tbuckley/cabot-search huggingface dataset:
Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in patients with idiopathic alveolar proteinosis
Authors: J F Seymour
Journal: Thorax (2003)

Conventional measures of the severity of alveolar proteinosis (AP) include alveolar-arterial oxygen gradient ([A - a]DO(2)), vital capacity (VC), and carbon monoxide transfer factor (TLCO), but alternative serological measures have been sought. Granulocyte-macrophage colony stimulating factor (GM-CSF) neutralising autoantibody is found in patients with idiopathic acquired AP. We have investigated the interrelationships between the levels of this antibody and those of surfactant protein (SP)-A and -B, lactate dehydrogenase (LDH), and conventional measures of disease severity, and the capacity of these parameters to predict the response to rhGM-CSF treatment.Blood levels of anti-GM-CSF antibodies, SP-A, SP-B, LDH, and [A - a]DO(2), VC, and TLCO were measured before rhGM-CSF treatment and every 2 weeks thereafter in 14 patients with AP.At baseline, high levels of anti-GM-CSF antibodies and increased SP-A and SP-B levels were seen in all patients, and LDH was raised in 83%. SP-A was highly correlated with [A - a]DO(2), VC, and TLCO (p</=0.02), but other markers were not. Only a normal LDH level was predictive of a response to rhGM-CSF treatment (p=0.03). During treatment a correlation between conventional and serological variables within patients was seen only between SP-A and [A - a]DO(2) (p=0.054), LDH levels and [A - a]DO(2) (p=0.010), and LDH levels and VC (p=0.019).Of the serological parameters studied, only SP-A and LDH levels were correlated with conventional measures of disease severity, with LDH most accurately reflecting [A - a]DO(2) and vital capacity. Only a normal LDH level predicted a higher likelihood of response to treatment with GM-CSF.
Preferential accumulation of CD103+ T cells in human livers; its association with extrathymic T cells
Authors: Yukihiro Shimizu, Masami Minemura, Hiroyuki Murata, Katsuharu Hirano, Yasuhiro Nakayama, Kiyohiro Higuchi, Akiharu Watanabe, Toshifumi Yasuyama, Kazuhiro Tsukada
Journal: Journal of Hepatology (2003)
Partnering to Reduce Risks and Improve Cardiovascular Outcomes
Authors: Daniel W. Jones, Eric D. Peterson, Robert O. Bonow, Raymond J. Gibbons, Barry A. Franklin, Ralph L. Sacco, David P. Faxon, Vincent J. Bufalino, Rita F. Redberg, Neil M. Metzler, Penelope Solis, Meighan Girgus, Kathy Rogers, Patrick Wayte, Timothy J. Gardner
Journal: Circulation (2009)

mission of the American Heart Association (AHA) is summarized by the statement, "Building healthier lives free of cardiovascular disease and stroke."Reaching this goal will take significant advances in both science and clinical care but also will require a new level of engagement and action on the part of the public and patients in their health and health care.Recently, the AHA published "Translating Research Into Practice for Healthcare Providers: The American Heart Association's Strategy for Building Healthier Lives Free of Cardiovascular Disease and Stroke," 1 which summarizes the AHA's efforts to actively foster cardiovascular research and evidence-based clinical care among healthcare providers.Although assisting the work of scientists and clinicians is critical to achieving the AHA's mission, it remains only part of the equation.Consumers and patients must be educated and engaged both to prevent cardiovascular events and to improve their outcomes after events occur.Recognizing this, the AHA has embarked on a robust set of initiatives designed to help individuals understand and modify their cardiovascular risk factors, to seek care when appropriate, to partner with their physicians and healthcare professionals to better treat their disease, and to help make changes in industry and workplaces.This report, the second of a 2-part series, summarizes the AHA's consumer-and patient-related activities to motivate healthy behaviors, improve risk factor control, and manage cardiovascular disease (CVD) and stroke.
First-in-Human Phase I Trial of Two Schedules of OSI-930, a Novel Multikinase Inhibitor, Incorporating Translational Proof-of-Mechanism Studies
Authors: Timothy A. Yap, Hendrik-Tobias Arkenau, D. Ross Camidge, Suzanne George, Natalie J. Serkova, Stephen J. Gwyther, Jennifer L. Spratlin, Rohit Lal, James Spicer, Nandita M. Desouza, Martin O. Leach, Jon Chick, Srinivasu Poondru, Ramesh Boinpally, Richard Gedrich, Katie Brock, Andrew Stephens, S. Gail Eckhardt, Stan B. Kaye, George Demetri, Michelle Scurr
Journal: Clinical Cancer Research (2013)

Abstract Purpose: OSI-930 is a novel, potent, oral small-molecule receptor tyrosine kinase inhibitor, predominantly against VEGF receptors (VEGFR), c-Kit, and platelet-derived growth factor receptors. A phase I trial was undertaken to determine safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of OSI-930 in patients with advanced solid tumors. Experimental Design: OSI-930 was administered once or twice a day using a modified accelerated titration design. Pharmacokinetics and plasma soluble VEGFR2 (sVEGFR2) studies were undertaken. Dynamic contrast-enhanced MRI (DCE-MRI) and 2[18F]fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) MTD expansion cohorts were conducted. Results: Fifty-eight patients received OSI-930 in 2 schedules; once a day schedule: 12 patients at doses up to 1,600 mg without reaching MTD; twice a day schedule: 46 patients at 400 mg (n = 7), 500 mg (n = 31), and 600 mg (n = 8). Dose-limiting toxicities were observed at 600 mg twice a day (n = 3): G3 rash (n = 2) and G4 γ-glutamyltransferase, establishing the MTD at 500 mg twice a day. Common G1–2 toxicities included fatigue, diarrhea, nausea, and rash. Antitumor responses were seen in 2 patients with advanced ovarian cancer [Response Evaluation Criteria in Solid Tumors (RECIST) partial response (PR) (n = 1); GCIG CA125 response (n = 1)]. Eleven of 19 heavily pretreated imatinib-resistant patients with gastrointestinal stromal tumors achieved RECIST stable disease (median duration: 126 days), with FDG-PET scans showing PRs in 4 of 9 patients. OSI-930 exposure increased with dose; substantial decreases in sVEGFR levels were observed with OSI-930 twice a day doses ≥400 mg, while DCE-MRI responses were shown in 4 of 6 patients. Conclusions: OSI-930 is safe and well tolerated, with pharmacokinetic–pharmacodynamic data supporting proof-of-mechanism with clinically relevant antitumor activity. Clin Cancer Res; 19(4); 909–19. ©2012 AACR.
Bronchial Thermoplasty for Severe Asthma
Authors: Momen M. Wahidi, Monica Kraft
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Section:ChooseTop of pageAbstract <<Bronchial Thermoplasty as...Mechanism of ActionEfficacy and SafetyProcedural AspectsCurrent Status of Bronchi...Advantages and Disadvanta...Future DirectionsConclusionsReferencesCITING ARTICLES
Regard Phase 3, Randomized Trial of Ramucirumab in Patients with Metastatic Gastric or Gej Adenocarcinoma Following Progression on First-Line Chemotherapy
Authors: Josep Tabernero, Jiri Tomasek, Dumitru Filip, Rodolfo Passalacqua, Chanchal Goswami, Howard Safran, Lucas Dos Santos, Giuseppe Aprile, David Ferry, Jae Yong Cho, Bohuslav Melichar, Mustapha Tehfe, Eldar Topuzov, John Zalcberg, Ian Chau, Jonathan Schwartz, Minori Koshiji, Yanzhi Hsu, Charles Fuchs
Journal: Annals of Oncology (2013)
Adolescent treatment compliance in asthma
Authors: R Dinwiddie, W G Muller
Journal: Journal of the Royal Society of Medicine (2002)

The term compliance is defined in the dictionary as ‘to consent’ or ‘to do as asked’. With adolescent behaviour these two definitions are not the same thing: many adolescents will consent to treatment in the clinic but do not do as asked when they return to normal day-to-day life. The term adherence in relation to treatment is also widely used and is defined as ‘wilful intention’. Non-adherence would therefore be the wilful intention not to do something. Ordinarily, the word compliance refers to taking the correct dose of prescribed medication at the correct intervals. In real life doses are often omitted and the intervals between doses are commonly longer than they should be; a rarer form of non-compliance is over-consumption of medication. Yet compliance affects many other aspects of the management of chronic conditions, such as avoidance of aggravating factors, monitoring, appointment-keeping, prevention or applying an emergency plan of action when needed.

The term concordance has also been introduced to reflect an alliance of equals, professional and patient, rather than one-sided obedience1. The direct involvement of patients in decision-making is now central to policy in the National Health Service. However, the concordance concept is not discussed further in the current review because of the scarcity of evidence-based data on its application to asthma treatment. Here we review the complex issues of compliance with asthma treatment in adolescence and how they can be assessed, understood and addressed.
Plant homeodomain finger protein 11 promotes class switch recombination to IgE in murine activated B cells
Authors: J. Ikari, A. Inamine, T. Yamamoto, H. Watanabe-Takano, N. Yoshida, L. Fujimura, T. Taniguchi, A. Sakamoto, M. Hatano, K. Tatsumi, T. Tokuhisa, M. Arima
Journal: Allergy (2013)

Background Polymorphisms of the Plant homeodomain finger protein 11 (PHF11) are strongly associated with high serum IgE levels and clinical severity of atopic patients. However, the precise mechanism has not been fully elucidated. We investigated the role of Phf11 in class switch recombination (CSR) to IgE by activated B cells. Methods We generated Phf11 transgenic (Lckd-Phf11-Tg) mice that express the exogenous murine Phf11 in lymphocytes under the control of distal Lck promoter. We examined IL-4-induced CSR to IgE in activated Lckd-Phf11-Tg B cells in vitro. We analyzed production of ovalbumin (OVA)-specific IgE and nose-scratching symptoms in Lckd-Phf11-Tg mice using an OVA-induced allergic rhinitis model. Results The exogenous Phf11 promoted CSR to IgG1 and IgE in activated B cells with an increase in germ line transcript (GLT) γ1 and GLT ε expression. The exogenous Phf11 augmented transcriptional activity of the GLT γ1 and GLT ε promoters through permissive histone modifications and binding of NF-κB and STAT6. Furthermore, the exogenous Phf11 bound to the GLT ε promoter with increased binding of NF-κB. Silencing of the endogenous Phf11 reduced the frequency of CSR to IgE and GLT ε expression, but not to IgG1 or GLT γ1 expression, in activated B cells. In an allergic rhinitis model, Lckd-Phf11-Tg mice showed a significant increase in the production of OVA-specific IgE and the frequency of nose scratching. Conclusion Phf11 accelerates CSR to IgE in activated B cells by increasing the transcriptional activity of GLT ε promoter and contributes to the exacerbation of allergic responses. These findings provide a novel therapeutic target for allergic diseases.
Phosphoinositide Metabolism and Hormone Action
Authors: K J Catt, T Balla
Journal: Annual Review of Medicine (1989)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Functional remodelling of arterial endothelium during early postnatal development in rats
Authors: Dina Gaynullina, Lubomir T. Lubomirov, Svetlana I. Sofronova, Vyacheslav U. Kalenchuk, Torsten Gloe, Gabriele Pfitzer, Olga S. Tarasova, Rudolf Schubert
Journal: Cardiovascular Research (2013)

Functional remodelling takes place permanently in the circulatory system. Whether this process also affects the anti-contractile effect of the endothelium during vasoconstrictor action is unknown. Therefore, the hypothesis was tested that the impact of the anti-contractile effect of the endothelium on agonist-induced contractions changes during early postnatal development.We studied isometric contractions in saphenous arteries of young (1-2 weeks) and adult (2-3 months) rats. Real-time PCR and western blot were performed to evaluate the levels of mRNA expression and protein phosphorylation, respectively. In young but not in adult rats, methoxamine-induced contractions of endothelium-intact vessels exhibited a lower sensitivity compared with endothelium-denuded vessels. The endothelial influence on methoxamine-induced contractions in arteries of young rats was completely blocked by inhibition of endothelial NO-synthase (eNOS) and guanylate cyclase. NO-donor-induced vessel relaxations were not different in young and adult rats. The expression level of eNOS mRNA was prominently higher in arteries from young compared with adult rats. eNOS inhibition alone induced tonic contractions of endothelium-intact arteries from young but not from adult animals that were associated with corresponding changes in phosphorylation of the myosin regulatory light chains, the regulatory subunit of smooth muscle cell myosin light chain phosphatase, and vasodilator-stimulated phosphoprotein, the latter two being considered to be good markers of NO/sGC/PKG pathway activity.We demonstrated that agonist-induced contractions in arteries of young rats are attenuated by the endothelium possessing an active NO-pathway. The active NO-pathway is due to a constitutive eNOS activity that disappears with age.
Low Load Inspiratory Muscle Training Increases Diaphragmatic Fiber Dimensions in Rats
Authors: HÉLÈNE ROLLIER, ANJA BISSCHOP, GHISLAINE GAYAN-RAMIREZ, RIK GOSSELINK, MARC DECRAMER
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

The effects of 8 wk of inspiratory resistive loading (30 min/d, 3 x/wk) on diaphragm mass, contractile properties, fatigue, and fiber dimensions were studied in 10 male Wistar rats. They were conditioned to breathe through a Hans-Rudolph device. Half of them had to overcome a moderate inspiratory resistance (MR; n = 5), whereas the others only had to overcome the small resistance (SR; n = 5) of the inspiratory valve of the device. Results were compared with control rats (C; n = 5) moving and breathing freely. At the end of training, animals submitted to MR and SR generated mean inspiratory pressures of -2.5 +/- 1.1 and -0.2 +/- 0.05 cm H2O, respectively. TI/Ttot was 0.60 +/- 0.06 and 0.57 +/- 0.05, respectively. Body and diaphragm weight were unaffected by loading. Little or no change in in vitro diaphragmatic twitch kinetics, force generation, and fatigability was found between the three groups. Nevertheless, cross-sectional area of all fiber types increased in the two loaded groups compared with control animals. This increase reached statistical significance for type I fibers in the MR group (846 +/- 74 microm2) compared with the C and SR groups (589 +/- 32 and 683 +/- 96 microm2, respectively, p < 0.05). For IIa fibers both training groups were significantly different from the control group (SR: 768 +/- 99 and MR: 790 +/- 108 versus C: 592 +/- 37 microm2, p < 0.05). A hypertrophy of type IIx/b fibers was seen in MR compared with control animals (C: 1,555 +/- 136, SR: 1,845 +/- 338, MR: 2,053 +/- 326 microm2, p < 0.05). No differences were present in fiber type proportions between the three groups. We conclude that in our training setup, 8 wk of intermittent long-term inspiratory loading stressed the diaphragm already with a small resistance resulting in hypertrophy of predominantly type IIa fibers. A higher resistance resulted in hypertrophy of all fiber types.
Prevalence of Cardiovascular Disease Risk Factors in U.S. Children and Adolescents With Diabetes
Authors: Beatriz L. Rodriguez, Wilfred Y. Fujimoto, Elizabeth J. Mayer-Davis, Giuseppina Imperatore, Desmond E. Williams, Ronny A. Bell, R. Paul Wadwa, Shana L. Palla, Lenna L. Liu, Ann Kershnar, Stephen R. Daniels, Barbara Linder
Journal: Diabetes Care (2006)

OBJECTIVE—The purpose of this study was to determine the prevalence and correlates of selected cardiovascular disease (CVD) risk factors among youth aged &amp;lt;20 years with diabetes. RESEARCH DESIGN AND METHODS—The analysis included 1,083 girls and 1,013 boys examined as part of the SEARCH for Diabetes in Youth study, a multicenter, population-based study of youth 0–19 years of age with diabetes. Diabetes type was determined by a biochemical algorithm based on diabetes antibodies and fasting C-peptide level. CVD risk factors were defined as follows: HDL cholesterol &amp;lt;40 mg/dl; age- and sex-specific waist circumference &amp;gt;90th percentile; systolic or diastolic blood pressure &amp;gt;90th percentile for age, sex, and height or taking medication for high blood pressure; and triglycerides &amp;gt;110 mg/dl. RESULTS—The prevalence of having at least two CVD risk factors was 21%. The prevalence was 7% among children aged 3–9 years and 25% in youth aged 10–19 years (P &amp;lt; 0.0001), 23% among girls and 19% in boys (P = 0.04), 68% in American Indians, 37% in Asian/Pacific Islanders, 32% in African Americans, 35% in Hispanics, and 16% in non-Hispanic whites (P &amp;lt; 0.0001). At least two CVD risk factors were present in 92% of youth with type 2 and 14% of those with type 1A diabetes (P &amp;lt; 0.0001). In multivariate analyses, age, race/ethnicity, and diabetes type were independently associated with the odds of having at least two CVD risk factors (P &amp;lt; 0.0001). CONCLUSIONS—Many youth with diabetes have multiple CVD risk factors. Recommendations for weight, lipid, and blood pressure control in youth with diabetes need to be followed to prevent or delay the development of CVD as these youngsters mature.
Glucagon-like peptide-1: a potent regulator of food intake in humans
Authors: J-P Gutzwiller, B Göke, J Drewe, P Hildebrand, S Ketterer, D Handschin, R Winterhalder, D Conen, C Beglinger
Journal: Gut (1999)

Background/Aims Studies in animals suggest a physiological role for glucagon-like peptide-1-(7–36)-amide (GLP-1) in regulating satiety. The role of GLP-1 in regulating food intake in man has, however, not been investigated. Subjects—Sixteen healthy male subjects were examined in a double blind placebo controlled fashion. Methods The effect of graded intravenous doses (0, 0.375, 0.75, and 1.5 pmol/kg/min) of synthetic human GLP-1 on food intake and feelings of hunger and satiety was tested in healthy volunteers. Results Graded GLP-1 infusions resulted in a dose dependent reduction in food intake (maximal inhibition 35%, p&lt;0.001 v control) and a similar reduction in calorie intake (32%; p&lt;0.001). Fluid ingestion was also reduced by GLP-1 (18% reduction, p&lt;0.01). No overt side effects were produced by GLP-1, but subjects experienced less hunger and early fullness in the period before a meal during GLP-1 infusion at the highest dose (p&lt;0.05). Conclusions Intravenous infusions of GLP-1 decrease spontaneous food intake even at physiological plasma concentrations, implying an important role for GLP-1 in the regulation of the early satiety response in humans.
Baroreflex sensitivity, clinical correlates, and cardiovascular mortality among patients with a first myocardial infarction. A prospective study.
Authors: M T La Rovere, G Specchia, A Mortara, P J Schwartz
Journal: Circulation (1988)

Experimental studies have shown that among dogs with a healed myocardial infarction, depressed baroreflex sensitivity (BRS) identifies a subgroup at higher risk for sudden death. We have examined the relation among BRS, several clinical cardiovascular variables, and subsequent mortality in 78 patients below the age of 65 years who have had a first myocardial infarction. BRS was assessed by calculating the regression line relating phenylephrine-induced increases in systolic blood pressure to the attendant changes in the RR interval. A reduced BRS primarily reflects an impairment in the vagal efferent component of the baroreceptor reflexes. The BRS of the entire population was 7.8 +/- 4.9 msec/mm Hg. BRS was lower among patients with an inferior myocardial infarction (6.1 +/- 3.3 vs. 8.9 +/- 5.8 msec/mm Hg, p = 0.03), with a three- versus a one-vessel disease (4.8 +/- 2.7 vs. 7.1 +/- 3.1 msec/mm Hg, p = 0.04), and with episodes of ventricular tachycardia (5.1 +/- 3.0 vs. 8.3 +/- 5.1, p = 0.03). There was no correlation between BRS and left ventricular ejection fraction or with mean pulmonary capillary wedge pressure at peak exercise, but a correlation (r = 0.35, p less than 0.001) was present with exercise tolerance. During the 24 months mean follow-up period, there were six cardiovascular deaths (7.6%), and four were sudden.(ABSTRACT TRUNCATED AT 250 WORDS)
Reply to: “Impaired expression of multidrug resistance–associated protein 2 and liver damage in erythropoietic protoporphyria”
Authors: Vincent W. Bloks, Torsten Plösch, Johan W. Jonker, Folkert Kuipers
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. To the Editor: With interest we have read the contribution of Hagiwara and colleagues1 describing two brothers with erythropoietic protoporphyria (EPP), a disorder of heme biosynthesis caused by mutations in the gene encoding ferrochelatase. Reduced ferrochelatase activity results in accumulation of the heme precursor protoporphyrin (PP) in erythrocytes, blood, and liver in humans as well as in corresponding animal models. Because of its hydrophobic nature, PP can only be removed from the body through secretion into bile followed by fecal elimination. Although liver fibrosis and cirrhosis have been described in EPP patients, acute liver failure appears to be a relatively rare complication. Hagiwara et al.1 report on two brothers with the same mutations in the ferrochelatase gene and similar blood levels of PP over time who, however, displayed different courses of liver damage. In an attempt to identify "the" differentiating factor in this specific disease, i.e., the factor that favors excessive hepatic PP accumulation, the authors focus on the hepatic expression and localization of the adenosine triphosphate–binding cassette (ABC) transporter ABCC2 (multidrug resistance protein 2 [MRP2]), a canalicular transporter protein, "because … MRP2 … is responsible for the excretion of PP into bile."1 Indeed, immunohistochemistry revealed low expression of the protein in the older brother, who developed liver damage, while it was well expressed at bile canalicular membranes in the younger one. Additionally, while exome sequencing revealed no specific ABCC2/MRP2 mutation, ABCC2/MRP2 messenger RNA levels were markedly lower in the older brother. Yet, we argue that reduced ABCC2/MRP2 expression is most likely a consequence, rather than a cause, of hepatic dysfunction in EPP. Earlier studies in Abcc2/Mrp2‐deficient rats unequivocally showed that this organic anion transporter is not responsible for PP deposition into bile, whereas more hydrophilic coproporphyrins do rely on Abcc2/Mrp2 activity for their hepatobiliary excretion.2 In fact, the mechanism of biliary PP excretion has remained elusive. A passive mode of excretion in which biliary lipids act as acceptors for the hydrophobic PP molecules has been proposed.3 More recently, evidence has been provided for a role of Abcg2 in hepatobiliary elimination of PP through high‐affinity transport of its glycoconjugates and, possibly, by low‐affinity transport of unconjugated PP.4 We therefore think that the observed relationship between ABCC2/MRP2 expression and hepatocellular PP deposition in these two patients is not causal in nature. The potential contribution of reduced expression of other transporters in the development of EPP‐associated liver disease deserves further investigation.