeno, M. Okamoto, N. Nishida, T. Nagata, S. Takata, Y. Tanizaki
Journal: European Respiratory Journal (2003)

Recently, it was shown that both mean lung density (MLD) and the relative lung area with an attenuation of &lt;-950 HU (RA 950 ) are related to severity of asthma in nonsmoking asthmatics. The aim of the present study was to examine whether reduced computed tomography (CT) lung density during exacerbation could change after treatment. A cross-sectional study was performed to compare CT lung density in 30 stable asthmatics, 30 unstable asthmatics and 25 control subjects. In order to investigate longitudinally the effect of treatment on decreased CT lung density, 17 asthmatics with an exacerbation were followed at the initiation of treatment and 2 months after relief. The MLD was significantly lower and the RA 950 significantly higher in unstable asthmatics than in controls and stable asthmatics. Both MLD and RA 950 changed significantly with administration of systemic glucocorticoid therapy. The changes in forced expiratory volume in one second correlated significantly with those in both MLD and RA 950 . The changes in residual volume also correlated significantly with those in both MLD and RA 950 . It was concluded that decreased computed tomographic lung density during an asthma exacerbation is at least partially reversible, and changes in mean lung density and the relative lung area with a radiation attenuation of &lt;−950 HU are related to the change in forced expiratory volume in one second and residual volume.
Corrigendum to ‘Staphylococcus aureus bloodstream infection: A pooled analysis of five prospective, observational studies’ [J Infect 68 (2014) 242–251]
Authors: Achim J. Kaasch, Gavin Barlow, Jonathan D. Edgeworth, Vance G. Fowler, Martin Hellmich, Susan Hopkins, Winfried V. Kern, Martin J. Llewelyn, Siegbert Rieg, Jesús Rodriguez-Baño, Matthew Scarborough, Harald Seifert, Alex Soriano, Robert Tilley, M. Esteé Tőrők, Verena Weiß, A. Peter R. Wilson, Guy E. Thwaites
Journal: Journal of Infection (2014)
What's new about social construction? Distinct roles needed for language and communication
Authors: Janet Wilde Astington
Journal: Behavioral and Brain Sciences (2004)

Carpendale &amp; Lewis's (C&amp;L's) theory falls in with an existing set of theories that children's understanding of mind is collaboratively constructed in linguistically mediated social interaction. This social constructivist view needs to be clear about the complementary contributions of the child and of the social environment. I distinguish between the child's individual linguistic ability and the dyad's social communication, proposing that each makes a contribution to theory-of-mind development, differently balanced in different individuals.
A SIMPLE SYSTEM OF SKELETON SPLINTING
Authors: C. M. Page
Journal: BMJ (1916)

JUNE _179 itgx I.MDICAI Jou_w. 84_-__attained, though much more slowly, without fasting and subnutrition, with its risk of depression and weakness, provided the patient is willing to keep permanently to the diet which has been found by careftul testing to be suitable to his case.At the present time the doctor, in order to decide as to the best treatment in severe cases, must judge of the temperament of the patient.To sorne it is purgatory to be continually having to thiink about tests and figures.These will do best witlh definite allowances in an otherwise rigid diet.In otlherfs the disadvantages of a lhalf-starved condition must be balanced against tlle mental effect of the absence of sugar.We do not yet know whether the pro- gress of the disease is arrested by this method in cases in which it would not be arrested by a permanent adherence to a rigid, thouglh plentiful, diet.For all milder cases, indeed for the majority of all cases, Dr. Allen's procedure offers great advantages.We lhave evidence enough tllat such patients, though not cured, may be freed from tlle signs and symptoms of their' complaint.This beneficent result lhas been attained throuah the
The herbal medicine Inchin-ko-to inhibits liver cell apoptosis induced by transforming growth factor ?1
Authors: M Yamamoto, K Ogawa, M Morita, K Fukuda, Y Komatsu
Journal: Hepatology (1996)

Transforming growth factor beta 1 (TGF-beta 1) is reported to play an important role in the induction of liver cell apoptosis. In this report, we demonstrate that TGF-beta 1 induces apoptosis in a rat Morris hepatoma McA-RH8994 cell line and rat primary cultured hepatocytes at similar doses and in a similar manner. Using McA-RH8994 cells, we screened a number of chemical reagents, aqueous extracts of crude drugs, and herbal medicines for their inhibitory activities on TGF-beta 1-induced apoptosis. The results indicate that Artemisiae capillaris spica (ACS) and the ACS-containing herbal medicine Inchin-ko-to, which are used for treatment of various liver disorders, exhibited the most potent anti-apoptotic activity. Various chemicals that were reported as inhibitors of apoptosis in other experimental systems showed no evident activity. By contrast, two of nine ACS ingredients we tested, capillin and capillene, showed activity at concentrations of submicrogram per milliliter. The inhibitory effects of Inchin-ko-to, capillin and capillene were also confirmed on TGF-beta 1-induced apoptosis of rat primary cultured hepatocytes. Inhibition of undesired apoptosis induced by TGF-beta 1 is expected to be beneficial for the treatment of various inflammatory liver diseases. Our findings therefore suggest the possibility that therapeutic effects of Inchin-ko-to on liver diseases might be associated with its inhibitory activity on TGF-beta 1-induced liver cell apoptosis.