tbuckley/cabot-search huggingface dataset:
Inhibition of Intestinal Cholesterol Absorption by Ezetimibe in Humans
Authors: Thomas Sudhop, Dieter Lütjohann, Annette Kodal, Michael Igel, Diane L. Tribble, Sukrut Shah, Inna Perevozskaya, Klaus von Bergmann
Journal: Circulation (2002)

Background— Ezetimibe has been shown to inhibit cholesterol absorption in animal models, but studies on cholesterol absorption in humans have not been performed thus far. Methods and Results— The effect of ezetimibe (10 mg/d) on cholesterol absorption and synthesis, sterol excretion, and plasma concentrations of cholesterol and noncholesterol sterols was investigated in a randomized, double-blind, placebo-controlled, crossover study in 18 patients with mild to moderate hypercholesterolemia. Treatment periods lasted 2 weeks with an intervening 2-week washout period. Fractional cholesterol absorption rates averaged 49.8±13.8% on placebo and 22.7±25.8% on ezetimibe, indicating a reduction of 54% (geometric mean ratio; P &lt; 0.001). Cholesterol synthesis increased by 89% from 931±1027 mg/d on placebo to 1763±1098 mg/d on ezetimibe ( P &lt;0.001), while the ratio of lathosterol-to-cholesterol, an indirect marker of cholesterol synthesis, was increased by 72% ( P &lt;0.001). Bile acid synthesis was insignificantly increased (placebo: 264±209 mg/d, ezetimibe: 308±184 mg/d; P =0.068). Mean percent changes from baseline for LDL and total cholesterol after ezetimibe treatment were −20.4% and −15.1%, respectively ( P &lt;0.001 for both), whereas campesterol and sitosterol were decreased by −48% and − 41%, respectively. Conclusion— In humans, ezetimibe inhibits cholesterol absorption and promotes a compensatory increase of cholesterol synthesis, followed by clinically relevant reductions in LDL and total cholesterol concentrations. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols sitosterol and campesterol, suggesting an effect on the absorption of these compounds as well.
The immunosuppressive and toxic effects of FK-506 are mechanistically related: pharmacology of a novel antagonist of FK-506 and rapamycin.
Authors: F J Dumont, M J Staruch, S L Koprak, J J Siekierka, C S Lin, R Harrison, T Sewell, V M Kindt, T R Beattie, M Wyvratt
Journal: The Journal of Experimental Medicine (1992)

FK-506 inhibits Ca(2+)-dependent transcription of lymphokine genes in T cells, and thereby acts as a powerful immunosuppressant. However, its potential therapeutic applications may be seriously limited by several side effects, including nephrotoxicity and neurotoxicity. At present, it is unclear whether these immunosuppressive and toxic effects result from interference with related biochemical processes. FK-506 is known to interact with FK-binding protein-12 (FKBP-12), an abundant cytosolic protein with cis-trans peptidyl-prolyl isomerase activity (PPIase) activity. Because rapamycin (RAP) similarly binds to FKBP-12, although it acts in a manner different from FK-506, by inhibiting T cell responses to lymphokines, such an interaction with FKBP-12 is not sufficient to mediate immunosuppression. Recently, it was found that the complex of FKBP-12 with FK-506, but not with RAP, inhibits the phosphatase activity of calcineurin. Here, we used L-685,818, the C18-hydroxy, C21-ethyl derivative of FK-506, to explore further the role of FKBP-12 in the immunosuppressive and toxic actions of FK-506. Although L-685,818 bound with high affinity to FKBP-12 and inhibited its PPIase activity, it did not suppress T cell activation, and, when complexed with FKBP-12, did not affect calcineurin phosphatase activity. However, L-685,818 was a potent antagonist of the immunosuppressive activity of both FK-506 and RAP. Moreover, L-685,818 did not induce any toxicity in dogs and rats or in a mouse model of acute FK-506 nephrotoxicity, but it blocked the effect of FK-506 in this model. Therefore, FK-506 toxicity involves the disruption of biochemical mechanisms related to those implicated in T cell activation. Like immunosuppression, this toxicity is not due to the inhibition of the PPIase activity of FKBP-12, but may be linked to the inhibition of the phosphatase activity of calcineurin by the drug FKBP-12 complex.
Four individually druggable MET hotspots mediate HGF-driven tumor progression
Authors: Cristina Basilico, Anna Hultberg, Christophe Blanchetot, Natalie de Jonge, Els Festjens, Valérie Hanssens, Sjudry-Ilona Osepa, Gitte De Boeck, Alessia Mira, Manuela Cazzanti, Virginia Morello, Torsten Dreier, Michael Saunders, Hans de Haard, Paolo Michieli
Journal: Journal of Clinical Investigation (2014)

Activation of MET by HGF plays a key role in tumor progression. Using a recently developed llama platform that generates human-like immunoglobulins, we selected 68 different antibodies that compete with HGF for binding to MET. HGF-competing antibodies recognized 4 distinct hotspots localized in different MET domains. We identified 1 hotspot that coincides with the known HGF β chain binding site on blades 2–3 of the SEMA domain β-propeller. We determined that a second and a third hotspot lie within blade 5 of the SEMA domain and IPT domains 2–3, both of which are thought to bind to HGF α chain. Characterization of the fourth hotspot revealed a region across the PSI-IPT 1 domains not previously associated with HGF binding. Individual or combined targeting of these hotspots effectively interrupted HGF/MET signaling in multiple cell-based biochemical and biological assays. Selected antibodies directed against SEMA blades 2–3 and the PSI-IPT 1 region inhibited brain invasion and prolonged survival in a glioblastoma multiforme model, prevented metastatic disease following neoadjuvant therapy in a triple-negative mammary carcinoma model, and suppressed cancer cell dissemination to the liver in a KRAS-mutant metastatic colorectal cancer model. These results identify multiple regions of MET responsible for HGF-mediated tumor progression, unraveling the complexity of HGF-MET interaction, and provide selective molecular tools for targeting MET activity in cancer.
What Is the Relationship between Airway Hyperresponsiveness and Atopy?
Authors: ANN J. WOOLCOCK, JENNIFER PEAT
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The nature of the relationship between airway hyperresponsiveness (AHR) and atopy (specific IgE to aeroallergens) is unknown and one of the most important questions about asthma. Is AHR a consequence of airway inflammation caused by allergic or other responses or is it a separately inherited state? It is clear from epidemiological studies that these two abnormalities are linked. However, not all allergic (atopic) people have AHR and not all airway-hyperresponsive people are allergic. Furthermore, there is some suggestion that the risk factors for the two abnormalities are different. In Australian children, there has been little increase in the prevalence of atopy but AHR and symptoms have increased so that more of the atopic group now have asthma (1). The data suggest that over the years between 1982 and 1992 in atopic children, the risk factors for AHR have increased or that protective factors have been lost. There have been almost no other studies of atopic status and AHR in randomly selected populations over a period of time to determine if this is happening elsewhere. This article outlines what is known, what is partially known, and the important questions that need to be answered.
Early Clinical Results of the Telemetric Adjustable Pulmonary Artery Banding FloWatch-PAB
Authors: Damien Bonnet, Antonio F. Corno, Daniel Sidi, Nicole Sekarski, Maurice Beghetti, Ingram Schulze-Neick, Margrit Fasnacht, Emmanuel Le Bret, Afksendyios Kalangos, Pascal R. Vouhé, Ludwig K. von Segesser
Journal: Circulation (2004)

Adjustment of pulmonary artery banding (PAB) may be a challenging procedure in complex congenital heart defects. Whatever the technique used, subsequent re-operations are frequently needed to control the pulmonary blood flow or pressures.To report the efficacy of a new telemetric adjustable PAB (FloWatch-PAB) operated with the help of an external control unit that transmits to the implant energy and commands to further narrow or release the pulmonary artery using radiofrequency waves.In a multicenter, prospective, nonrandomized, single-arm clinical investigation, 13 children (median age, 4.5 months; range, 6 days to 11 years; median weight, 4.2 kg; range, 3.1 to 27 kg) underwent implantation of the FloWatch-PAB through median sternotomy in 8 and left thoracotomy in 5. The diagnosis was multiple ventricular septal (VSD) defects with complex anatomy in 3, single ventricle without pulmonary stenosis in 2, VSD with elevated pulmonary vascular resistance (PVR) in 2, atrio-ventricular canal (AVC) with elevated pulmonary vascular resistance in 1, AVC with diminutive right ventricle in 1, complex transposition of the great arteries in 3, and pulmonary atresia with complex pulmonary arteries anatomy in 1. All patients had normosystemic systolic pulmonary artery pressure. Additional procedures were performed in 7: atrial septectomy in 2, double aortic arch division in 1, patent ductus arteriosus ligation in 2, and coarctation repair in 2. There were no early or late deaths or device-related complications in a mean follow-up of 24 weeks (range, 18 to 42 weeks). A mean of 5.8 telemetric regulations per patient using the FloWatch-PAB were required to adjust the tightening of the PAB to the clinical needs (narrowing 74%, releasing 26%). At last follow-up, systolic pulmonary artery pressure was within normal range in all patients but 1. Systemic oxygen saturation demonstrated optimal regulation of the pulmonary blood flow in all according to each specific defect. Four patients were successfully corrected (VSD closure, AVSD repair, and 2 arterial switches with VSD closure). The device was easily removed and the pulmonary artery re-expanded spontaneously.This new device is safe and allows optimal adjustment of PAB in complex heart defects. In children requiring PAB, the use of this technology can obviate the need for early re-operations and appears to be a valuable option in the panel of surgical alternatives for selected infants.
Determination of Molecular Marker Expression Can Predict Clinical Outcome in Colon Carcinomas
Authors: Gennaro Galizia, Eva Lieto, Francesca Ferraraccio, Michele Orditura, Ferdinando De Vita, Paolo Castellano, Vincenzo Imperatore, Ciro Romano, Fortunato Ciardiello, Bruno Agostini, Carlo Pignatelli
Journal: Clinical Cancer Research (2004)

Conventional staging procedures are often unable to precisely predict prognosis in colorectal cancer (CRC). In this study, we set out to investigate the possible role of molecular/structural indicators involved in cell cycle regulation (p27 and p53), apoptosis (p53 and p27), and tumor neoangiogenesis [p53, vascular endothelial growth factor (VEGF), and microvessel count] in predicting tumor behavior and clinical outcome in CRC patientsAnalysis of the above indicators was performed by immunohistochemistry on 104 CRC patient samples and 25 normal colon mucosa specimens.Intense p27 nuclear staining was found in normal colon mucosa, with p53 nuclear staining and VEGF cytoplasmic accumulation <10%, and low microvessel count. In contrast, in CRC samples, p27 was down-regulated in 53.8%, p53 protein was overexpressed in 52%, and VEGF stained positive in 67.3% of the cases, respectively. Multiple regression analysis showed that molecular markers were strongly correlated. In patients treated with curative surgery, a significant relationship was seen between p27 down-regulation and Dukes' stage, nodal status, and the presence of distant metastases. VEGF overexpression correlated significantly with Dukes' stage, tumor (t) and metastasis (m) parameters, and left site. Stepwise regression selected p27, p53, VEGF, and Dukes' stage as the best combination of variables capable of predicting both disease-specific and disease-free survival.The investigated indicators may be useful for the prediction of outcome and recurrence rate in curatively treated CRC patients. In conjunction with clinical and pathological staging, they may provide a stronger indication of clinical outcome than staging alone and help better select therapeutic options in CRC patients.
Effectiveness and economic evaluation of a nurse delivered home exercise programme to prevent falls. 1: Randomised controlled trial
Authors: M C. Robertson
Journal: BMJ (2001)

To assess the effectiveness of a trained district nurse individually prescribing a home based exercise programme to reduce falls and injuries in elderly people and to estimate the cost effectiveness of the programme.Randomised controlled trial with one year's follow up.Community health service at a New Zealand hospital.240 women and men aged 75 years and older.121 participants received the exercise programme (exercise group) and 119 received usual care (control group); 90% (211 of 233) completed the trial.Number of falls, number of injuries resulting from falls, costs of implementing the programme, and hospital costs as a result of falls.Falls were reduced by 46% (incidence rate ratio 0.54, 95% confidence interval 0.32 to 0.90). Five hospital admissions were due to injuries caused by falls in the control group and none in the exercise group. The programme cost $NZ1803 (523 pound sterling) (at 1998 prices) per fall prevented for delivering the programme and $NZ155 per fall prevented when hospital costs averted were considered.A home exercise programme, previously shown to be successful when delivered by a physiotherapist, was also effective in reducing falls when delivered by a trained nurse from within a home health service. Serious injuries and hospital admissions due to falls were also reduced. The programme was cost effective in participants aged 80 years and older compared with younger participants.
Dental Service in 2008 Summer Olympic Games
Authors: Xiao-Jiang Yang, Patrick Schamach, Jian-Ping Dai, Xiao-Zhen Zhen, Biao Yi, Hongchen Liu, Min Hu, Tony Clough, Yuan Li, Chun-mei Ma
Journal: British Journal of Sports Medicine (2010)

How to organise an appropriate team to provide quality dental care during the Olympic Games has become an important consideration for each successive host country. The aims of this study were to document dental services provided at the Olympic Games and to provide data for planning future events. SET-UP OF THE DENTAL CARE DEPARTMENT: There were six dental chairs in six independent treatment rooms, one technical laboratory, a sterilising room and an x-ray room equipped with one digital panoramic screening machine and one intraoral x-ray machine in the polyclinic in the Olympic Village in Beijing. Shifts comprised 80 dentists and 28 nurses who were organised into three shifts working from 08:00 until 23:00.In the 2008 Olympic Games, there were 1607 cases involving 1126 patients requiring dental care: 795 cases from 516 athletes; 483 cases from 370 coaches and other staff; and 99 cases from volunteers. Endodontic treatments, permanent fillings, oral hygiene, mouthguards and treatment of pericoronitis were the most frequent procedures in dental care. The Mouthguard Service was extremely popular and well utilised. 122 athletes received new custom-made mouthguards in Beijing.As the utilisation of the dental service grows, and the burden of providing care for such a large cohort increases, a well-organised dental team becomes increasingly important. More general-practice dentists were needed in the team. Different kinds of specialist were suggested for working in the team-for example, oral and maxillofacial surgeons, sport dentists for mouthguards and endodontists.
Hematological characterization of congenital osteopetrosis in op/op mouse. Possible mechanism for abnormal macrophage differentiation.
Authors: W W Wiktor-Jedrzejczak, A Ahmed, C Szczylik, R R Skelly
Journal: The Journal of Experimental Medicine (1982)

Compared with normal littermates, the op/op mice had very few macrophages in the peritoneal cavity and severely reduced numbers of monocytes in the peripheral blood. Moreover, osteopetrotic animals demonstrated an altered distribution of hemopoietic tissue with a 10-fold decrease in the number of marrow cells. Liver hemopoiesis persisted in 4-wk-old mice as evidenced by the presence of hemopoietic stem cells (HSC). Moreover, the concentration of HSC was decreased in marrow and increased in the spleen of op/op mice. In spite of the paucity of cells of monocyte-macrophage lineage in vivo, progenitor cells from hemopoietic tissues of op/op mice formed increased numbers of monocyte-macrophage colonies in vitro in the presence of exogenous colony-stimulating activity (CSA). The source of this critical CSA was a medium conditioned by stromal fibroblastoid colonies formed in vitro by normal marrow cells. Therefore, these data suggest that op/op mice possess normal monocyte-macrophage-osteoclast progenitor cells but these cells are unable to fully differentiate in the op/op mouse microenvironment. In support of this, in cultures of stromal fibroblastoid colonies from op/op marrow or spleen, the concomitant growth of macrophages, normally very dense, was drastically reduced. Moreover, transplantation of op/op spleen cells into lethally irradiated littermate recipients resulted in their hemopoietic reconstitution without signs of macrophage defect. Thus, the op/op splenic cells do not transfer the disease and are capable of normal differentiation in normal in vivo environment. These observations support the hypothesis that the defect in op/op mice is a result of the failure of hemopoietic stromal fibroblastoid cells to release sufficient amounts of CSA necessary for normal differentiation of cells of the monocyte-macrophage lineage.
Effect of intrahepatic portal-systemic shunting on hepatic ammonia extraction in patients with cirrhosis
Authors: Fumio Nomura, Kunihiko Ohnishi, Hidetaka Terabayashi, Toshiaki Nakai, Kazumasa Isobe, Kazuhiro Takekoshi, Kunio Okuda
Journal: Hepatology (1994)

Increased plasma ammonia levels in patients with advanced cirrhosis have been attributed to reduced conversion of enteric ammonia to urea by the diseased liver and to entry of enteric ammonia into systemic circulation by way of portal-systemic shunts. Because single-pass extraction is high for portal venous ammonia, reduction of portal blood supply to hepatocytes may have detrimental effects on the hepatic extraction of ammonia. To assess how the development of intrahepatic portal-systemic shunts alters hepatic ammonia metabolism, we determined portal and hepatic venous ammonia levels along with measurements of intrahepatic portal-systemic shunts using 99m Tc-macroaggregated albumin in 46 patients with portal hypertension. Hepatic venous ammonia levels in the groups of patients with idiopathic portal hypertension, Child class A cirrhosis and Child class B or C cirrhosis were 36 ± 17, 75 ± 26 and 93 ± 52 μg/dl, respectively, in increasing order, and portal venous ammonia extraction rates as calculated with the equation (portal venous ammonia — hepatic venous ammonia)/portal venous ammonia × 100% were decreased in the same order (77% ± 14%,50% ± 21%,40% ± 25%, respectively). Furthermore, we noted a significant negative correlation between the intrahepatic shunt indexes as calculated by counts per minute in lungs/counts per minute in lungs and liver × 100% and the ammonia extraction rates. It was noteworthy that among Child class C patients, the ammonia extraction rates were significantly lower in patients with high intrahepatic shunt indexes than in those with low shunt indexes. These results demonstrate a significant direct relationship between hepatic ammonia extraction rates and intrahepatic shunting in cirrhosis. (Hepatology 1994;20:1478-1481).
A Controlled Trial of Web-Based Diabetes Disease Management
Authors: James B. Meigs, Enrico Cagliero, Anil Dubey, Patricia Murphy-Sheehy, Catharyn Gildesgame, Henry Chueh, Michael J. Barry, Daniel E. Singer, David M. Nathan
Journal: Diabetes Care (2003)

OBJECTIVE—To test effects of a web-based decision support tool, the diabetes Disease Management Application (DMA), developed to improve evidence-based management of type 2 diabetes. RESEARCH DESIGN AND METHODS—We conducted a group randomized controlled trial of 12 intervention and 14 control staff providers and 307 intervention and 291 control patients with type 2 diabetes in a hospital-based internal medicine clinic. Providers were randomly assigned from May 1998 through April 1999 to have access to the DMA (intervention) or not to have access (control). The DMA displays interactive patient-specific clinical data, treatment advice, and links to other web-based care resources. We compared patients in the intervention and control groups for changes in processes and outcomes of care from the year preceding the study through the year of the study by intention-to-treat analysis. RESULTS—The DMA was used for 42% of scheduled patient visits. The number of HbA1c tests obtained per year increased significantly in the intervention group (+0.3 tests/year) compared with the control group (−0.04 tests/year, P = 0.008), as did the number of LDL cholesterol tests (intervention, +0.2 tests/year; control, +0.01 tests/year; P = 0.02) and the proportions of patients undergoing at least one foot examination per year (intervention, +9.8%; control, −0.7%; P = 0.003). Levels of HbA1c decreased by 0.2 in the intervention group and increased by 0.1 in the control group (P = 0.09); proportions of patients with LDL cholesterol levels &amp;lt;130 mg/dl increased by 20.3% in the intervention group and 10.5% in the control group (P = 0.5). CONCLUSIONS—Web-based patient-specific decision support has the potential to improve evidence-based parameters of diabetes care.
Cardiac Troponin Elevation, Cardiovascular Morbidity, and Outcome After Subarachnoid Hemorrhage
Authors: Andrew M. Naidech, Kurt T. Kreiter, Nazli Janjua, Noeleen D. Ostapkovich, Augusto Parra, Christopher Commichau, Brian-Fred M. Fitzsimmons, E. Sander Connolly, Stephan A. Mayer
Journal: Circulation (2005)

Background— Cardiac troponin I (cTI) release occurs frequently after subarachnoid hemorrhage (SAH) and has been associated with a neurogenic form of myocardial injury. The prognostic significance and clinical impact of these elevations remain poorly defined. Methods and Results— We studied 253 SAH patients who underwent serial cTI measurements for clinical or ECG signs of potential cardiac injury. These patients were drawn from an inception cohort of 441 subjects enrolled in the Columbia University SAH Outcomes Project between November 1998 and August 2002. Peak cTI levels were divided into quartiles or classified as undetectable. Adverse in-hospital events were prospectively recorded, and outcome at 3 months was assessed with the modified Rankin Scale. Admission predictors of cTI elevation included poor clinical grade, intraventricular hemorrhage, loss of consciousness at ictus, global cerebral edema, and a composite score of physiological derangement (all P ≤0.01). Peak cTI level was associated with an increased risk of echocardiographic left ventricular dysfunction (odds ratio [OR], 1.3 per quintile; 95% CI, 1.0 to 1.7; P =0.03), pulmonary edema (OR, 2.1 per quintile; 95% CI, 1.6 to 2.7; P &lt;0.001), hypotension requiring pressors (OR, 1.9 per quintile; 95% CI, 1.5 to 2.3; P &lt;0.001), and delayed cerebral ischemia from vasospasm (OR, 1.3 per quintile; 95% CI, 1.07 to 1.7; P =0.01). Peak cTI levels were predictive of death or severe disability at discharge after controlling for age, clinical grade, and aneurysm size (adjusted OR, 1.4 per quintile; 95% CI, 1.1 to 1.9; P =0.02), but this association was no longer significant at 3 months. Conclusions— cTI elevation after SAH is associated with an increased risk of cardiopulmonary complications, delayed cerebral ischemia, and death or poor functional outcome at discharge.