tbuckley/cabot-search huggingface dataset:
Effect of Food on the Pharmacokinetic Behavior of the Potent Oral Taxane BMS-275183
Authors: Linda E. Bröker, Manual Valdivieso, Mary Jo Pilat, Pamela DeLuca, Xiaofei Zhou, Susan Parker, Giuseppe Giaccone, Patricia M. LoRusso
Journal: Clinical Cancer Research (2008)

Abstract Purpose: BMS-275183 is a potent oral paclitaxel analogue that previously showed promising activity. The goal of the present trial was to investigate whether food affects the pharmacokinetics of BMS-275183. Additionally, we evaluated its pharmacokinetic variability using flat-fixed dosing compared with dosing individualized by body surface area (BSA). Patients and Methods: The patients were treated with 200 mg of BMS-275183 under fasting condition (A), after a standard low-fat meal (B), or after a high-fat meal (C). The patients were randomized to one of six treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA). The fourth (D) and consecutive weekly doses were normalized by BSA and consisted of 200 mg/m2. Pharmacokinetic sampling was done up to 72 hours after the first four doses and analyzed with a validated liquid chromatography/mass spectrometry assay. Results: A total of 31 patients were treated. Pharmacokinetic data were available for 26 patients (A and C), 24 patients (B), and 21 patients (D). Compared with administration under fasted conditions, a decrease of 39% and 63% in the maximal observed drug concentration was observed when BMS-275183 was administered after a low-fat and a high-fat meal, respectively. There was no change in systemic exposure as measured by the area under the plasma concentration versus time curve extrapolated to infinity (AUCinf). No apparent relationship was observed between AUCinf and BSA for either the 200 mg or the 200 mg/m2 regimen. BMS-275183 was well tolerated with grade 3 and 4 toxicity in eight patients. One partial response was observed in a non–small cell lung cancer patient. Conclusions: Food intake does not affect the pharmacologic exposure to BMS-275183. BMS-275183 can be given orally by flat dosing instead of BSA-normalized dosing.
PATHOGENESIS OF EXPERIMENTAL SHOCK
Authors: Aaron Janoff, Gerald Weissmann, Benjamin W. Zweifach, Lewis Thomas
Journal: The Journal of Experimental Medicine (1962)

Fatal shock was produced in animals by drum trauma, temporary occlusion of the superior mesenteric artery, and bacterial endotoxin. Measurements were made of release of beta glucuronidase and cathepsins from the large granule fractions of livers, and of levels of circulating beta glucuronidase and acid phosphatase in these animals. Experiments were also carried out with animals rendered tolerant by previous exposure to sublethal amounts of trauma or by pretreatment with cortisone. The results show that release of beta glucuronidase and cathepsins from the large granule fraction of liver was increased during traumatic and endotoxin shock in the rat. Similarly, circulating levels of acid phosphatase and beta glucuronidase were increased during traumatic shock in rats and rabbits, and during endotoxin shock in rats. The data also indicate that tolerance to traumatic injury, induced by prior conditioning, prevented the increase in levels of circulating acid phosphatase normally observed after stress, and may have been associated with an increased stability of hepatic lysosomal particles. In addition, cortisone, which appears to "stabilize" hepatic lysosomes in vivo, also reduced the increase in plasma acid phosphatase brought about by endotoxin and trauma. From the foregoing observations, it is suggested that: (a) Disruption of lysosomes and release of their contained enzymes in free, active form may occur in liver and intestine of shocked animals. (b) The activation of lysosomal hydrolases within cells and their release into the circulation may play an important role in exacerbating tissue injury and accelerating the development of irreversibility during shock. (c) The increased stability of lysosomes of tolerant and of cortisone-treated animals may constitute an important component of the resistance of these animals to shock.
Diabetes-Related Complications, Glycemic Control, and Falls in Older Adults
Authors: Ann V. Schwartz, Eric Vittinghoff, Deborah E. Sellmeyer, Kenneth R. Feingold, Nathalie de Rekeneire, Elsa S. Strotmeyer, Ronald I. Shorr, Aaron I. Vinik, Michelle C. Odden, Seok Won Park, Kimberly A. Faulkner, Tamara B. Harris
Journal: Diabetes Care (2008)

Older adults with type 2 diabetes are more likely to fall, but little is known about risk factors for falls in this population. We determined whether diabetes-related complications or treatments are associated with risk of falls in older diabetic adults.In the Health, Aging, and Body Composition cohort of well-functioning older adults, participants reported falls in the previous year at annual visits. Odds ratios (ORs) for more frequent falls among 446 diabetic participants whose mean age was 73.6 years, with an average follow-up of 4.9 years, were estimated with continuation ratio models.In the first year, 23[corrected]% reported falling; 22, 26, 30[corrected], and 31[corrected]% fell in subsequent years. In adjusted models, reduced peroneal nerve response amplitude (OR 1.50 -95% CI 1.07-2.12], worst quartile versus others); higher cystatin-C, a marker of reduced renal function (1.38 [1.11-1.71], for 1 SD increase); poorer contrast sensitivity (1.41 [0.97-2.04], worst quartile versus others); and low A1C in insulin users (4.36 [1.32-14.46], A1C <or=6 vs. >8%) were associated with risk of falls. In those using oral hypoglycemic medications but not insulin, low A1C was not associated with risk of falls (1.29 [0.65-2.54], A1C <or=6 vs. >8%). Adjustment for physical performance explained some, but not all, of these associations.In older diabetic adults, reducing diabetes-related complications may prevent falls. Achieving lower A1C levels with oral hypoglycemic medications was not associated with more frequent falls, but, among those using insulin, A1C <or=6% increased risk of falls.
Evidence of local exercise-induced systemic oxidative stress in chronic obstructive pulmonary disease patients
Authors: A Couillard, C. Koechlin, J P P Cristol, Alain Varray, C. Prefaut, C. Préfaut
Journal: European Respiratory Journal (2002)

Chronic inactivity may not be the sole factor involved in the myopathy of chronic obstructive pulmonary disease (COPD) patients. One hypothesis is that exercise-induced oxidative stress that leads to muscle alterations may also be involved. This study investigated whether exercise localised to a peripheral muscle group would induce oxidative stress in COPD patients. Eleven COPD patients (FEV<sub>1</sub> 1.15±0.4 L (mean±sd)) and 12 healthy age-matched subjects with a similar low quantity of physical activity performed endurance exercise localised to a peripheral muscle group, the quadriceps of the dominant leg. The authors measured plasma levels of thiobarbituric reactive substances (TBARs) as an index of oxidative stress, the release in superoxide anion (O<sub>2</sub>·<sup>−</sup>) by stimulated phagocytes as an oxidant, and blood vitamin E as one antioxidant. Quadriceps endurance was significantly lower in the COPD patients compared with healthy subjects (136±16 s <i>versus</i> 385±69 s (mean±sem), respectively). A significant increase in TBARs 6 h after quadriceps exercise was only found in the COPD patients. In addition, significantly higher O<sub>2</sub>·<sup>−</sup> release and lower blood vitamin E levels were found in COPD patients than in controls at rest. This blood vitamin E level was significantly correlated with the resting level of plasma TBARs in the COPD patients. This study mainly showed that quadriceps exercise induced systemic oxidative stress in chronic obstructive pulmonary disease patients and that vitamin E levels were decreased in these patients at rest. The exact relevance of these findings to chronic obstructive pulmonary disease myopathy needs to be elucidated.
Exposure to Traffic and Left Ventricular Mass and Function
Authors: Victor C. Van Hee, Sara D. Adar, Adam A. Szpiro, R. Graham Barr, David A. Bluemke, Ana V. Diez Roux, Edward A. Gill, Lianne Sheppard, Joel D. Kaufman
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: Ambient air pollution has been associated with heart failure morbidity and mortality. The mechanisms responsible for these associations are unknown but may include the effects of traffic-related pollutants on vascular or autonomic function.Objectives: We assessed the cross-sectional relation between long-term air pollution, traffic exposures, and important end-organ measures of alterations in cardiac function—left ventricular mass index (LVMI) and ejection fraction—in the Multi-Ethnic Study of Atherosclerosis, a multicenter study of adults without previous clinical cardiovascular disease.Methods: A total of 3,827 eligible participants (aged 45–84 yr) underwent cardiac magnetic resonance imaging between 2000 and 2002. We estimated air pollution exposures using residential proximity to major roadways and interpolated concentrations of fine particulate matter (less than 2.5 microns in diameter). We examined adjusted associations between these exposures and left ventricular mass and function.Measurements and Main Results: Relative to participants living more than 150 m from a major roadway, participants living within 50 m of a major roadway showed an adjusted 1.4 g/m2 (95% CI, 0.3–2.5) higher LVMI, a difference in mass corresponding to a 5.6 mm Hg greater systolic blood pressure. Ejection fraction was not associated with proximity to major roadways. Limited variability in estimates of fine particulate matter was observed within cities, and no associations with particulate matter were found for either outcome after adjustment for center.Conclusions: Living in close proximity to major roadways is associated with higher LVMI, suggesting chronic vascular end-organ damage from a traffic-related environmental exposure. Air pollutants or another component of roadway proximity, such as noise, could be responsible.
Relation of Biventricular Function Quantified by Stress Echocardiography to Cardiopulmonary Exercise Capacity in Adults With Mustard (Atrial Switch) Procedure for Transposition of the Great Arteries
Authors: Wei Li, Tim S. Hornung, Darrel P. Francis, Christine O’Sullivan, Alison Duncan, Michael Gatzoulis, Michael Henein
Journal: Circulation (2004)

Mustard repair for transposition of the great arteries (TGA) is frequently associated with impaired systemic (right) ventricular function and sometimes exercise intolerance. We hypothesized that a simple quantitative measurement of ventricular function, during rest and pharmacological stress, could identify abnormalities and predict objective exercise capacity.We quantified the performance of systemic and pulmonary (left) ventricles by using echocardiography, at rest and during dobutamine stress, in 27 adults who had undergone Mustard repair for TGA. Systolic and diastolic function of the systemic ventricle were markedly disturbed with respect to pulmonary ventricular function. We also measured exercise capacity by cardiopulmonary exercise testing for peak oxygen uptake. Exercise capacity was significantly predicted by systemic ventricular long-axis excursion both at rest (r=0.66, P<0.001) and at peak dobutamine stress (r=0.53, P=0.006) but not by pulmonary ventricular long-axis excursion at rest (r=0.04) or on stress (r=0.11). Exercise capacity was also predicted by the septal long-axis excursion at rest (r=0.61, P=0.001) but not pulmonary ventricular free wall excursion (P>0.05) or fractional shortening (P>0.05). Peak aortic velocity at maximum dobutamine stress correlated with exercise capacity (r=0.46, P=0.029) but not at rest (r=0.36). Multivariate analysis revealed systemic ventricular long-axis excursion to be the sole significant independent predictor of exercise capacity.Systemic ventricular function is depressed in most patients with Mustard repair. Quantitative echocardiographic evaluation shows systemic ventricular function to be a key determinant of exercise capacity.
Randomised crossover study of the Flutter device and the active cycle of breathing technique in non-cystic fibrosis bronchiectasis
Authors: C S Thompson
Journal: Thorax (2002)

AUTHOR:e-mail address please Background: Airway clearance techniques are an important part of the routine care of patients with bronchiectasis. The use of the Flutter, a hand held pipe-like device causing oscillating positive expiratory pressure within the airways, has been proposed as an alternative to more conventional airway clearance techniques. Methods: A randomised crossover study was performed in 17 stable patients with non-cystic fibrosis bronchiectasis at home, in which 4 weeks of daily active cycle of breathing technique (ACBT) were compared with 4 weeks of daily physiotherapy with the Flutter device. Results: No significant differences between the two techniques were found. Median weekly sputum weights were similar with a median treatment difference of 7.64 g (p=0.77) and there was no evidence of treatment order or order interaction effects (p=0.70). Health status (Chronic Respiratory Disease Questionnaire) and ventilatory function did not change significantly during either treatment period. There was no significant change in peak expiratory flow rate or in breathlessness (Borg score) after individual physiotherapy sessions with either technique. A questionnaire indicated subjectively that patients preferred the Flutter (11/17) to ACBT for routine use. Conclusions: Daily use of the Flutter device in the home is as effective as ACBT in patients with non-cystic fibrosis bronchiectasis and has a high level of patient acceptability.
Examination of Current Dietary Recommendations for Individuals with Diabetes Mellitus
Authors: R Arky, J Wylie-Rosett, B El-Beheri
Journal: Diabetes Care (1982)

The dietary recommendations recently published by the American, British, and Canadian diabetes associations reflect unanimity among the organizations as regards decreasing the fat content and increasing the carbohydrate with fiber content in diabetic meal plans. Each organization suggests that moderation in sodium intake is appropriate. Furthermore there is agreement that dietary strategies for the two major clinical classes of diabetes differ.
Emerging Therapies Mimicking the Effects of Amylin and Glucagon-Like Peptide 1
Authors: Matthew C. Riddle, Daniel J. Drucker
Journal: Diabetes Care (2006)

Current therapies for type 2 diabetes are frequently associated with inadequate control of postprandial hyperglycemia, weight gain, and, in the case of oral agents, loss of efficacy over time. A better understanding of physiological responses to meals is leading to the development of new agents whose therapeutic action is based on the enhancement of gastrointestinal hormone action. These therapies are associated with slowing of gastric emptying, stimulation of insulin and inhibition of glucagon secretion, improved control of postprandial hyperglycemia, and control of body weight. This review summarizes several limitations in the treatment of type 2 diabetes and describes the mechanisms of action and clinical data obtained with amylin and glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase IV (DPP-IV) inhibitors for the treatment of diabetes.

Despite considerable effort by patients and physicians, the results of treating type 2 diabetes are often disappointing. This review examines the limitations of current antihyperglycemic therapies and assesses the potential of the emerging class of agents that mimic or enhance the actions of amylin and GLP-1, which are both gastrointestinal peptide hormones that in concert with insulin and glucagon regulate fuel homeostasis and eating behavior (1–4). Several agents from this class have been recently approved for clinical use or are in the advanced stages of development. Their mechanisms of action and therapeutic effects, as described in peer-reviewed publications, will be discussed.

The evidence-based target for glycemic control is an HbA1c (A1C) ≤7% (5), although several groups have proposed an A1C target of 6.5% based on epidemiological analyses (6,7). In clinical trials, patients have achieved A1C values near 7% using basal-bolus insulin treatment in type 1 (8) or type 2 (9) diabetes or combinations of oral treatments and insulin for type 2 diabetes (10). However, routinely maintaining glycemic control at …
Nonoperative Management of Biliary Obstruction
Authors: S L Dawson, P R Mueller
Journal: Annual Review of Medicine (1985)

CD40 is a cell-surface member of the TNF (tumor necrosis factor) receptor superfamily. Upon activation, CD40 can license dendritic cells to promote antitumor T cell activation and re-educate macrophages to destroy tumor stroma. Numerous agonist CD40 ...Read More
HUMAN INTESTINAL DISACCHARIDASES AND HEREDITARY DISACCHARIDE INTOLERANCE. THE HYDROLYSIS OF SUCROSE, ISOMALTOSE, PALATINOSE (ISOMALTULOSE), AND A 1,6-α-OLIGOSACCHARIDE (ISOMALTO-OLIGOSACCHARIDE) PREPARATION*
Authors: Arne Dahlqvist, Salvatore Auricchio, Giorgio Semenza, Andreas Prader
Journal: Journal of Clinical Investigation (1963)
Idiopathic pulmonary fibrosis: guidelines for diagnosis and clinical management have advanced from consensus-based in 2000 to evidence-based in 2011
Authors: G. Raghu
Journal: European Respiratory Journal (2011)

<h3>ABSTRACT</h3> Fumarate hydratase (FH) is a remarkable catalyst that decreases the free energy of the catalyzed reaction by 30 kcal mol<sup>−1</sup>, much larger than most exceptional enzymes with extraordinary catalytic rates. Two classes of FH are observed in nature: class-I and class-II, that have different folds, yet catalyze the same reversible hydration/dehydration reaction of the dicarboxylic acids fumarate/malate, with equal efficiencies. Using class-I FH from the hyperthermophilic archaeon <i>Methanocaldococcus jannaschii</i> (Mj) as a model along with comparative analysis with the only other available class-I FH structure from <i>Leishmania major (</i>Lm), we provide insights into the molecular mechanism of catalysis in this class of enzymes. The structure of MjFH apo-protein has been determined, revealing that large inter-subunit rearrangements occur across apo- and the holo-protein forms, with a largely preorganized active site for substrate binding. Site-directed mutagenesis of active site residues, kinetic analysis and computational studies including DFT and natural population analysis, together show that residues interacting with the carboxylate group of the substrate play a pivotal role in catalysis. Our study establishes that an electrostatic network at the active site of class-I FH, polarizes the substrate fumarate through interactions with its carboxylate groups, thereby permitting an easier addition of a water molecule across the olefinic bond. We propose a mechanism of catalysis in FH that occurs through transition state stabilization involving the distortion of the electronic structure of the substrate olefinic bond mediated by the charge polarization of the bound substrate at the enzyme active site.
'Senile' osteoporosis reconsidered
Authors: N. M. Resnick
Journal: JAMA (1989)

Osteoporosis is a devastating, morbid, and costly condition whose ravages are felt most profoundly by women over age 70 years. Yet most research on its prevention and treatment has focused on perimenopausal women, although there are significant differences between perimenopausal and older women in factors related to bone mineral metabolism, rates of bone loss, the structural integrity of remaining bone, risk factors for fractures, and the types of fractures sustained. Currently recommended therapies, which slow bone loss in perimenopausal women, may be of less benefit for older women whose loss of bone has already slowed or ceased and whose remaining bone may be of inadequate quantity and quality to prevent fracture. Thus, the application of currently available modalities is unlikely to mitigate significantly the consequences of osteoporosis in this population. Further research is urgently needed, and some directions for future investigation are suggested. (<i>JAMA</i>1989;261:1025-1029)
Parsing Aortic Aneurysms
Authors: Mark W. Majesky, Xiu Rong Dong, Virginia J. Hoglund
Journal: Circulation Research (2011)

A ortic aneurysms are progressive enlargements of the aorta that can lead to life-threatening degenerative changes in the structure of the artery wall including medial dissections and wall rupture.The abdominal aorta is the most common site of aneurysm formation, yet the ascending thoracic aorta can also exhibit aneurysmal expansion with potentially dire outcomes.Ascending aortic aneurysms are frequently associated with connective tissue diseases such as Marfan's syndrome, a disorder of the extracellular matrix protein fibrillin-1. 1Mouse models carrying hypomorphic mutations in fibrillin-1 also develop aortic dilations associated with macrophage infiltration, elastin fragmentation, and enhanced transforming growth factor (TGF)␤ signaling in the artery wall. 2 Aortic aneurysms in fibrillin-1 hypomorphic mice can be prevented by treatment with either anti-TGF␤ neutralizing antibodies or with the angiotensin II (Ang II) type 1 (AT 1 ) receptor antagonist losartan. 3Indeed, chronic infusion of Ang II into apoE Ϫ/Ϫ mice is an effective experimental model to induce aortic aneurysm formation and to study the molecular pathways underlying its pathogenesis. 4
Dietary and Pharmacologic Management to Prevent Recurrent Nephrolithiasis in Adults: A Clinical Practice Guideline From the American College of Physicians
Authors: Amir Qaseem, Paul Dallas, Mary Ann Forciea, Melissa Starkey, Thomas D. Denberg
Journal: Annals of Internal Medicine (2014)

The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the comparative effectiveness and safety of preventive dietary and pharmacologic management of recurrent nephrolithiasis in adults.This guideline is based on published literature on this topic that was identified using MEDLINE, the Cochrane Database of Systematic Reviews (through March 2014), Google Scholar, ClinicalTrials.gov, and Web of Science. Searches were limited to English-language publications. The clinical outcomes evaluated for this guideline include symptomatic stone recurrence, pain, urinary tract obstruction with acute renal impairment, infection, procedure-related illness, emergency department visits, hospitalizations, quality of life, and end-stage renal disease. This guideline grades the quality of evidence and strength of recommendations using ACP's clinical practice guidelines grading system. The target audience for this guideline is all clinicians, and the target patient population is all adults with recurrent nephrolithiasis (≥1 prior kidney stone episode).ACP recommends management with increased fluid intake spread throughout the day to achieve at least 2 L of urine per day to prevent recurrent nephrolithiasis. (Grade: weak recommendation, low-quality evidence).ACP recommends pharmacologic monotherapy with a thiazide diuretic, citrate, or allopurinol to prevent recurrent nephrolithiasis in patients with active disease in which increased fluid intake fails to reduce the formation of stones. (Grade: weak recommendation, moderate-quality evidence).