tbuckley/cabot-search huggingface dataset:
Significant Effect of Capecitabine on the Pharmacokinetics and Pharmacodynamics of Warfarin in Patients With Cancer
Authors: Ross Camidge, Bruno Reigner, Jim Cassidy, Susan Grange, Markus Abt, Erhard Weidekamm, Duncan Jodrell
Journal: Journal of Clinical Oncology (2005)

Purpose Clinical cases of capecitabine and other fluorouracil-based chemotherapies potentiating the effects of coumarin derivatives have been reported. This study assessed the influence of capecitabine on the pharmacokinetics (PK) and pharmacodynamics (PD) of warfarin. Patients and Methods Four patients with advanced/metastatic cancer completed the study, receiving a single oral dose of 20 mg warfarin before the start of standard capecitabine treatment (day 1), and again during the third cycle of capecitabine (day 61). PK parameters of warfarin and capecitabine and PD parameters of warfarin were assessed on days 1 and 61. Results During capecitabine treatment, the area under the plasma concentration time curve from 0 to infinity (AUC 0-∞ ) of S-warfarin increased by 57% (90% CI, 32% to 88%) with a 51% prolongation of the elimination half-life (t 1/2 ; 90% CI, 32% to 74%). Exposure to R-warfarin was not significantly affected. Plasma concentrations of capecitabine and its metabolites were not influenced by warfarin. During capecitabine treatment, the effect of warfarin on the baseline corrected AUC of the International Normalized Ratio (INR) increased by 2.8 times (90% CI, 1.33 to 5.70), with the maximum observed INR value almost doubling. Because of the administration of vitamin K to some patients with elevated INRs, these figures are likely to underestimate the true PD effect. Mean baseline factor VII levels dropped while on capecitabine therapy, potentially contributing to the observed PD interaction, though this effect did not reach statistical significance. Conclusion There is a significant pharmacokinetic interaction between capecitabine and S-warfarin, resulting in exaggerated anticoagulant activity. Patients receiving warfarin anticoagulant therapy concomitantly with capecitabine should have their INR closely monitored and warfarin doses adjusted accordingly.
Cellular origin of pro-coagulant and (anti)-fibrinolytic factors in bleomycin-injured lungs
Authors: M. Wygrecka, P. Markart, C. Ruppert, K. Petri, K. T. Preissner, W. Seeger, A. Guenther
Journal: European Respiratory Journal (2007)

Excessive pro-coagulant and decreased fibrinolytic activities in the alveolar compartment have been repeatedly documented for inflammatory and fibrotic lung diseases. The current authors determined the contribution of different resident lung cells to the altered local production of coagulation- and fibrinolysis-system components in bleomycin-injured mouse lungs via cell-specific and quantitative assessment of mRNA levels of various pro-coagulant and (anti)-fibrinolytic factors. Laser-assisted microdissection technology was used to sample specific cell populations in combination with subsequent mRNA analysis by real-time quantitative reverse transcriptase-PCR. Additionally, western blot analysis, immunohistochemistry and activity assays were performed. Following bleomycin challenge, the strongest induction of tissue factor and plasminogen activator inhibitor (PAI)-1 mRNA expression was observed in alveolar macrophages (approximately 250- and 60-fold induction, respectively). These factors were also upregulated in alveolar type II cells, but to an approximately six-fold lesser extent. In contrast, PAI-2 expression was induced exclusively in alveolar macrophages. A slight increase of urokinase-type plasminogen activator (uPA) expression was also observed in alveolar macrophages (two-fold induction), but uPA activity was reduced due to a disproportionate increase of PAI production. Alveolar macrophages and, to a lesser extent, alveolar type II cells are the main sources of locally produced pro-coagulant and anti-fibrinolytic factors in bleomycin-injured lungs.
"The school of health", a multi-area approach for smoking prevention at school. I. methodological setting
Authors: Roberto Boffi, Chiara Marabelli, Elena Munarini, Micaela Lina, Cinzia De Marco, Roberto Mazza, Ario Ruprecht, Eleonora Bruno, Ivan Pozzati, Giovanni Invernizzi
Journal: European Respiratory Journal (2013)

Introduction.  Environmental and individual factors influence tobacco use and school is a fundamental setting to prevent tobacco use. Research data suggest that multicomponent school based interventions may be effective.   Aim.  To investigate the impact of a multi-area intervention with practical experiences on smoking perception and behavior.   Methods.  277 adolescents aged 13-17 attending 12 classes of Lombardy high schools participated to a 6-months intervention in 2011-12. Students took part to laboratories on tobacco use and healthy food choices. During lifestyle laboratory, students were given information about tobacco use, peer pressure, smoking risks, and refusal skills. During scientific laboratory real time measurement of deposition in the lungs of tobacco-derived fine particles, and measurement of passive smoking were carried out. Questionnaires on smoking and eating behavior were collected. Levels of carbon monoxide were also measured before and after the intervention. Students built up an educational website (www.lascuoladellasalute.it), a Youtube channel and a Facebook page. Outdoor smoking pollution in parks was carried out, and the results were presented in a press conference. The preliminary results of the project were presented by the students to a wide audience of students of other schools. Teachers and school administrators were involved to contribute a smoke-free school.   Conclusions.  Preliminary impact evaluation of the intervention showed encouraging results (see the accompanying abstract).
Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin
Authors: Thuy L. Phung, Keren Ziv, Donnette Dabydeen, Godfred Eyiah-Mensah, Marcela Riveros, Carole Perruzzi, Jingfang Sun, Rita A. Monahan-Earley, Ichiro Shiojima, Janice A. Nagy, Michelle I. Lin, Kenneth Walsh, Ann M. Dvorak, David M. Briscoe, Michal Neeman, William C. Sessa, Harold F. Dvorak, Laura E. Benjamin
Journal: Cancer Cell (2006)
HIV-1 Antigen–specific and –nonspecific B Cell Responses Are Sensitive to Combination Antiretroviral Therapy
Authors: Lynn Morris, James M. Binley, Brian A. Clas, Sebastian Bonhoeffer, Thomas P. Astill, Rhonda Kost, Arlene Hurley, Yunzhen Cao, Martin Markowitz, David D. Ho, John P. Moore
Journal: The Journal of Experimental Medicine (1998)

We studied how combination antiviral therapy affects B cell abnormalities associated with HIV-1 infection, namely elevated circulating immunoglobulin (Ig)G antibody-secreting cell (ASC) frequencies and hypergammaglobulinemia. Within a few weeks of starting antiviral therapy, there is a marked decline in IgG-ASC frequency in both acutely and chronically infected people, whereas the hypergammaglobulinemia often present during chronic infection is more gradually resolved. These reductions are sustained while HIV-1 replication is suppressed. HIV-1 antigen–specific B cell responses are also affected by therapy, manifested by a rapid decline in circulating gp120-specific ASCs. Anti-gp120 titers slowly decrease in chronically infected individuals and usually fail to mature in acutely infected individuals who were promptly treated with antiretroviral therapy. Long-term nonprogressors have high titer antibody responses to HIV-1 antigens, but no detectable gp120-specific IgG-ASC, and normal (or subnormal) levels of total circulating IgG-ASC. Overall, we conclude that HIV-1 infection drives B cell hyperactivity, and that this polyclonal activation is rapidly responsive to decreases in viral replication caused by combination antiviral therapy.
Relationship between changes in intraluminal pressure and transmural potential difference in the human and canine jejunum in vivo.
Authors: N W Read, R H Smallwood, R J Levin, C D Holdsworth, B H Brown
Journal: Gut (1977)

Recordings of transmural potential difference (PD) across the jejunum of conscious man in situ are characterised by spontaneous fluctuations of up to 10 mV. In 25 of 31 subjects (comprising seven normal controls and 24 patients under investigation for malabsorption, six of whom had coeliac disease) we observed a clear association between these fluctuations and changes in intraluminal pressure recorded at the same site. The most frequent PD changes were associated with type III pressure waves. These consisted predominantly of large waver (3-1 +/- 0-1 mV; mean +/- SEM, n = 317) which reached maximal amplitude approximately 45 seconds after the pressure peak and had a duration of 120 +/- 3 s, but also included less frequent spikes (0-5 +/- 0-1 mV; n = 110) concurrent with the pressure wave with a duration of 5 +/- 1 s. Although by recording at two sites in the jejunum 10 cm apart we were able to demonstrate that type III pressure waves appeared to be propagated aborally at a median rate of 60 cm per minute, the apparent rates of propagation of the corresponding PD waves were much more variable. The largest PD changes (7-8 +/- 0-4 mV; n = 19), lasting several minutes, were found in association with runs of type I waves (basic rhythm) superimposed on a type III wave. Both pressure and PD activities were suppressed by intramuscular propantheline bromide. Intraluminal pilocarpine caused a transient rise in PD not always accompanied by a change in pressure. Distention of the jejunum by rapid injection of a bolus of isotonic sodium chloride produced a delayed rise in the PD which could be prevented by prior administration of propantheline bromide. Experiments using Thirty-Vella loops of proximal jejunum in conscious dogs confirmed the effect of jejunal distension on the PD and also demonstrated that spontaneous retching is preceded by an increase in the PD. Consideration of these results in conjunction with data from other workers suggests the hypothesis that the larger spontaneous fluctuations in transmural PD in the jejunum of conscious man are caused by changes in electrogenic secretion associated with intestinal motility and mediated by cholinergic mechanisms. The possible association of increased secretory activity with motility may have functions of lubrication as well as diluting and mixing the chyme for easier digestion and absorption.
Chest physical therapy for children hospitalised with acute pneumonia: a randomised controlled trial
Authors: C Paludo, L Zhang, C S Lincho, D V Lemos, G G Real, J A Bergamin
Journal: Thorax (2008)

The indication for chest physical therapy as an adjunct to the treatment of children hospitalised with acute pneumonia remains controversial and there is a lack of robust scientific evidence for the effectiveness of this modality in these patients.A randomised controlled trial was conducted in two tertiary hospitals in southern Brazil. Children aged 29 days to 12 years hospitalised with pneumonia between February and October 2006 were recruited; 51 were randomly allocated to the intervention group (chest physical therapy plus standard treatment for pneumonia) and 47 to the control group (standard treatment for pneumonia alone). The primary outcome was time to clinical resolution. The secondary outcomes were length of stay in hospital and duration of respiratory symptoms and signs.There were no significant differences in terms of median time to clinical resolution (4.0 vs 4.0 days, p = 0.84) and median length of hospital stay (6.0 vs 6.0 days, p = 0.76) between the intervention and control groups. The intervention group had a longer median duration of coughing (5.0 vs 4.0 days, p = 0.04) and of rhonchi on lung auscultation (2.0 vs 0.5 days, p = 0.03) than the control group.Chest physical therapy as an adjunct to standard treatment does not hasten clinical resolution of children hospitalised with acute pneumonia and may prolong duration of coughing and rhonchi.
Phase II, Open-Label, Randomized, Multicenter Study Comparing the Efficacy and Safety of Olaparib, a Poly (ADP-Ribose) Polymerase Inhibitor, and Pegylated Liposomal Doxorubicin in Patients With <i>BRCA1</i> or <i>BRCA2</i> Mutations and Recurrent Ovarian Cancer
Authors: Stan B. Kaye, Jan Lubinski, Ursula Matulonis, Joo Ern Ang, Charlie Gourley, Beth Y. Karlan, Amit Amnon, Katherine M. Bell-McGuinn, Lee-May Chen, Michael Friedlander, Tamar Safra, Ignace Vergote, Mark Wickens, Elizabeth S. Lowe, James Carmichael, Bella Kaufman
Journal: Journal of Clinical Oncology (2011)

Purpose Olaparib (AZD2281), an orally active poly (ADP-ribose) polymerase inhibitor that induces synthetic lethality in BRCA1- or BRCA2-deficient cells, has shown promising clinical efficacy in nonrandomized phase II trials in patients with ovarian cancer with BRCA1 or BRCA2 deficiency. We assessed the comparative efficacy and safety of olaparib and pegylated liposomal doxorubicin (PLD) in this patient population. Patients and Methods In this multicenter, open-label, randomized, phase II study, patients with ovarian cancer that recurred within 12 months of prior platinum therapy and with confirmed germline BRCA1 or BRCA2 mutations were enrolled. Patients were assigned in a 1:1:1 ratio to olaparib 200 mg twice per day or 400 mg twice per day continuously or PLD 50 mg/m 2 intravenously every 28 days. The primary efficacy end point was Response Evaluation Criteria in Solid Tumors (RECIST) –assessed progression-free survival (PFS). Secondary end points included objective response rate (ORR) and safety. Results Ninety-seven patients were randomly assigned. Median PFS was 6.5 months (95% CI, 5.5 to 10.1 months), 8.8 months (95% CI, 5.4 to 9.2 months), and 7.1 months (95% CI, 3.7 to 10.7 months) for the olaparib 200 mg, olaparib 400 mg, and PLD groups, respectively. There was no statistically significant difference in PFS (hazard ratio, 0.88; 95% CI, 0.51 to 1.56; P = .66) for combined olaparib doses versus PLD. RECIST-assessed ORRs were 25%, 31%, and 18% for olaparib 200 mg, olaparib 400 mg, and PLD, respectively; differences were not statistically significant. Tolerability of both treatments was as expected based on previous trials. Conclusion The efficacy of olaparib was consistent with previous studies. However, the efficacy of PLD was greater than expected. Olaparib 400 mg twice per day is a suitable dose to explore in further studies in this patient population.
Colorectal cancer screening: a global overview of existing programmes
Authors: Eline H Schreuders, Arlinda Ruco, Linda Rabeneck, Robert E Schoen, Joseph J Y Sung, Graeme P Young, Ernst J Kuipers
Journal: Gut (2015)

Colorectal cancer (CRC) ranks third among the most commonly diagnosed cancers worldwide, with wide geographical variation in incidence and mortality across the world. Despite proof that screening can decrease CRC incidence and mortality, CRC screening is only offered to a small proportion of the target population worldwide. Throughout the world there are widespread differences in CRC screening implementation status and strategy. Differences can be attributed to geographical variation in CRC incidence, economic resources, healthcare structure and infrastructure to support screening such as the ability to identify the target population at risk and cancer registry availability. This review highlights issues to consider when implementing a CRC screening programme and gives a worldwide overview of CRC burden and the current status of screening programmes, with focus on international differences.
Single-Dose Perinatal Nevirapine plus Standard Zidovudine to Prevent Mother-to-Child Transmission of HIV-1 in Thailand
Authors: Marc Lallemant, Gonzague Jourdain, Sophie Le Coeur, Jean Yves Mary, Nicole Ngo-Giang-Huong, Suporn Koetsawang, Siripon Kanshana, Kenneth McIntosh, Vallop Thaineua
Journal: New England Journal of Medicine (2004)

Although zidovudine prophylaxis decreases the rate of transmission of the human immunodeficiency virus (HIV) type 1 substantially, a large number of infants still become infected. We hypothesized that the administration, in addition to zidovudine, of a single dose of oral nevirapine to mothers during labor and to neonates would further reduce transmission of HIV.We conducted a randomized, double-blind trial of three treatment regimens in Thai women who were receiving zidovudine therapy during the third trimester of pregnancy. In one group, mothers and infants received a single dose of nevirapine (nevirapine-nevirapine regimen); in another, mothers and infants received nevirapine and placebo, respectively (nevirapine-placebo regimen); and in the last, mothers and infants received placebo (placebo-placebo regimen). The infants also received one week of zidovudine therapy and were formula-fed. The end point of the study was infection with HIV in the infants, established by virologic testing.Between January 15, 2001, and February 28, 2003, a total of 1844 Thai women were enrolled. At the first interim analysis, the independent data monitoring committee stopped enrollment in the placebo-placebo group. Among women who delivered before the interim analysis, the as-randomized Kaplan-Meier estimates of the transmission rates were 1.1 percent (95 percent confidence interval, 0.3 to 2.2) in the nevirapine-nevirapine group and 6.3 percent (95 percent confidence interval, 3.8 to 8.9) in the placebo-placebo group (P<0.001). The final per-protocol transmission rate in the nevirapine-nevirapine group, 1.9 percent (95 percent confidence interval, 0.9 to 3.0), was not significantly inferior to the rate in the nevirapine-placebo group (2.8 percent; 95 percent confidence interval, 1.5 to 4.1). Nevirapine had an effect within subgroups defined by known risk factors such as viral load and CD4 count. No serious adverse effects were associated with nevirapine therapy.A single dose of nevirapine to the mother, with or without a dose of nevirapine to the infant, added to oral zidovudine prophylaxis starting at 28 weeks' gestation, is highly effective in reducing mother-to-child transmission of HIV.
The Metalloprotease-Disintegrin ADAM8 Is Essential for the Development of Experimental Asthma
Authors: Silvia Naus, Marie-Renée Blanchet, Klaus Gossens, Colby Zaph, Jörg W. Bartsch, Kelly M. McNagny, Hermann J. Ziltener
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Expression of the metalloprotease ADAM8 is increased in patients with asthma, but the functional significance of elevated ADAM8 expression in the context of asthma pathogenesis remains elusive.To study development of asthma in ADAM8-deficient mice.Ovalbumin-induced asthma was studied in wild-type, ADAM8-deficient, and ADAM8-chimeric mice. Lung inflammation was assessed by histology, analysis of bronchoalveolar lavage, and airway hyperresponsiveness.ADAM8-deficient mice are highly resistant to the development of ovalbumin-induced airway inflammation and hyperresponsiveness. ADAM8 expression was induced in both hematopoietic cells and the nonhematopoietic microenvironment after induction of asthma, and ADAM8 expression in both cell populations was required for the full manifestation of asthma. Interestingly, loss of ADAM8 on T cells alone was sufficient to significantly decrease the asthma response. The attenuated response was not due to an intrinsic defect in antigen presentation or cytokine production but reflected an impaired migration of T cells, eosinophils, CD11b(+) CD11c(-), and CD11c(+) cells from blood vessels to the lung and alveolar space, suggesting a general hematopoietic cell deficiency in the absence of ADAM8.The results show that ADAM8 plays a proinflammatory role in airway inflammation. The milder disease outcome in the absence of ADAM8 suggests that this protein might be an interesting new target in treatment of this, and potentially other, inflammatory diseases in which recruitment of inflammatory cells is an essential part of pathogenesis.
The Emerging Functions and Mechanisms of Mammalian Fatty Acid–Binding Proteins
Authors: Judith Storch, Betina Corsico
Journal: Annual Review of Nutrition (2008)

Fatty acid-binding proteins (FABPs) are abundant intracellular proteins that bind long-chain fatty acids with high affinity. Nine separate mammalian FABPs have been identified, and their tertiary structures are highly conserved. The FABPs have unique tissue-specific distributions that have long suggested functional differences among them. In the last decade, considerable progress has been made in understanding the specific functions of the FABPs and, in some cases, their mechanisms of action at the molecular level. The FABPs appear to be involved in the extranuclear compartments of the cell by trafficking their ligands within the cytosol via interactions with organelle membranes and specific proteins. Several members of the FABP family have been shown to function directly in the regulation of cognate nuclear transcription factor activity via ligand-dependent translocation to the nucleus. This review will focus on these emerging functions and mechanisms of the FABPs, highlighting the unique functional properties of each as well as the similarities among them.
Effects of biofeedback on obstructive defecation--reconditioning of the defecation reflex?
Authors: M Papachrysostomou, A N Smith
Journal: Gut (1994)

Twenty two patients with obstructive defecation were recruited for relaxation training by domiciliary self regulatory biofeedback. Each patient served as his or her own control for anorectal and proctographic assessments. Biofeedback training improved the obstructive symptoms of the patients and showed significant change in various parameters related to the obstructive defecation syndrome. As examined by isotope dynamic proctography: the defecation rate (% of evacuation/defecation time) was significantly increased (p &lt; 0.05), the anorectal angles at rest and during attempted defecation were made more obtuse (p &lt; 0.05), and the pelvic floor movements were made more dynamic on voluntary contraction of the anal sphincter (p &lt; 0.03). The external anal sphincter electromyographic voltage recorded during defecation was significantly reduced (p &lt; 0.0005) as was the surface anal plug electromyographic electrode voltage (p &lt; 0.0001), which was associated with a greatly reduced anismus index (p &lt; 0.0001). The rectal sensation was improved (p &lt; 0.05), concomitantly. Biofeedback thus improves the defecation act in patients suffering from inappropriate contraction of the pelvic floor and sphincter musculature. Furthermore, this study has shown that biofeedback objectively influences the defecation reflex leading to an improved quality of higher control of bowel function.