tbuckley/cabot-search huggingface dataset:
Lenticular opacities in glaucoma patients receiving echothiophate iodide therapy. Preliminary report
Authors: A. De Roetth
Journal: JAMA (1966)

Echothiophatee) iodide has been used in ophthalmology for the past eight years. 1 During the last few years it has become one of the drugs most frequently employed in the treat ment of glaucoma. It is an irreversible inhibitor of cholinesterase and an excellent drug for control of chronic simple glaucoma, postiridectomy angle-closure glaucoma, and various secondary glaucomas. 2,3 However, unfavorable local and systemic side effects have been reported. 4-7 The most important local side effects are spasm of the ciliary muscle, producing severe pain in the eye, and edema of the anterior uveal tract which may result in angle closure and an acute attack of glaucoma. The systemic side effects include gastrointestinal, respiratory, cardiac, and central-nervous-system symptoms, which in their severest form potentially may even be lethal.  During the past year many of my colleagues have noticed the development of cataracts in their glaucoma patients treated with echothiophate iodide.
Sex Differences in Renal Responses to Hyperglycemia, <scp>l</scp>-Arginine, and <scp>l</scp>-NMMA in Humans With Uncomplicated Type 1 Diabetes
Authors: David Z.I. Cherney, James W. Scholey, Etienne B. Sochett
Journal: Diabetes Care (2012)

Women exhibit exaggerated renal hemodynamic responses to hyperglycemia, which may promote kidney disease progression. Our aim was to determine if increased nitric oxide generation by l-arginine infusion would reverse this deleterious response to clamped hyperglycemia in women with type 1 diabetes mellitus.Renal function, blood pressure, and plasma cyclic guanosine monophosphate (cGMP) were measured in 20 men and 15 women with type 1 diabetes mellitus during clamped euglycemia and clamped hyperglycemia. Renal function, blood pressure, and plasma cGMP responses to graded infusions of intravenous l-arginine and N(G)-monomethyl-l-arginine (l-NMMA) were measured during clamped hyperglycemia.Subjects were young, normotensive, normoalbuminuric men and women who adhered to a high-sodium, moderate-protein diet. Plasma cGMP levels during euglycemia were generally lower in men compared with women, and systolic blood pressure (SBP) was higher in men. In response to hyperglycemia, cGMP levels did not change in men but did decline in women (Δ-1.10 ± 0.20 vs. Δ+0.05 ± 0.20 pmol/L, between-group effect of hyperglycemia on cGMP; P = 0.012). Hyperglycemia also was associated with an increase in SBP, glomerular filtration rate (GFR) (124 ± 6 to 143 ± 7 mL/min/1.73 m(2); P = 0.003) and filtration fraction (FF) in women, but these parameters did not change in men. In response to l-arginine during hyperglycemia, the increase in cGMP was exaggerated in women versus men and GFR and FF decreased in women only, back toward baseline values observed during clamped euglycemia. l-NMMA infusion did not exaggerate changes in hemodynamic function in response to hyperglycemia. l-Arginine reversed the renal hemodynamic effects of hyperglycemia in women, suggesting that nitric oxide is an important regulator of sex-dependent vascular responses to hyperglycemia in humans.
Scanning electron microscopy of rheumatoid arthritis peripheral blood polymorphonuclear leucocytes.
Authors: D A McCarthy, C M Holburn, B K Pell, S R Moore, A P Kirk, J D Perry
Journal: Annals of the Rheumatic Diseases (1986)

Peripheral blood polymorphonuclear leucocytes (PMNs) were isolated from six normal individuals and from 27 patients with rheumatoid arthritis (RA) by the Ficoll-Hypaque rapid single step centrifugation technique, fixed in suspension, and examined by scanning electron microscopy (SEM). In addition, four of the preparations from normal individuals and eight from patients with RA were examined by transmission electron microscopy (TEM). Most PMNs in preparations from normal subjects were spherical, unpolarised, and had their surface membrane elaborated into irregular ridges and small ruffles; they contained few phagocytic vacuoles and large numbers of electron dense primary and secondary granules. A minority of the cells were non-spherical, polarised, and had portions of their surface membrane elaborated into ruffled pseudopodia. In contrast, preparations of RA PMNs frequently contained fewer unpolarised PMNs and a higher number of polarised PMNs than did preparations of normal PMNs. Some preparations of RA PMNs also contained substantial numbers of spherical cells whose surface was covered mainly by bulges and blebs. Concurrent examination by TEM showed that RA PMNs frequently contained more phagocytic vacuoles and fewer electron dense primary and secondary granules than normal PMNs. The morphological and ultrastructural changes seen in RA PMNs resembled those which normal PMNs are known to undergo on exposure to C5a in vitro, during adherence to endothelial cells in vivo, or during phagocytosis in vivo or in vitro. Our observations, therefore, provide a useful morphological correlation to those in vitro studies in which differences in the functional activity of RA and normal PMNs have been shown. The possibility that the difference seen between RA and normal PMNs is artefactual and does not represent the genuine in vivo states of these cells is discussed.
Urban-rural differences in questionnaire-derived markers of asthma in Kenyan school children
Authors: JA Odhiambo, LW Ng'ang'a, MW Mungai, CM Gicheha, JK Nyamwaya, F Karimi, PT Macklem, MR Becklake
Journal: European Respiratory Journal (1998)

Grade 4 Kenyan children attending 10 randomly selected public primary schools in Nairobi (urban) and the Muranga District (rural) were surveyed to establish the prevalence of symptom markers of asthma and to assess the impact of urbanization. A respiratory health and home environment questionnaire was administered at school to parents or guardians. The questionnaire response rates were 94.2% (568/ 603) for Nairobi and 89.6% (604/674) for Muranga. The prevalence rates for asthma, defined as "attacks of shortness of breath with wheeze", were 95% for urban and 3.0% for rural children (odds ratio (OR) urban versus rural: 3.42; 95% confidence interval (CI): -1.96-5.91). This urban-rural gradient persisted after adjusting for urban-rural differences in host factors (including duration of breastfeeding and family history of asthma and/or allergy), but was largely explained by urban-rural differences in environmental factors, including indoor animals, sharing a bedroom with a smoker, parental education, house ventilation and exposure to motor vehicle fumes en route to school (adjusted OR: 1.59; 95% CI: 0.70-3.55). Similar results were obtained for all other symptoms. These findings confirm the clinical impression that asthma is an important illness in Kenya and underline the need for the further study of environmental factors amenable to intervention, particularly in urban areas.
Neonatal tuberculosis and cardiac inflammatory myofibroblastic tumor presenting as supraventricular tachycardia: A rarity of kinds
Authors: Maria Niña Banque
Journal: European Respiratory Journal (2011)

This a case of a one month old female neonate who was admitted for respiratory distress. On admission, electrocardiogram showed supraventricular tachycardia. A 2-D echo showed a mass anterior to the left ventricle and the right ventricular outflow tract (RVOT). Chest radiograph showed a left upper lung haziness and computed tomography (CT) scan of the chest showed a non calcified anterior mediastinal mass with central enhancement. Intramyocardial mass biopsy revealed a large anteriorly located intramyocardial mass covering the RVOT, the great vessels and a portion of the right atrium. Final histopathology result revealed inflammatory pseudotumor, myofibroblastic in nature. Smooth muscle actin (SMA) was positive in many localized spindle cells indicative of their myofibroblastic nature while histiocyte markers- CD68 and S100 were both negative. Because of a high index of suspicion, a tuberculosis work-up was done which showed that the patient was positive for tuberculin test (18mm in diameter). Contact screening revealed 3 out of the 6 household contacts were positive for pulmonary tuberculosis. Patient was started on anti-tuberculosis medications and on the fifth month of treatment, the patient was asymptomatic, growing well and the mass regressed in size by 50%.
Long-acting 2-agonists in adult asthma and the pattern of risk of death and severe asthma outcomes: a study using the GPRD
Authors: F. de Vries, E. Setakis, B. Zhang, T. P. van Staa
Journal: European Respiratory Journal (2010)

The objective of this study was to describe risks of death and asthma outcomes with prescription of long-acting β<sub>2</sub>-agonists (LABA), short-acting β<sub>2</sub>-agonists (SABA) or inhaled corticosteroids (ICS) in general practice. The study population included β<sub>2</sub>-agonist users aged ≥18 yrs, who were in the UK General Practice Research Database (GPRD), which is linked to the national registry of hospitalisations. The study included 507,966 patients with 5.5 million SABA, 4.0 million ICS and 1.3 million LABA prescriptions. Rates of asthma outcome increased with more severe treatment steps. The mortality rate was increased with least and most severe treatment steps. Higher relative rates (RR) of outcomes were found in recent starters and heavy long-term users with LABA, SABA and ICS. The RRs in heavy long-term users were 1.9 for all-cause mortality and 3.0 for asthma death with SABA, 1.4 and 1.6, respectively, with LABA and 1.7 and 2.2, respectively, with ICS. The RR of death was statistically similar over time between LABA and ICS despite changes in exposure. Risks for death and asthma outcomes varied substantially with exposure characteristics. The statistical power for detecting increases in asthma death was low. The results of this study did not indicate that LABA exposure was associated with an increased risk for all-cause mortality.
Spatial non-uniformity of excitation-contraction coupling can enhance arrhythmogenic-delayed afterdepolarizations in rat cardiac muscle
Authors: M. Miura, Y. Wakayama, H. Endoh, M. Nakano, Y. Sugai, M. Hirose, H. E.D.J. ter Keurs, H. Shimokawa
Journal: Cardiovascular Research (2008)

We examined whether non-uniform muscle contraction affects delayed afterdepolarizations (DADs) by dissociating Ca2+ from myofilaments within the border zone (BZ) between contracting and stretched regions. Force, sarcomere length (SL), membrane potential, and [Ca2+]i dynamics were measured in 31 ventricular trabeculae from rat hearts. Non-uniform muscle contraction was produced by exposing a restricted region of muscle to a jet of solution containing 20 mmol/L 2,3-butanedione monoxime (BDM). DADs were induced by 7.5 s-2 Hz stimulus trains at an SL of 2.0 µm (24°C, [Ca2+]o 2.0 mmol/L). The BDM jet enhanced DADs (n = 6, P < 0.05) and aftercontractions (n = 6, P < 0.05) with or without 100 µmol/L streptomycin and occasionally elicited an action potential. A stretch pulse from an SL of 2.0 µm to 2.1 or 2.2 µm during the last stimulated twitch of the trains accelerated Ca2+ waves in proportion to the increment of force by the stretch (P < 0.01) with or without streptomycin. In the presence of 1 mmol/L caffeine, rapid shortening of the muscle after the stretch pulse increased [Ca2+]i within the BZ, whose amplitude correlated with the increment of force by the stretch (n = 15, P < 0.01). These results suggest that non-uniform muscle contraction can enhance DADs by dissociating Ca2+ from myofilaments within the BZ and thereby cause triggered arrhythmias.
Considerations for the Use of Imaging Tools for Phase II Treatment Trials in Oncology
Authors: Lalitha K. Shankar, Annick Van den Abbeele, Jeff Yap, Robert Benjamin, Scott Scheutze, T.J. FitzGerald
Journal: Clinical Cancer Research (2009)

Abstract In the context of assessing tumor response, imaging tools have the potential to play a vital role in phase II and III treatment trials. If the imaging test is able to predict potential phase III success in a reliable fashion, it would be a useful tool in phase II trial design as it may provide for a more rapid and timely response assessment. The benefits and challenges of using anatomic imaging measures as well as the promising molecular imaging measures, primarily fluorodeoxyglucose-positron emission tomography, are discussed here. The general issues related to successful implementation of advanced imaging in the context of phase II treatment trials are discussed.
Type-2 problems are difficult to learn, but generalize well (in general)
Authors: M. Gareth Gaskell
Journal: Behavioral and Brain Sciences (1997)

Learning a mapping involves finding regularities in a training set and generalization to novel patterns. Clark &amp; Thornton's type distinction has been discussed in terms of generalization, but has limited value in this respect. However, in terms of detection of regularities in the training set, the distinction is more valid, as it provides a measure of complexity and correlates with the size of search space.
Functionally Overlapping Roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the Elimination of Methotrexate and Its Main Toxic Metabolite 7-Hydroxymethotrexate <i>In vivo</i>
Authors: Maria L.H. Vlaming, Zeliha Pala, Anita van Esch, Els Wagenaar, Dirk R. de Waart, Koen van de Wetering, Cornelia M.M. van der Kruijssen, Ronald P.J. Oude Elferink, Olaf van Tellingen, Alfred H. Schinkel
Journal: Clinical Cancer Research (2009)

Abstract Purpose: ABCC2 (MRP2) and ABCG2 (BCRP) transport various endogenous and exogenous compounds, including many anticancer drugs, into bile, feces, and urine. We investigated the possibly overlapping roles of Abcg2 and Abcc2 in the elimination of the anticancer drug methotrexate (MTX) and its toxic metabolite 7-hydroxymethotrexate (7OH-MTX). Experimental Design: We generated and characterized Abcc2;Abcg2-/- mice, and used these to determine the overlapping roles of Abcc2 and Abcg2 in the elimination of MTX and 7OH-MTX after i.v. administration of 50 mg/kg MTX. Results: Compared with wild-type, the plasma areas under the curve (AUC) for MTX were 1.6-fold and 2.0-fold higher in Abcg2-/- and Abcc2-/- mice, respectively, and 3.3-fold increased in Abcc2;Abcg2-/- mice. The biliary excretion of MTX was 23-fold reduced in Abcc2;Abcg2-/- mice, and the MTX levels in the small intestine were dramatically decreased. Plasma levels of 7OH-MTX were not significantly altered in Abcg2-/- mice, but the areas under the curve were 6.2-fold and even 12.4-fold increased in Abcc2-/- and Abcc2;Abcg2-/- mice, respectively. This indicates that Abcc2 compensates for Abcg2 deficiency but that Abcg2 can only partly compensate for Abcc2 absence. Furthermore, 21-fold decreased biliary 7OH-MTX excretion in Abcc2;Abcg2-/- mice and substantial 7OH-MTX accumulation in the liver and kidney were seen. We additionally found that in the absence of Abcc2, Abcg2 mediated substantial urinary excretion of MTX and 7OH-MTX. Conclusions: Abcc2 and Abcg2 together are major determinants of MTX and 7OH-MTX pharmacokinetics. Variations in ABCC2 and/or ABCG2 activity due to polymorphisms or coadministered inhibitors may therefore substantially affect the therapeutic efficacy and toxicity in patients treated with MTX.
Estimating Hepatic Glucokinase Activity Using a Simple Model of Lactate Kinetics
Authors: Darko Stefanovski, Jang H. Youn, Matthew Rees, Richard M. Watanabe, Marilyn Ader, Viorica Ionut, Anne U. Jackson, Michael Boehnke, Francis S. Collins, Richard N. Bergman
Journal: Diabetes Care (2012)

Glucokinase (GCK) acts as a component of the "glucose sensor" in pancreatic β-cells and possibly in other tissues, including the brain. However, >99% of GCK in the body is located in the liver, where it serves as a "gatekeeper", determining the rate of hepatic glucose phosphorylation. Mutations in GCK are a cause of maturity-onset diabetes of the young (MODY), and GCKR, the regulator of GCK in the liver, is a diabetes susceptibility locus. In addition, several GCK activators are being studied as potential regulators of blood glucose. The ability to estimate liver GCK activity in vivo for genetic and pharmacologic studies may provide important physiologic insights into the regulation of hepatic glucose metabolism.Here we introduce a simple, linear, two-compartment kinetic model that exploits lactate and glucose kinetics observed during the frequently sampled intravenous glucose tolerance test (FSIGT) to estimate liver GCK activity (K(GK)), glycolysis (K(12)), and whole body fractional lactate clearance (K(01)). RESULTS To test our working model of lactate, we used cross-sectional FSIGT data on 142 nondiabetic individuals chosen at random from the Finland-United States Investigation of NIDDM Genetics study cohort. Parameters K(GK), K(12), and K(01) were precisely estimated. Median model parameter estimates were consistent with previously published values.This novel model of lactate kinetics extends the utility of the FSIGT protocol beyond whole-body glucose homeostasis by providing estimates for indices pertaining to hepatic glucose metabolism, including hepatic GCK activity and glycolysis rate.
Apoptotic Action of 17 -Estradiol in Raloxifene-Resistant MCF-7 Cells In Vitro and In Vivo
Authors: H. Liu
Journal: JNCI Journal of the National Cancer Institute (2003)

Background: Resistance to tamoxifen, a selective estrogen receptor modulator (SERM), involves changes that prevent apoptosis and enhance cell proliferation and survival. Paradoxically, estrogen treatment inhibits the growth of long-term tamoxifen-treated breast tumors. Because of the increasing use of raloxifene, another SERM, to prevent osteoporosis and potentially reduce breast cancer risk, some women will develop raloxifene-resistant breast cancer. We developed a raloxifene-resistant MCF-7 cell model (MCF-7/Ral) and investigated the nature of raloxifene-resistant breast cancer and its response to estradiol. Methods: Raloxifene resistance and hormone responsiveness were assessed by proliferation assays and cell cycle analysis in parental MCF-7 and MCF-7/Ral cells. Nuclear factor κB (NF-κB) activity was investigated with a transient transfection assay. Apoptosis was investigated by annexin V staining, mRNA was measured by real-time polymerase chain reaction, and protein was measured by western blotting. Tumorigenesis was studied by injecting MCF-7 or MCF-7/Ral cells into ovariectomized athymic mice (10 per group) and monitoring tumor size weekly. All statistical tests were two-sided. Results: Basal NF-κB activity was higher in MCF-7/Ral cells (1.6 U, 95% confidence interval [CI] = 1.2 to 2.0 U) than in MCF-7 cells (0.8 U, 95% CI = 0.4 to 1.1 U; P = .004). When cultured with 1 μM raloxifene, MCF-7/Ral cells grew statistically significantly (P<.001) faster than MCF-7 cells. Estradiol treatment of MCF-7/Ral cells arrested cells in G2/M phase of the cell cycle, decreased NF-κB activity (0.2 U, 95% CI = 0.2 to 0.3 U; P<.001), increased expression of Fas protein and mRNA (4.5-fold, 95% CI = 2.8- to 6.3-fold versus 0.5-fold, 95% CI = 0.3- to 0.8-fold for control treatment; P<.001), and induced apoptosis. Treatment with either raloxifene or tamoxifen stimulated MCF-7/Ral tumor growth, suggesting that such tumors were resistant to both drugs. When a 9-week raloxifene or tamoxifen treatment was followed by a 5-week estradiol treatment, estradiol statistically significantly reduced the size of tumors stimulated by raloxifene or tamoxifen (at week 14, P = .004 for raloxifene and P<.001 for tamoxifen). Conclusions: Growth of raloxifene-resistant MCF-7/Ral cells in vitro and in vivo is repressed by estradiol treatment by a mechanism involving G2/M-phase arrest, decreased NF-κB activity, and increased Fas expression to induce apoptosis.
Properties of an Fc gamma-binding protein isolated from human leukemic B cells.
Authors: J Thoenes, H Stein
Journal: The Journal of Experimental Medicine (1979)

A selectively Fc gamma-binding protein was isolated from purified and radioiodinated cell membranes from two cases of B-type chronic lymphocytic leukemia and one case of B-type prolymphocytic leukemia by binding to IgG aggregates, horseradish peroxidase-anti-peroxidase IgG complexes, and sheep erythrocyte membrane sheets densely coated with IgG. This protein could not be isolated from the cell membranes of an Fc gamma-receptor-negative chronic lymphocytic leukemia of the T type or from membranes of human erythrocytes. The Fc gamma-binding protein was efficiently solubilized by a mixture of Na-EDTA and 2-mercaptoethanol, but not with one of these agents alone, indicating that both divalent cations and disulfide bridges are involved in the linkage of the Fc gamma-binding protein to the cell membrane. In sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the Fc gamma-binding protein revealed an apparent mol wt of 28,000 and in isoelectric focusing it showed an isoelectric point of 5.5. The electrophoretic mobility of the 28,000-dalton protein did not change after reduction and alkylation. It was determined that the NH2-terminal amino acid of the protein was glycine. The isolated protein was unable to agglutinate antibody-coated erythrocytes. These findings suggest that the 28,000-dalton IgG-affined protein was composed to O2-enriched buffer lacking reducing agents, the 28,000-dalton protein aggregated to a 115,000-dalton molecule. The isolated Fc gamma-binding protein proved to be different from C1q or its subunits.
Phase II Trial of Cetuximab in Combination With Fluorouracil, Leucovorin, and Oxaliplatin in the First-Line Treatment of Metastatic Colorectal Cancer
Authors: Josep Tabernero, Eric Van Cutsem, Eduardo Díaz-Rubio, Andrés Cervantes, Yves Humblet, Thierry André, Jean-Luc Van Laethem, Patrick Soulié, Esther Casado, Chris Verslype, Javier Sastre Valera, Giampaolo Tortora, Fortunato Ciardiello, Oliver Kisker, Aimery de Gramont
Journal: Journal of Clinical Oncology (2007)

This phase II study investigated the efficacy and safety of cetuximab combined with standard oxaliplatin-based chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX-4]) in the first-line treatment of epidermal growth factor receptor-expressing metastatic colorectal cancer (mCRC).The activity of cetuximab plus oxaliplatin was investigated in colon cancer cell lines and xenograft models. In the clinical study, patients with mCRC received on day 1 of a 14 day cycle, cetuximab (initial dose 400 mg/m(2) during week 1, then 250 mg/m(2) weekly) followed by FOLFOX-4 (oxaliplatin 85 mg/m(2) on day 1; leucovorin 200 mg/m(2) on days 1 and 2, followed by fluorouracil 400 mg/m(2) bolus then 600 mg/m(2) intravenous infusion during 22 hours on days 1 and 2).The preclinical studies confirmed the supra-additive activity of cetuximab to oxaliplatin. In the clinical study, 43 patients were included, with a median age of 65 years (range, 43 to 78 years). Response rates (RRs) were 79% (unconfirmed) and 72% (confirmed), with 95% disease control. Median progression-free survival (mPFS) and median duration of response were 12.3 and 10.8 months, respectively. Ten patients (23%) underwent resection with curative intent of previously unresectable metastases. After a median follow-up of 30.5 months, median overall survival (mOS) was 30.0 months. Cetuximab did not increase the characteristic toxicity of FOLFOX-4 and was generally well tolerated.Cetuximab in combination with FOLFOX-4 is a highly active first-line treatment for mCRC, showing encouraging RR, mPFS, and mOS values. The treatment resulted in a high resectability rate, which could potentially result in an improved cure rate. This combination is under phase III development.