tbuckley/cabot-search huggingface dataset:
First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014
Authors: Bristi Basu, Emma Dean, Martina Puglisi, Alastair Greystoke, Michael Ong, Wendy Burke, Maria Cavallin, Graham Bigley, Christopher Womack, Elizabeth A. Harrington, Stephen Green, Elisabeth Oelmann, Johann S. de Bono, Malcolm Ranson, Udai Banerji
Journal: Clinical Cancer Research (2015)

AZD2014 is a novel, oral, m-TORC 1/2 inhibitor that has shown in vitro and in vivo efficacy across a range of preclinical human cancer models.A rolling six-dose escalation was performed to define an MTD (part A), and at MTD a further cohort of patients was treated to further characterize toxicities and perform pre- and posttreatment biopsies (part B). AZD2014 was administered orally twice a day continuously. Flow cytometry, ELISA, and immunohistochemistry were used to quantify pharmacodynamic biomarkers. Pharmacokinetic analysis was carried out by mass spectrometry.A total of 56 patients were treated across a dose range of 25 to 100 mg. The MTD was 50 mg twice daily. The dose-limiting toxicities were fatigue and mucositis. At the MTD, the most common adverse events (AE) were fatigue (78%), nausea (51%), and mucositis (49%), but these were equal to or greater than grade 3 in only 5% of patients. Drug levels achieved at the MTD (AUC SS: 6686 ng·h/mL, Cmax ss 1,664 ng/mL) were consistent with activity in preclinical models. A reduction in p-S6 levels and Ki67 staining was observed in 8 of 8 and 5 of 9 evaluable paired biopsy samples. Partial responses were seen in a patient with pancreatic cancer and a patient with breast cancer, who were found to have a PDGFR and ERBB2 mutation, respectively.The recommended phase II dose for further evaluation of AZD2014 is 50 mg twice daily, and at this dose it has been possible to demonstrate pharmacologically relevant plasma concentrations, target inhibition in tumor, and clinical responses.
Echocardiographic assessment of a normal adult aging population.
Authors: G Gerstenblith, J Frederiksen, F C Yin, N J Fortuin, E G Lakatta, M L Weisfeldt
Journal: Circulation (1977)

Echocardiograms were performed on 105 male participants in the National Institutes on Aging's volunteer Longitudinal Study Program. All subjects (25--84 years of age) were physically active and had no evidence of hypertension or cardiovascular disease. Measurements were made of the initial diastolic (E-F) slope of the anterior mitral valve leaflet, the aortic and left ventricular cavity dimensions, and the thickness of the posterior left ventricular wall. Fractional shortening of the minor semi-axis of the left ventricle and the velocity of circumferential fiber shortening were also determined. It was found that increasing age correlated with a decrease mitral valve E-F slope and increased aortic root diameter and left ventricular wall thickness. Aging did not affect left ventricular cavity dimension, fractional shortening of the minor semi-axis, and velocity of circumferential fiber shortening. These findings suggest that aging in the normal male is associated with altered left ventricular diastolic filling, increased aortic root diameter and left ventricle hypertrophy but little change in contractile ability in the resting state.
Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease
Authors: Vanessa Brochard, Béhazine Combadière, Annick Prigent, Yasmina Laouar, Aline Perrin, Virginie Beray-Berthat, Olivia Bonduelle, Daniel Alvarez-Fischer, Jacques Callebert, Jean-Marie Launay, Charles Duyckaerts, Richard A. Flavell, Etienne C. Hirsch, Stéphane Hunot
Journal: Journal of Clinical Investigation (2008)

Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of dopamine-containing neurons. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. However, the pathogenic role of the adaptive immune system in PD remains enigmatic. Here we showed that CD8+ and CD4+ T cells but not B cells had invaded the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration. We further demonstrated that MPTP-induced dopaminergic cell death was markedly attenuated in the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (Rag1-/- and Tcrb-/- mice). Importantly, similar attenuation of MPTP-induced dopaminergic cell death was seen in mice lacking CD4 as well as in Rag1-/- mice reconstituted with FasL-deficient splenocytes. However, mice lacking CD8 and Rag1-/- mice reconstituted with IFN-gamma-deficient splenocytes were not protected. These data indicate that T cell-mediated dopaminergic toxicity is almost exclusively arbitrated by CD4+ T cells and requires the expression of FasL but not IFNgamma. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD.
Donor antibodies to HNA-3a implicated in TRALI reactions prime neutrophils and cause PMN-mediated damage to human pulmonary microvascular endothelial cells in a two-event in vitro model
Authors: Christopher C. Silliman, Brian R. Curtis, Patricia M. Kopko, Samina Y. Khan, Marguerite R. Kelher, Randy M. Schuller, Baindu Sannoh, Daniel R. Ambruso
Journal: Blood (2006)
Whole genome sequencing reveals potential spread of Clostridium difficile between humans and farm animals in the Netherlands, 2002 to 2011
Authors: C W Knetsch, T R Connor, A Mutreja, S M van Dorp, I M Sanders, H P Browne, D Harris, L Lipman, E C Keessen, J Corver, E  J Kuijper, T D Lawley
Journal: Eurosurveillance (2014)

Farm animals are a potential reservoir for human Clostridium difficile infection (CDI), particularly PCR ribotype 078 which is frequently found in animals and humans. Here, whole genome single-nucleotide polymorphism (SNP) analysis was used to study the evolutionary relatedness of C. difficile 078 isolated from humans and animals on Dutch pig farms. All sequenced genomes were surveyed for potential antimicrobial resistance determinants and linked to an antimicrobial resistance phenotype. We sequenced the whole genome of 65 C. difficile 078 isolates collected between 2002 and 2011 from pigs (n?=?19), asymptomatic farmers (n?=?15) and hospitalised patients (n?=?31) in the Netherlands. The collection included 12 pairs of human and pig isolates from 2011 collected at 12 different pig farms. A mutation rate of 1.1 SNPs per genome per year was determined for C. difficile 078. Importantly, we demonstrate that farmers and pigs were colonised with identical (no SNP differences) and nearly identical (less than two SNP differences) C. difficile clones. Identical tetracycline and streptomycin resistance determinants were present in human and animal C. difficile 078 isolates. Our observation that farmers and pigs share identical C. difficile strains suggests transmission between these populations, although we cannot exclude the possibility of transmission from a common environmental source.
On the definition of viability in isolated perfused skin preparations
Authors: J.E. Riviere, K.F. Bowman, Nancy A. Monteiro-Riviere
Journal: British Journal of Dermatology (1987)

Journal Article On the definition of viability in isolated perfused skin preparations Get access J.E. Riviere, J.E. Riviere School of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27612, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar K.F. Bowman, K.F. Bowman School of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27612, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar Nancy A. Monteiro‐Riviere Nancy A. Monteiro‐Riviere School of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27612, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 116, Issue 5, 1 May 1987, Pages 739–741, https://doi.org/10.1111/j.1365-2133.1987.tb05911.x Published: 01 May 1987
Supervised discharge of mentally ill people
Authors: S Hampson, P Davison
Journal: BMJ (1994)

EDITOR, - We endorse Robert Bluglass's comments1 concerning recommendations for the care of mentally ill people in the community.2 In particular, we share his concern that, in its present form, supervised discharge may not be an advance on current guardianship arrangements.

We recently conducted a postal survey to determine the attitudes of consultant general psychiatrists working with adults in the Oxford region towards the proposed new legal powers (supervised discharge, extended leave of absence, and guardianship). Part of the questionnaire was adapted from a survey into attitudes towards community supervision orders.3 After five weeks there had been a 71% (37/52) response rate.

Supervised discharge - Thirty …
Tc-99m Colloid Lung Uptake in a Rare Case of Toxoplasmosis with Liver Involvement
Authors: I GARTY, I TAL, A KAYNAN
Journal: Clinical Nuclear Medicine (1984)

Intensive lung accumulation of colloid (Tc-99m phytate) was demonstrated in a child suffering from acquired toxoplasmosis with a rare manifestation of severe liver damage. The possible mechanism and clinical importance of colloid lung concentration in this case is briefly discussed, including a review of the literature on this subject.
Birth Cohort Analysis of Prevalence of Cigarette Smoking Among Hispanics in the United States
Authors: Luis G. Escobedo
Journal: JAMA (1989)

To investigate historical trends of cigarette smoking among Mexican-Americans, Cuban-Americans, and Puerto Rican-Americans, we conducted a birth cohort analysis of smoking prevalence by using smoking histories of 8286 adults and adolescents from the 1982-1983 Hispanic Health and Nutrition Examination Survey. We constructed smoking prevalence curves for men and women among successive ten-year birth cohorts. Birth cohort-specific prevalence rates were higher for men than for women. Rates, however, decreased among successive cohorts of men. Conversely, rates increased among successive cohorts of Cuban-American and Puerto Rican-American women. For example, peak rates among the 1911 through 1920 cohorts were 26% (Cuban-American women) and 25% (Puerto Rican-American women) compared with peak rates of 43% and 52%, respectively, among comparable groups from 1951 through 1960. These results demonstrate that despite a reduction of cigarette smoking among successive cohorts of Hispanic men, Hispanic women have made little progress or have actually increased their cigarette smoking.
Determination of Left Ventricular Filling Pressure by Doppler Echocardiography in Patients With Coronary Artery Disease: Critical Role of Left Ventricular Systolic Function
Authors: Kazuhiro Yamamoto, Rick A Nishimura, Hari P Chaliki, Christopher P Appleton, David R Holmes, Margaret M Redfield
Journal: Journal of the American College of Cardiology (1997)
(4) Pyoderma gangrenosum and ulcerative proctitis
Authors: P.J.A. Holt, E. Waddington
Journal: British Journal of Dermatology (1973)

Journal Article (4) Pyoderma gangrenosum and ulcerative proctitis Get access P.J.A. Holt, P.J.A. Holt Department of Dermatology, University Hospital of Wales, Cardiff Search for other works by this author on: Oxford Academic Google Scholar E. Waddington E. Waddington Department of Dermatology, University Hospital of Wales, Cardiff Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 89, Issue s9, 1 July 1973, Pages 33–35, https://doi.org/10.1111/j.1365-2133.1973.tb03437.x Published: 01 July 1973
Failure of Quality Control to Detect Errors in the Preparation of Technetium-99m Disofenin (DISIDA)
Authors: MYRON L. LECKLITNER, ANTHONY R. BENEDETTO, JOHN D. STRAW
Journal: Clinical Nuclear Medicine (1985)

Uptake of Tc-99m disofenin is so strongly hepatobiliary that striking appearance of radioactivity in the reticuloendothelial system (RES) is almost certainly caused by improper preparation of the disofenin kit. Four patients who received injections of Tc-99m disofenin demonstrated a pronounced RES biodistribution in addition to the expected hepatobiliary pattern. Since routine quality control testing had not forewarned us of this gross lack of radiochemical purity, Tc-99m disofenin kits were subjected to a variety of insults to elucidate the mechanisms of quality control failure. Assessment of radiochemical purity was conducted using instant thin-layer chromatography (ITLC) and two solvent systems. We concluded that both Tc-99m pertechnetate and Tc-99m sulfur colloid had been injected into the cold disofenin kit. Visual inspections were not reliable for verifying the final radiopharmaceutical product because of dilution of the sulfur colloid by pertechnetate. ITLC testing failed because the assay method being used at that time did not accurately assess the hydrolyzed fraction (colloidal component). Recommendations are made to preclude recurrence of the errors that occurred.
Rethinking Health: ICT-Enabled Services to Empower People to Manage Their Health
Authors: Anita Honka, Kirsikka Kaipainen, Henri Hietala, Niilo Saranummi
Journal: IEEE Reviews in Biomedical Engineering (2011)

Lifestyle is a key determinant in the prevention and management of chronic diseases. If we would exercise regularly, eat healthy, control our weight, sleep enough, manage stress, not smoke and use alcohol only moderately, 90% of type II diabetes, 80% of coronary heart disease, and 70% of stroke could be prevented. Health statistics show that lifestyle related diseases are increasing at an alarming rate. Public health promotion campaigns and healthcare together are not effective enough to stop this "tsunami". The solution that is offered is to empower people to manage their health with the assistance of ICT-enabled services. A lot of R&D and engineering effort is being invested in Personal Health Systems. Although some progress has been made, the market for such systems has not yet emerged. The aim of this critical review is to identify the barriers which are holding back the growth of the market. It looks into the theoretical foundations of behavior change support, the maturity of the technologies for behavior change support, and the business context in which behavior change support systems are used.
Noninvasive assessment of acute effects of nifedipine on rest and exercise hemodynamics and cardiac function in patients with aortic regurgitation
Authors: Wei Feng Shen, Gary S. Roubin, Kunihiko Hirasawa, Roger F. Uren, Brian F. Hutton, Phillip J. Harris, Peter J. Fletcher, David T. Kelly
Journal: Journal of the American College of Cardiology (1984)
Zileuton, a 5‐lipoxygenase inhibitor, increases production of thromboxane A<sub>2</sub> and platelet aggregation in patients with asthma
Authors: Xujun Wu, Anil Dev, Alfred Ba Tun Leong
Journal: American Journal of Hematology (2003)

Abstract Leukotrienes, generated from arachidonic acid via the lipoxygenase pathway, play an important role in the pathophysiology of asthma. Therefore, leukotriene inhibitors, such as Zileuton, are used in the treatment of asthma. However, thromboxanes, generated from arachidonic acid via the cyclooxygenase pathway, play an important role in platelet aggregation and thrombosis. Therefore, we studied whether Zileuton, by shifting arachidonic acid to the cyclooxygenase pathway, enhances thromboxane production and, hence, platelet aggregation. Blood samples were collected from 10 asthmatic patients before and 2 weeks after standard Zileuton treatment. Spontaneous platelet aggregation was measured in platelet‐rich plasma. Platelet‐rich plasma was also used to determine thromboxane B 2 , a stable metabolite of thromboxane A 2 , as the indirect measure of thromboxane A 2 because thromboxane A 2 is too unstable for assay. Baseline thromboxane B 2 and platelet aggregation values in the 10 asthmatic patients were normal. Treatment with Zileuton for 2 weeks significantly increased thromboxane B 2 levels from baseline levels of 267 ± 54 μg/l to 389 ± 62 μg/l after 2 weeks of treatment ( P &lt; 0.0002). Spontaneous platelet aggregation also increased significantly from baseline values of 4.2 ± 2.4% to 6.8 ± 2.8% after 2 weeks of treatment ( P &lt; 0.0001). These results establish that Zileuton, an effective drug for asthma, adversely affects in vitro platelet function. The findings suggest that this drug, and perhaps related agents also, may pose a thrombotic risk; clinical attention will be needed to address this possibility. Am. J. Hematol. 74:23–25, 2003. © 2003 Wiley‐Liss, Inc.
Swallowable capsule technology: current perspectives and future directions in image acquisition and processing
Authors: A. Sanchez-Yague, T. Nguyen-Tang
Journal: Endoscopy (2009)

We read with interest the article by Twomey and Marchesi, “Swallowable capsule technology: current perspectives and future directions” [1]. They divide the current developments in capsule technology in four different areas: drug delivery, chemical sensing, controlled motion, and battery-less power. In our view capsule image acquisition and processing is an important topic not covered in the article.
Effect of octreotide on gastrointestinal pressure profiles in health and in functional and organic gastrointestinal disorders.
Authors: K Haruma, J A Wiste, M Camilleri
Journal: Gut (1994)

The somatostatin analogue, octreotide, restores normal pressure profiles in disorders of upper gut motility. This study aimed to evaluate the acute effects of octreotide in five healthy subjects and in 50 consecutive patients with functional (n = 22) or organic (n = 28) dysmotility. Antroduodenojejunal manometry was performed during three hours' fasting, for two hours after a standard meal, and 30 minutes after subcutaneous injection of 50 micrograms octreotide. Antral motility, before and after octreotide, and characteristics of spontaneous migrating motor complexes and octreotide induced activity fronts were compared. Octreotide inhibited antral motility and induced a small intestinal activity front followed by motor quiescence in all healthy subjects and patients. The duration and propagation velocity of activity fronts were greater than those of spontaneous migrating motor complexes. Thirty per cent of activity fronts began simultaneously at different levels of small bowel, and in 20%, a second, normally propagated activity front developed within 30 minutes of octreotide injection. Octreotide induces rapidly propagated, long activity fronts, even in patients with neuropathology, and this may initially facilitate the intestinal propulsion of chyme. Propulsion may not occur, however, if octreotide induces simultaneous activity fronts or if the activity front is followed by prolonged quiescence. Inhibition of antral motility suggests that octreotide may not be effective in gastroparesis.
Man the Meal-Eater and His Interaction With Parenteral Nutrition
Authors: Carey P. Page
Journal: JAMA (1980)

CYCLIC parenteral nutrition provides hypertonic dextrose and amino acids alternating with dextrose-free periods. The periodicity of intermittent dextrose-amino acid administration may vary, as may the nature and quantity of substrate administered during the dextrose-free period. This technique of parenteral feeding has been prompted by awareness of man as a meal-eater and of his ability to institute hormonal and metabolic responses that are matched to the existing nutritional status and the varying input of nutrient materials that maintain body composition and functional capacity despite periodic feeding in a nonsteady state.1  Continual total parenteral nutrition (TPN) with hypertonic dextrose and amino acid solutions alters the hormonal milieu in which man normally maintains life, body composition, and function. Periodic feeding profiles are possible and may be appropriate in the group of patients characterized in Table 1. In this communication we review briefly how man, the meal-eater, responds to periodic feeding and how
Meteorology and Climate of Plymouth
Authors: J. Merrifield
Journal: BMJ (1871)

lieve that the explanation is to be sought for in Africa, in the Desert of Sahara.This immense tract of sunburnt sand, which covers a consider- able portion of the continent of Africa, may be considered one vast furnace.The atmosphere heated on its surface is constantly rising up into the higher atmospheric regions, and thus creating a vacuum.To fill this vacuum, the Mediterranean winds, north, north-east, and east, are pulled down before they reach the coast of Spain, probably within fifty or a hundred miles of it.Thus diverted, they pass over the Algerine or Mount Atlas Switzerland; there deposit their moisture, making it in winter and spring a moist verdant region, to lose them- selves in the great sandy desert.That the boisterous winds which make the western Mediterranean so troubled a sea in winter, are thus diverted, is certain.The coast of eastern Spain is proverbially a calm sea.At Alicante there is a saying that their sea is " a sea for women and children."The steamers from Marseilles to Algiers pass between the Balearic Islands, about seventy miles from the mainland, and constantly in winter they have to contend with very bad weather.As constantly do they escape from it by steam- ing east to the Spanish coast.This is so much the case, that a detention on the Spanish coast going or coming from Algiers is a common, at some seasons a regular, incident of the voyage.Whatever the explanation, the fact is certain that from Malaga to Barcelona, on the east coast, there is very little rain, not more than forty days in the year, often not that-much less than on the Genoese Riviera, also an exceptionally dry region.The winter temperature is also so exceptionally mild that there can never be more than a few degrees of frost, as evidenced by the flourishing existence of orange and lemon trees, of subtropical palms, and of other plants which cannot stand more than a few degrees of winter frost.I only found, however, at Malaga, flourishing in the open air, the cool stove plants, heliotropes lantanus, pelargoniums, etc., which I and my neighbours grow in our gardens, unprotected, at Mentone and in the more sheltered parts of the Riviera.At Murcia and Valencia, these plants were grown in pots and placed under cover in winter.The conclusion which I legitimately draw is, that the winter temperature is as warm, indeed a shade warmer, at Malaga than at Mentone, but that, on the rest of the Spanish coast, the winter temperature is rather lower than at Mentone and the more shel- tered regions of the Riviera.The climate, soil, and vegetation are, however, the same in both regions.Medically speaking, therefore, they are suited to the same morbid states, to all who require a dry, sunny, bracing, stimulating, mild winter climate.Malaga would, thus, be one of our most valuable resorts were it not for its filthy, unhygienic state, which renders it unfit for the residence of a healthy, and still more of an unhealthy person.Although most sincere in the expression