tbuckley/cabot-search huggingface dataset:
Ximelagatran vs Warfarin for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation
Authors: Gregory W Albers, Hans-Christoph Diener, Lars Frison, Margaretha Grind, Mark Nevinson, Stephen Partridge, Jonathan L Halperin, Jay Horrow, S Bertil Olsson, Palle Petersen, Alec Vahanian
Journal: JAMA (2005)

In patients with nonvalvular atrial fibrillation, warfarin prevents ischemic stroke, but dose adjustment, coagulation monitoring, and bleeding limit its use.To compare the efficacy of the oral direct thrombin inhibitor ximelagatran with warfarin for prevention of stroke and systemic embolism.Double-blind, randomized, multicenter trial (2000-2001) conducted at 409 North American sites, involving 3922 patients with nonvalvular atrial fibrillation and additional stroke risk factors.Adjusted-dose warfarin (aiming for an international normalized ratio [INR] 2.0 to 3.0) or fixed-dose oral ximelagatran, 36 mg twice daily.The primary end point was all strokes (ischemic or hemorrhagic) and systemic embolic events. The primary analysis was based on demonstrating noninferiority within an absolute margin of 2.0% per year according to the intention-to-treat model.During 6405 patient-years (mean 20 months) of follow-up, 88 patients experienced primary events. The mean (SD) INR with warfarin (2.4 [0.8]) was within target during 68% of the treatment period. The primary event rate with ximelagatran was 1.6% per year and with warfarin was 1.2% per year (absolute difference, 0.45% per year; 95% confidence interval, -0.13% to 1.03% per year; P<.001 for the predefined noninferiority hypothesis). When all-cause mortality was included in addition to stroke and systemic embolic events, the rate difference was 0.10% per year (95% confidence interval, -0.97% to 1.2% per year; P = .86). There was no difference between treatment groups in rates of major bleeding, but total bleeding (major and minor) was lower with ximelagatran (37% vs 47% per year; 95% confidence interval for the difference, -14% to -6.0% per year; P<.001). Serum alanine aminotransferase levels rose to greater than 3 times the upper limit of normal in 6.0% of patients treated with ximelagatran, usually within 6 months and typically declined whether or not treatment continued; however, one case of documented fatal liver disease and one other suggestive case occurred.The results establish the efficacy of fixed-dose oral ximelagatran without coagulation monitoring compared with well-controlled warfarin for prevention of thromboembolism in patients with atrial fibrillation requiring chronic anticoagulant therapy, but the potential for hepatotoxicity requires further investigation.
Abstract 1161: PKA-activated p85alpha Prevents Neointimal Hyperplasia after Balloon Endothelial Denudation without Impairing Endothelial Regeneration.
Authors: Antonio Curcio, Daniele Torella, Cosimo Gasparri, Anna L Cavaliere, Daniela De Serio, Angelo Leone, Valentina Galuppo, Francesca C Surace, Enrico Avvedimento, Ciro Indolfi
Journal: Circulation (2006)
Countries hit by Ebola need $700m to rebuild health systems
Authors: Anne Gulland
Journal: BMJ (2015)

The governments of Guinea, Liberia, and Sierra Leone face a health service funding shortfall of nearly $700m (£450m; €630m), the World Health Organization has said.

In advance of a donors’ conference on 9 and 10 July organised by the UN secretary general, Ban Ki-moon, the three governments have calculated how much funding they will need to rebuild their health systems up until the end of 2017. Guinea has budgeted for $1.18bn and still needs to raise $387m. Liberia has said it needs to raise $169.7m out of a total of $550m. And Sierra Leone still needs to raise $140m out of a total budget of $361m.

At …
CALGB 50401: A randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma.
Authors: John Leonard, Sin-Ho Jung, Jeffrey L. Johnson, Nancy Bartlett, Kristie A. Blum, Bruce D. Cheson
Journal: Journal of Clinical Oncology (2012)

8000 Background: Lenalidomide (L) and rituximab (R) are active as single agents in follicular (FL) and other B-cell lymphomas, although combination strategies have not been previously assessed in a randomized fashion. Methods: CALGB 50401 is a randomized phase II study, initially designed to evaluate 3 regimens: R alone (375 mg/m2 weekly x 4), L alone (15 mg cycle 1, then escalated to 20 mg cycles 2-12, administered days 1-21 q 28 days x 12 cycles) or the combination of L+ R (other 2 arms combined). The R alone arm was discontinued due to slow accrual with 3 enrolled subjects. Eligibility included recurrent FL, prior therapy with rituximab alone or in combination, and TTP of ≥ 6 months from last rituximab dose. Prophylactic ASA or LMW heparin was recommended for patients at high risk for thrombosis. Results: Of 94 pts registered to L or LR, 89 (45 L and 44 LR) received at least one dose and had adequate data for analysis. Baseline characteristics include median age 63 (range 34-85) and 60% with intermediate- or high-risk FLIPI. Grade 3-4 adverse events (AE) were most commonly neutropenia (16% L,19% LR), fatigue (9% L, 14% LR) and thrombosis (16% - 7 pts L, 4% - 2 pts LR, p=0.158), and overall were seen in 49% (L) and 52% (LR) with 9% grade 4 in each arm. The full regimen was completed in 33% (L) and 59% (LR) of patients, with the difference due to more progressions or non-responders in the L group. In both arms about 19% of subjects discontinued therapy early due to AEs and dose intensity was over 80%. Objective response rates are L - 49% (13% CR) and LR - 75% (32% CR). With a median follow-up of 1.5 years (range 0.1- 3.6 years), median EFS is 1.2 years (L) and 2.0 years (LR), p=0.0063, log-rank test. Conclusions: Lenalidomide + rituximab is more active than lenalidomide alone in patients with recurrent FL with similar toxicity. A trend toward lower thrombosis risk with LR may relate to greater anti-tumor efficacy. The LR regimen warrants further study in FL including as a backbone for addition of novel agents in relapsed and frontline settings.
Abstract 16321: Increases in Red Cell Distribution Width as a Biomarker for Deep Vein Thrombosis
Authors: Peter Whittaker, Holly H Chiu, Karin Przyklenk
Journal: Circulation (2011)

Emerging evidence suggests a role for red cell distribution width (RDW) as a marker for poor outcome in many diseases; the higher RDW, the worse the prognosis. Although the mechanisms responsible f...
Type III allergy skin testing
Authors: E. Terho, A. J. Frew
Journal: Allergy (1995)

Immune-complex-mediated hypersensitivity has been implicated in a small number of allergic respiratory conditions. These include EAA and ABPA. In addition, there is some evidence of type IV hypersensitivity in EAA and BFL, together with activation of complement via the alternative pathway (4, 8, 26). Positive immediate skin tests are now usually regarded as an essential criterion for the diagnosis of ABPA. These reflect the presence of antigen-specific IgE, but this test is not specific for ABPA, as other atopic subjects may also be sensitized to A. fumigatus without any evidence of the parenchymal features that are required to diagnose ABPA. For FL, skin tests with currently available antigens show poor discrimination between affected patients and exposed but healthy individuals. There is little evidence that vascular deposition of immune complexes in the skin contributes to the delayed skin responses in EAA, and skin tests in FL are not specific for type III hypersensitivity. Further refinement of methodology and antigen extracts may improve the specificity of skin tests in FL, but in many cases the aetiology of EAA is multifactorial and the true causative antigens may not have been identified. Therefore, the diagnosis of EAA remains based on history and clinical findings, supported by the presence of precipitins, and sometimes by bronchial biopsy and lavage appearances (25).
Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia.
Authors: S Amadori, W Arcese, G Isacchi, G Meloni, M C Petti, B Monarca, A M Testi, F Mandelli
Journal: Journal of Clinical Oncology (1991)

Thirty-two patients with refractory acute myeloid leukemia (AML) received salvage therapy with a single course of mitoxantrone 6 mg/m2 intravenous (IV) bolus, etoposide 80 mg/m2 IV for a period of 1 hour, and cytarabine (Ara-C) 1 g/m2 IV for a period of 6 hours daily for 6 days (MEC). Eighteen patients were primarily resistant to conventional daunorubicin and Ara-C induction treatment; eight patients had relapsed within 6 months from initial remission; six patients had relapsed after a bone marrow transplantation (BMT) procedure. Overall, 21 patients (66%) achieved a complete remission (CR), two (6%) died of infection during induction, and nine (28%) had resistant disease. Age greater than 50 years was the only factor predictive for a significantly lower response rate (P = .03). The median remission duration was 16 weeks; the overall median survival was 36 weeks. Severe myelosuppression was observed in all patients resulting in fever or documented infections in 91% of patients. Nonhematologic toxicity was minimal. We conclude that the MEC regimen has significant antileukemic activity and acceptable toxicity in salvage AML. Its benefit in front-line AML therapy is being investigated.
Equivalence of Three or Four Cycles of Bleomycin, Etoposide, and Cisplatin Chemotherapy and of a 3- or 5-Day Schedule in Good-Prognosis Germ Cell Cancer: A Randomized Study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council
Authors: Ronald de Wit, J. Trevor Roberts, Peter M. Wilkinson, Pieter H.M. de Mulder, Graham M. Mead, Sophie D. Fosså, Pat Cook, Linda de Prijck, Sally Stenning, Laurence Collette
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To test the equivalence of three versus four cycles of bleomycin, etoposide, and cisplatin (BEP) and of the 5-day schedule versus 3 days per cycle in good-prognosis germ cell cancer. PATIENTS AND METHODS: The study was designed as a 2 × 2 factorial trial. The aim was to rule out a 5% decrease in the 2-year progression-free survival (PFS) rate. The study included the assessment of patient quality of life. A cycle of BEP consisted of etoposide 500 mg/m 2 , administered at either 100 mg/m 2 days 1 through 5 or 165 mg/m 2 days 1 through 3, cisplatin 100 mg/m 2 , administered at either 20 mg/m 2 days 1 through 5 or 50 mg/m 2 days 1 and 2. Bleomycin 30 mg was administered on days 1, 8, and 15 during cycles 1 through 3. The randomization procedure allowed some investigators to participate only in the comparison of three versus four cycles. RESULTS: From March 1995 until April 1998, 812 patients were randomly assigned to receive three or four cycles: of these, 681 were also randomly assigned to the 5-day or the 3-day schedule. Histology, marker values, and disease extent are well balanced in the treatment arms of the two comparisons. The projected 2-year PFS is 90.4% on three cycles and 89.4% on four cycles. The difference in PFS between three and four cycles is −1.0% (80% confidence limit [CL], −3.8%, +1.8%). Equivalence for three versus four cycles is claimed because both the upper and lower bounds of the 80% CL are less than 5%. In the 5- versus 3-day comparison, the projected 2-year PFS is 88.8% and 89.7%, respectively (difference, −0.9%, (80% CL, −4.1%, +2.2%). Hence, equivalence is claimed in this comparison also. Frequencies of hematologic and nonhematologic toxicities were essentially similar. Quality of life was maintained better in patients receiving three cycles; no differences were detected between 3 and 5 days of treatment. CONCLUSION: We conclude that three cycles of BEP, with etoposide at 500 mg/m 2 , is sufficient therapy in good-prognosis germ cell cancer and that the administration of the chemotherapy in 3 days has no detrimental effect on the effectiveness of the BEP regimen.
Membrane Changes Associated with Platelet Activation
Authors: James N. George, Roger M. Lyons, Rebecca K. Morgan
Journal: Journal of Clinical Investigation (1980)

The effect of aggregation and secretion on membrane proteins was studied in washed human platelets. Reversible aggregation without secretion was stimulated by ADP and secretion without aggregation was stimulated by thrombin in the presence of EDTA. No loss of platelet surface glycoproteins occurred during reversible ADP-induced platelet aggregation, as measured by quantitative polyacrylamide gel electrophoresis analysis of platelets that were labeled with 125I-diazotized diiodosulfanilic acid (DD125ISA) before ADP stimulation. Also, no new proteins became exposed on the platelet surface after ADP aggregation, as determined by DD125ISA labeling after stimulation. Thrombin-induced platelet secretion also caused no loss of platelet surface glycoproteins. However, after platelet secretion two new proteins were labeled by DD125ISA: (a) actin and (b) the 149,000-mol wt glycoprotein (termed GP-G), which is contained in platelet granules and secreted in response to thrombin. The identity of DD125ISA-labeled actin was confirmed by four criteria: (a) comigration with actin in three different sodium dodecyl sulfate-polyacrylamide gel electrophoresis systems, (b) elution from a particulate fraction in low ionic strength buffer, (c) co-migration with actin in isoelectric focusing, and (d) binding to DNase I. The identity of actin and its appearance on the platelet surface after thrombin-induced secretion was also demonstrated by the greater binding of an anti-actin antibody to thrombin-treated platelets, measured with 125I-staphylococcal protein A.
Proteolytic activity present in house-dust-mite extracts degrades ENA-78/CXCL5 and reduces neutrophil migration
Authors: L. Keglowich, M. Tamm, N. Miglino, P. Borger
Journal: European Respiratory Journal (2014)

Bronchial smooth muscle (BSM) cells are a major source of pro-inflammatory and pro-angiogenic cytokines and chemokines, including VEGF and CXC-chemokines. CXC-chemokines act primarily on neutrophils, mediating their recruitment to and activation at the side of inflammation. In humans, house-dust mite (HDM) allergens can cause asthmatic exacerbations and trigger an inflammatory response through protease-dependent mechanisms.  We investigated the effect HDM extract on the release of pro-angiogenic and proinflammatory cytokines from BSM cells. Human primary BSMC were stimulated with HDM extract in the absence or presence of fetal calf serum (FCS). Twenty angiogenic cytokines were detected by a specific antibody array and modified protein levels were confirmed by ELISA. Neutrophil migration was detected using a 96-well Boyden chamber.  The concentration of ENA-78/CXCL5 in conditioned medium collected from BSMC stimulated with HDM extract was significantly reduced, whereas ENA-78/CXCL5 mRNA levels were not altered. In the presence of 5% FCS the inhibitory effect of HDM on ENA-78/CXCL5 expression was abrogated. Furthermore, recombinant ENA-78/CXCL5 was degraded by incubation with HDM extract, which was prevented by addition of FCS as well as by addition of a serine protease inhibitor. Neutrophil migration towards recombinant ENA-78/CXCL5 was reduced in HDM extract stimulated conditions.  We conclude that HDM proteases degrade ENA-78/CXCL5. These data imply that exposure to HDM allergens may alter ENA-78/CXCL5 levels in the lungs and may affect angiogenesis and the inflammatory response in the airways of asthma patients.
Transplantation of Human Umbilical Cord Blood Cells in Macrophage-Depleted SCID Mice: Evidence for Accessory Cell Involvement in Expansion of Immature CD34+CD38−Cells
Authors: Monique M.A. Verstegen, Paula B. van Hennik, Wim Terpstra, Cor van den Bos, Jenne J. Wielenga, Nico van Rooijen, Rob E. Ploemacher, Gerard Wagemaker, Albertus W. Wognum
Journal: Blood (1998)
Prothrombin Complex Concentrate in Combination with Fibrinogen Plus Tranexamic Acid Is More Effective Than Mono-Therapy with Prothrombin Complex Concentrate in a Dabigatran Anticoagulation Experimental Polytrauma Model
Authors: Oliver Grottke, Markus Honickel, Henri M.H. Spronk, Hugo ten Cate, Joanne van Ryn, Rolf Rossaint
Journal: Blood (2014)
STUDIES ON INHIBITION OF L-DOPA DECARBOXYLASE IN VITRO AND IN VIVO
Authors: W.G. Clark
Journal: Pharmacological Reviews (1959)

Studies relating to the inhibition in vitro are reviewed, with some emphasis on inactivation of coenzyme by the substrate and its analogues, and on carbonyl trapping agents, but more specifically on analogues of certain hydroxycinnamic acids which inhibit dopa-, dops- and 5-HTP-decarboxylases. The structural features of such inhibitors are analyzed, as well as their specificity and competitive nature.

The nature and characteristics of dopa decarboxylation in vivo are discussed, particularly as affected by the absence of visceral organs, and by the thyroid hormone, adrenal cortex, sex and vitamin B6.

A review and analysis is made of the work pointing to changes in apoenzyme and coenzyme caused by hyperthyroidism and vitamin B6 deficiency.

Chemical and pharmacological evidence is presented which shows that the substances which inhibit dopa decarboxylase in vitro also are generally effective in vivo. Twenty-five in vitro inhibitors and 50 structurally related noninhibitors have been assessed in several hundred animals. This has led to an understanding of the structural requirements for effective inhibition in vivo , which are essentially the same as for inhibition in vitro .

A possible alternate biosynthetic route to noradrenaline and adrenaline may be by transamination of hydroxyphenylpyruvic acids and subsequent decarboxylation of the resulting amino acids, which is blocked by the inhibitors at the decarboxylation step.

The duration of inhibition and the detoxication of the inhibitors have been studied, and various structural modifications and pharmacological procedures have been investigated for prolonging the duration of the inhibition.

One inhibitor was shown to inhibit the biosynthesis of adrenal medullary adrenaline in insulin-treated rats.
The burden of mesothelioma mortality: Estimation as the first step to prevention
Authors: Aiza Jamil, Bandipalyam Prathibha
Journal: European Respiratory Journal (2011)

Background:  Mesothelioma is a rare cancer that principally affects the pleura and is almost always caused by asbestos exposure. Mesothelioma incidence has increased in South East England of which East Kent is a major part, particularly for men aged over 70 years, reflecting areas of asbestos use in shipbuilding and industry in the past.   Methods:  The aim of the study is to estimate the current burden of cancer in the area of East Kent in the UK attributable to occupational factors, and identify carcinogenic agents, industries and occupations for targeting risk prevention.  Data of all cases diagnosed at East Kent Hospitals NHS Trust were collected retrospectively from April 2009 to March 2010.   Results:  There were a total of 15 cases in East Kent Hospital NHS trust, UK over the period of one year which is a significantly high number as compared to previous years, the current population being 614,576. All of them were male. Median age was 74 years and median survival from diagnosis was 8.9 months. 85% had documented evidence of definite or probable exposure to asbestos. There were 7 cases that were treated with chemotherapy, 6 patients had radiotherapy and 2 patients with advanced malignancy had palliative treatment. No patient had radical surgery and there was minimal difference in relative survival between men with localised and non-localised disease.   Conclusion:  In Great Britain, where asbestos use continued later than many other countries, the peak is anticipated to occur later between 2011 and 2115. Cancer networks, especially those with primary care trusts with high incidence, need to be aware of this disease and ensure that risk reduction strategies and services are in place to assist these patients.
Impact of older age on the efficacy of newer adjuvant therapies in &gt;12,500 patients (pts) with stage II/III colon cancer: Findings from the ACCENT Database
Authors: N. A. Jackson McCleary, J. Meyerhardt, E. Green, G. Yothers, A. de Gramont, E. Van Cutsem, M. O’Connell, C. Twelves, L. Saltz, D. Sargent
Journal: Journal of Clinical Oncology (2009)

4010 Background: Prior studies suggested that older and younger pts with colon cancer receive similar benefit from IV fluoropyrimidine (FU) adjuvant (adj) therapy (rx). Combination and/or oral FU rx are increasingly given as adj rx. We sought to determine the impact of pts age &lt;70 v ≥70 yrs on colon cancer recurrence and mortality from adj rx with these newer options. Methods: We used data from 10,499 pts &lt;70 yrs and 2,170 pts ≥70 yrs in 6 phase III adj rx trials comparing IV FU to combinations with irinotecan, oxaliplatin or oral FU (capecitabine and UFT/LV) in stage II/III colon cancer from the ACCENT database. Endpoints were overall survival (OS; time to death), disease-free survival (DFS; time to recurrence or death), and time to recurrence (TTR; censoring at last follow-up). Cox models were stratified by age and adjusted for gender and stage; interaction testing was used to explore the differential benefit by age. Results: Approximately 75% of pts had stage III disease (74% age&lt;70, 77% age≥70). OS, DFS, and TTR were statistically significantly improved for those in the experimental v control arms among pts &lt;70 but not those &gt;70 ( table ); the interaction between age and rx was statistically significant for all endpoints (p=0.01 for OS, DFS, and TTR). These results were consistent whether experimental rx was oxaliplatin-based, irinotecan-based or oral FU. Deaths in first 6 month of adj rx were not statistically significantly different between experimental and control arm. Conclusions: Our results show conclusively that pts &gt;70 do not receive the same benefit from combination and/or oral FU as those &lt;70. Any benefit, if present, compared to IV FU/LV would not be clinically meaningful. Outcomes of experimental (combination or oral FU) vs control (IV 5-FU) by treatment and age [Table: see text] [Table: see text]
Interaction between aclidinium bromide and formoterol fumarate; effects on human bronchial smooth muscle
Authors: Mario Cazzola, Luigi Calzetta, Clive P. Page, Francesco Facciolo, Amadeu Gavaldà, Maria Gabriella Matera
Journal: European Respiratory Journal (2014)

Background 

Combining a long-acting β2-agonist (LABA) with a long-acting muscarinic antagonist (LAMA) could simplify COPD therapy.

Aim 

To investigate the interaction of aclidinium (LAMA) and formoterol (LABA) on isolated human bronchi.

Methods 

Bronchial rings from 18 patients were incubated in Krebs-Henseleit solution (37°C) aerated with O2/CO2 (95/5%) under 0.5–1.0 g tension. The response to aclidinium and formoterol, alone or in combination, at isoeffective concentrations, was assessed at sub-maximal tone (70% maximal contraction, EC70) induced by acetylcholine. The duration of action (20% maximal relaxation, EC20) was studied in tissue contracted with 10 Hz electrical field stimulation (EFS).

Bronchial tone was expressed as % of maximal response to papaverine (Emax) and potency as the negative logarithm of IC50 or EC50 (pD2). Drug mixture effects were analyzed by Bliss Independence theory. Values (n=3) are mean±SEM.

Results 

The drugs induced potent, concentration-dependent relaxation of bronchi (pD2: aclidinium 8.5±0.1, formoterol 8.8±0.1; Emax: aclidinium 97.5±2.6%, formoterol 96.4±1.1%). Drug interaction was synergistic at low concentrations (aclidinium: 1.1–2.1 nM, formoterol 0.8–1.2 nM), enhancing relaxation +18.4±2.7%, compared with the expected effect.

At low concentrations the combination enhanced the relaxant response to EFS during the first hour (p<0.001); maximal synergistic interaction was at ≅2 hours (82.36±2.54%), during washout. Relaxation (68.4±2.2%) was higher than expected (38.5±1.9%) from 0–6 hours (p<0.001).

Conclusions: Aclidinium and formoterol at low concentrations synergistically inhibited smooth muscle tone.