tbuckley/cabot-search huggingface dataset:
Weight change and change in tibial cartilage volume and symptoms in obese adults
Authors: Andrew J Teichtahl, Anita E Wluka, Stephanie K Tanamas, Yuanyuan Wang, Boyd J Strauss, Joseph Proietto, John B Dixon, Graeme Jones, Andrew Forbes, Flavia M Cicuttini
Journal: Annals of the Rheumatic Diseases (2014)

Introduction There is a paucity of data examining the effects of weight change on knee joint structures and symptoms. This study examined the effect of weight change on change in knee cartilage volume and symptoms in an obese cohort. Methods 112 obese subjects (Body Mass Index ≥30 kg/m 2 ) were recruited from various community sources to examine the effect of obesity on musculoskeletal health. Tibial cartilage volume, determined by MRI, and knee symptoms, determined by the Western Ontario and McMaster Osteoarthritis Index (WOMAC) were collected at baseline and an average of 2.3 years later. Results Percentage weight change was associated with change in medial tibial cartilage volume (β −1.2 mm 3 , 95% CI −2.3 to −0.1 mm 3 , p=0.03) that was consistent throughout the spectrum of weight loss through to mild weight gain. Percentage weight change was not associated with change in the lateral tibial (p=0.93) or patella (p=0.32) cartilage volumes. Percentage weight change was associated with change in all WOMAC subscales (all p≤0.01): pain (β −1.8 mm, 95% CI −3.2 to −0.4 mm), stiffness (β −1.6 mm, 95% CI −2.5 to −0.7 mm) and function (β −6.9 mm, 95% CI −11.6 to −2.1 mm). Conclusions The linearity of effect implies that weight loss is associated with reduced medial cartilage volume loss and improved knee symptoms, while weight gain is associated with increased medial cartilage volume loss and worse knee symptoms. These results suggest that in obese people, small amounts of weight change may have the potential for a disease modifying effect on both knee joint structure and symptoms. While weight loss is an important primary management strategy in obese individuals, avoidance of further weight gain should also be a clinical goal.
Targeted Disruption of <i>Smad4</i> in Cardiomyocytes Results in Cardiac Hypertrophy and Heart Failure
Authors: Jian Wang, Ning Xu, Xinheng Feng, Ning Hou, JiShuai Zhang, Xuan Cheng, Yeguang Chen, Youyi Zhang, Xiao Yang
Journal: Circulation Research (2005)

Transforming growth factor-βs (TGF-βs) are pleiotropic cytokines involved in many physiological and pathological processes, including heart development and heart disease. Smad4 is the central intracellular mediator of TGF-β signaling. To investigate the function of Smad4 in heart development further, we generated a strain of cardiomyocyte-specific Smad4 knockout mice using the Cre– lox P system. Unexpectedly, the deletion of Smad4 in cardiomyocytes resulted in cardiac hypertrophy characterized by an increase in the size of cardiac myocytes, age-associated fibrosis, and reexpression of certain fetal genes. Approximately 70% of the Smad4 mutant mice died spontaneously between 5 and 12 months of age. Echocardiography and an invasive hemodynamic study of the left ventricle revealed markedly decreased cardiac contractility in Smad4 mutant mice compared with littermate controls. Moreover, phosphorylated extracellular signal–regulated kinase (ERK) 1/2 and mitogen-activated protein kinase–ERK (MEK) 1 were increased in the Smad4 mutants, suggesting that an upregulation of MEK1–ERK1/2 signaling as a consequence of deletion of Smad4 underlies the impaired cardiac function. These results reveal an important function of Smad4 in cardiac remodeling and suggest that an altered cellular response to TGF-β could be a mechanism by which cardiac myocytes undergo hypertrophy.
The ELF panel: a new crystal ball in hepatology?
Authors: M. Pinzani
Journal: Gut (2010)

The development of non-invasive methods, particularly serum markers and transient elastography, for the evaluation of fibrosis progression and their validation for use in clinical practice certainly represents a relevant advancement in hepatology. Although non-invasive methods were designed to predict the fibrotic stage of chronic liver diseases (CLDs) and, ultimately, replace liver biopsy in clinical practice, there is now a large consensus on the use of these methods as cross-sectional discriminators of three major stages: absence or very limited fibrosis, advanced fibrosis/cirrhosis and the stage in between these two extremes, often referred to as the ‘gray area’. Overall, the application of these methods, alone or in combination, reduces the number of liver biopsies by at least 50%.1

Serum markers for the prediction of the stage of liver fibrosis are grouped in two categories: ( a ) ‘direct markers’ reflecting the shedding into the systemic circulation of peptides involved in the accumulation of fibrillar extracellular matrix (fibrogenesis); involved in its degradation (fibrolysis); or involved, more generally, in tissue inflammation, and ( b ) ‘indirect markers’ a mixture of common biochemical abnormalities found in CLDs and clinical parameters. The predictive ability of several possible combinations of these markers is enhanced by their inclusion in a mathematic algorithm. At present, most of the information on serum markers is associated with their diagnostic accuracy for a given fibrotic stage. As shown in figure 1, each individual marker included in the algorithms proposed so far coincides with a specific phase of disease progression. Accordingly, what …
Pathogen–Host Interactions in<i>Pseudomonas aeruginosa</i>Pneumonia
Authors: Ruxana T. Sadikot, Timothy S. Blackwell, John W. Christman, Alice S. Prince
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Pseudomonas aeruginosa is an important pathogen causing a wide range of acute and chronic infections. P. aeruginosa rarely causes infection in the normal host, but is an efficient opportunistic pathogen causing serious infections in patients who are mechanically ventilated, individuals who are immunocompromised, and patients with malignancies or HIV infection. Among these risk groups, the most vulnerable hosts are neutropenic and patients who are mechanically ventilated. In addition, P. aeruginosa is the most prevalent chronic infection contributing to the pathogenesis of cystic fibrosis. Because of the ubiquitous nature of P. aeruginosa and its ability to develop resistance to antibiotics, it continues to be problematic from a treatment perspective. The pathogenicity of P. aeruginosa is largely caused by multiple bacterial virulence factors and genetic flexibility enabling it to survive in varied environments. Lung injury associated with P. aeruginosa infection results from both the direct destructive effects of the organism on the lung parenchyma and exuberant host immune responses. This article focuses on the major bacterial virulence factors and important aspects of the host immunity that are involved in the pathogenesis of serious P. aeruginosa infection. In addition to antibiotic therapy, strategies directed toward enhancing host defense and/or limiting excessive inflammation could be important to improve outcome in P. aeruginosa lung infections.
Clinical Activity of mTOR Inhibition With Sirolimus in Malignant Perivascular Epithelioid Cell Tumors: Targeting the Pathogenic Activation of mTORC1 in Tumors
Authors: Andrew J. Wagner, Izabela Malinowska-Kolodziej, Jeffrey A. Morgan, Wei Qin, Christopher D.M. Fletcher, Natalie Vena, Azra H. Ligon, Cristina R. Antonescu, Nikhil H. Ramaiya, George D. Demetri, David J. Kwiatkowski, Robert G. Maki
Journal: Journal of Clinical Oncology (2010)

PURPOSE Perivascular epithelioid cell tumors (PEComas) represent a family of mesenchymal neoplasms, mechanistically linked through activation of the mTOR signaling pathway. There is no known effective therapy for PEComa, and the molecular pathophysiology of aberrant mTOR signaling provided us with a scientific rationale to target this pathway therapeutically. On this mechanistic basis, we treated three consecutive patients with metastatic PEComa with an oral mTOR inhibitor, sirolimus. PATIENTS AND METHODS Patients with advanced PEComa were treated with sirolimus and consented to retrospective collection of data from their medical records and analysis of archival tumor specimens. Tumor response was determined by computed tomography scans obtained at the clinical discretion of the treating physicians. Tumors were assessed for immunohistochemical evidence of mTORC1 activation and genetic evidence of alterations in TSC1 and TSC2. Results Radiographic responses to sirolimus were observed in all patients. PEComas demonstrated loss of TSC2 protein expression and evidence of baseline mTORC1 activation. Homozygous loss of TSC1 was identified in one PEComa. CONCLUSION Inhibition of mTORC1, pathologically activated by loss of the TSC1/TSC2 tumor suppressor complex, is a rational mechanistic target for therapy in PEComas. The clinical activity of sirolimus in PEComa additionally strengthens the pathobiologic similarities linking PEComas to other neoplasms related to the tuberous sclerosis complex.
Crystal Retention Capacity of Cells in the Human Nephron
Authors: Anja Verhulst, Marino Asselman, Veerle P. Persy, Marieke S.J. Schepers, Mark F. Helbert, Carl F. Verkoelen, Marc E. De Broe
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Nephrolithiasis requires formation of crystals followed by their retention and accumulation in the kidney. Crystal retention can be caused by the association of crystals with the epithelial cells lining the renal tubules. The present study investigated the interaction between calcium oxalate monohydrate (COM) crystals and primary cultures of human proximal (PTC) and distal tubular/collecting duct cells (DTC). Both PTC and DTC were susceptible to crystal binding during the first days post-seeding (4.9 ± 0.8 μg COM/cm2), but DTC lost this affinity when the cultures developed into confluent monolayers with functional tight junctions (0.05 ± 0.02 μg COM/cm2). Confocal microscopy demonstrated the expression of the transmembrane receptor protein CD44 and its ligands osteopontin (OPN) and hyaluronic acid (HA) at the apical membrane of proliferating tubular cells; at confluence, CD44 was expressed at the basolateral membrane and OPN and HA were no longer detectable. In addition, a particle exclusion technique revealed that proliferating cells were surrounded by HA-rich pericellular matrices or "cell coats" extending several microns from the cell surface. Disintegration of these coats with hyaluronidase significantly decreased the cell surface affinity for crystals. Furthermore, CD44, OPN, and HA were also expressed in vivo at the luminal side of tubular cells in damaged kidneys. These results suggest (1) that the intact distal tubular epithelium of the human kidney does not bind crystals, and (2) that crystal retention in the human kidney may depend on the expression of CD44-, OPN-, and-HA rich cell coats by damaged distal tubular epithelium. E-mail: [email protected]
DUAL RADIOTHERAPY IN MALIGNANT DISEASE
Authors: S. G. Scott
Journal: BMJ (1921)

f 77The arteries of the ear in such a cat contract on stimulation of the nerves or on injecting adrenin, but not the dilated veins and-capillaries.*Stock.The work of Dale and his co-workers indicates that shock produced by histamine.has its origin in primary failure of the peripheral circulation.All the capillaries open and venules dilate at once, and there is increased passage of fluid from the blood into the tissues, and so the circulation fails while the heart is beating efficiently.While Dale injected histamine, I watched the venules dilate in the mesentery and the flow slow down and almost become arrested in these and in the capillaries, but have not so far been able to see the opening up of closed capillaries, probably because the capillaries are already dilated by exposure.Histamine is formed by decarboxylization of the amino-acid histidine, which is derived from proteins, and it is conceivable that such substances are produced in trauma.Herein we have an explanation of shock differing from that of acid causation put forward byAlmroth Wright.FBe it noted, histamine acts in the cat anaesthetized by ether,, but not in the normal cat, or one anaesthetized by nitrous oxi4d and oxygen.The last is by far the best anaesthetic.for preventing, shock, and as P. Bert proved forty years ago, and ,Dale and I have confirmed recently, may be given with ease Ind safety and efficiency of depth in a pressure chamber at + 7 lb.pressure.An operating chamber can easily be constructed, so that the patient, surgeon, and anaesthetist are all within the chamber at slightly increased atmospheric pressure.The effect of inhaling gas and oxygen, given in the usual way from a bag in such a chamber, is an intrease of partial pressure, or concentration, of both in the blood, and deep anaesthesia with no want of oxygen.Effects of Oxygen Inhalation.
Statin Therapy, Cardiovascular Events, and Total Mortality in the Heart and Estrogen/Progestin Replacement Study (HERS)
Authors: David M. Herrington, Eric Vittinghoff, Feng Lin, Josephine Fong, Fran Harris, Donald Hunninghake, Vera Bittner, Helmut G. Schrott, Roger S. Blumenthal, Robert Levy
Journal: Circulation (2002)

Background — Although effects of statins on cardiovascular outcomes are well established in men, fewer data exist for women. Furthermore, the effects of statins plus hormone replacement therapy (HRT) on cardiovascular outcomes are uncertain. Methods and Results — We examined statin use, cardiovascular events, and total mortality in the Heart and Estrogen/progestin Replacement Study (HERS), a randomized clinical trial of estrogen plus progestin versus placebo in postmenopausal women with heart disease (n=2763). A nonrandomized comparison of statin users and nonusers revealed lower rates of the primary outcome, nonfatal myocardial infarction or coronary heart disease death (relative hazard [RH]=0.79, 95% confidence intervals [CI] 0.63 to 0.99, P =0.04), and total mortality (RH=0.67, 95% CI 0.51 to 0.87, P =0.003). Rates of venous thromboembolic events were also lower among statin users (RH=0.45, 95% CI 0.23 to 0.88, P =0.02). HRT resulted in a significant increase in early risk for primary events in women who did not use statins (RH=1.75, 95% CI 1.02 to 3.03, P =0.04) but not in statin users (RH=1.34, 95% CI 0.63 to 2.86, P =0.45). Adjustment for postrandomization statin use showed no effect of HRT on risk for the primary outcome (RH=0.96, 95% CI 0.77 to 1.29; P =0.72). Conclusions — In HERS, statin use was associated with lower rates of cardiovascular events, venous thromboembolic events, and total mortality. These data provide strong support for statin use in eligible women with coronary disease.
Medical therapy for COPD: lessons from the real world
Authors: P.M.A. Calverley
Journal: European Respiratory Journal (2002)

Few people would deny that chronic obstructive pulmonary (COPD) is a major cause of mortality globally and is likely to increase in importance 1, 2. Although the very varied quality of community prevalence data have to be relied upon to draw these conclusions, the use of randomised controlled trials to evaluate the efficacy of treatment for COPD is more reliable. This approach has now yielded a large body of scientific data, which confirm that long-acting β-agonists (LABA) improve lung function and health status in stable COPD 3–5 whilst also increasing the time between exacerbations 4, 6. Likewise, large-scale 3-yr randomised studies have failed to find any effect of inhaled corticosteroids on the rate of decline of the forced expiratory volume in one second (FEV1), but in more severe patients, these drugs reduce the number of exacerbations 7–10. Two large 1-yr studies have shown that combining these treatments reduces further symptomatic improvements and larger pulmonary function changes than either alone. These studies have thus far only been presented at scientific meetings but have been submitted for publication.

Data based on randomised controlled trials have many advantages but there are some disadvantages to be considered. Patients who enter these studies, especially the larger ones (1–3 yrs), have to be motivated, compliant with treatment and clinically stable in the weeks or …
Reduction of Cardiovascular Risk by Regression of Electrocardiographic Markers of Left Ventricular Hypertrophy by the Angiotensin-Converting Enzyme Inhibitor Ramipril
Authors: James Mathew, Peter Sleight, Eva Lonn, David Johnstone, Janice Pogue, Qilong Yi, Jackie Bosch, Bruce Sussex, Jeffrey Probstfield, Salim Yusuf
Journal: Circulation (2001)

Background Electrocardiographic markers of left ventricular hypertrophy (LVH) predict poor prognosis. We determined whether the ACE inhibitor ramipril prevents the development and causes regression of ECG-LVH and whether these changes are associated with improved prognosis independent of blood pressure reduction. Methods and Results In the Heart Outcomes Prevention Evaluation (HOPE) study, patients at high risk were randomly assigned to ramipril or placebo and followed for 4.5years. ECGs were recorded at baseline and at study end. We compared prevention/regression and development/persistence of ECG-LVH in the two groups and related these changes to outcomes. At baseline, 676 patients had LVH (321 in the ramipril group and 355 in the placebo group) and 7605 patients did not have LVH (3814 in the ramipril group and 3791 in the placebo group). By study end, 336 patients in the ramipril group (8.1%) compared with 406 in the placebo group (9.8%) had development/persistence of LVH; in contrast, 3799 patients in the ramipril group (91.9%) compared with 3740 in the placebo group (90.2%) had regression/prevention of LVH ( P =0.007). The effect of ramipril on LVH was independent of blood pressure changes. Patients who had regression/prevention of LVH had a lower risk of the predefined primary outcome (cardiovascular death, myocardial infarction, or stroke) compared with those who had development/persistence of LVH (12.3% versus 15.8%, P =0.006) and of congestive heart failure (9.3% versus 15.4%, P &lt;0.0001). Conclusions The ACE inhibitor ramipril decreases the development and causes regression of ECG-LVH independent of blood pressure reduction, and these changes are associated with reduced risk of death, myocardial infarction, stroke, and congestive heart failure.
Characterisation of gastrin receptors on a rat pancreatic acinar cell line (AR42J). A possible model for studying gastrin mediated cell growth and proliferation.
Authors: J L Scemama, D Fourmy, A Zahidi, L Pradayrol, C Susini, A Ribet
Journal: Gut (1987)

Trophic changes of the exocrine pancreas after in vivo gastrin (G)/CCK treatment are well documented but up to now the study of the mechanisms involved is restricted by the lack of a suitable in vitro model. Nevertheless the in vivo trophic effect induced by gastrin/CCK peptides has been associated with an increase of ornithine decarboxylase (ODC) activity. In the present work, using the AR42J cell line in which CCK receptors and stimulation of amylase release by CCK peptides has already been demonstrated, we investigated the presence of gastrin binding sites and the possible modulation of proliferation by an inhibitor of ODC activity. 125I-BH-G17ns binding is saturable, reversible and specific. Potencies of the different analogues tested are G17ns greater than CCK8 greater than CCK8ns greater than or equal to G6s greater than G/CCK4. Furthermore dBt cGMP, a non-peptide antagonist for CCK receptors, does not compete for gastrin binding. This indicates the existence of a subclass of gastrin binding sites. Difluoromethyl ornithine (DFMO) (1 mM), an irreversible inhibitor of ODC, inhibits cell growth from day 3 up to day 7. This growth inhibition is dose dependent and closely related to an intracellular polyamine modulation. Putrescine and spermidine levels fell under detectable values while spermine levels increased. All these data suggest that this cell line could be a useful in vitro model to study the mechanisms of gastrin induced growth control.
Obesity and the risk of psoriatic arthritis: a population-based study
Authors: Thorvardur Jon Love, Yanyan Zhu, Yuqing Zhang, Lindsay Wall-Burns, Alexis Ogdie, Joel M Gelfand, Hyon K Choi
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Obesity is associated with an increased risk of psoriasis; however, its potential impact on the risk of psoriatic arthritis (PsA) remains unclear. <h3>Objectives</h3> To evaluate the association between body mass index (BMI) and the risk of PsA among patients with psoriasis from the general population. <h3>Methods</h3> The authors conducted a cohort study using data from The Health Improvement Network, an electronic medical records database representative of the UK general population, collected between 1995 and 2010. The exposure of interest was the first BMI measured after psoriasis diagnosis and endpoints were incident cases of physician-diagnosed PsA. The authors estimated the RR of PsA after adjusting for age, sex, and histories of trauma, smoking and alcohol consumption. <h3>Results</h3> Among 75 395 individuals with psoriasis (43% male, mean follow-up of 5 years, and mean age of 52 years), 976 developed PsA (incidence rate, 26.5 per 10 000 person-years). The PsA incidence rates increased with increasing BMI. Compared with psoriasis patients with BMI &lt;25 kg/m<sup>2</sup>, the RRs for developing PsA were 1.09 (0.93–1.28) for BMIs from 25.0 to 29.9, 1.22 (1.02–1.47) for BMIs from 30.0 to 34.9 and 1.48 (1.20–1.81) for BMIs ≥35.0. In our secondary analysis among all individuals, regardless of psoriasis (∼2 million), the corresponding multivariate RRs tended to be stronger (1.0, 1.17, 1.57, 1.96; p for trend &lt;0.001). <h3>Conclusions</h3> This general population study suggests that obesity is associated with an increased risk of incident PsA and supports the importance of weight reduction among psoriasis patients who often suffer from the metabolic syndrome and obesity.
Emotion-Focused Psychotherapy for Patients With Panic Disorder
Authors: M. Katherine Shear, Patricia Houck, Catherine Greeno, Sophia Masters
Journal: American Journal of Psychiatry (2001)

Recent studies have suggested that most patients treated for panic disorder receive forms of psychotherapy other than cognitive behavior therapy, even though there is little information about the efficacy of such treatments or how they compare to proven active treatments. The authors compared one of these other forms, emotion-focused psychotherapy (given to 30 patients with panic disorder), to results obtained with recommended standard treatment (either cognitive behavior therapy [N=36] or imipramine [N=22]). The authors also compared emotion-focused psychotherapy to results obtained in subjects given pill placebo (N=24).Subjects met DSM-IV criteria for panic disorder with no more than mild agoraphobia. Treatment consisted of approximately 3 months of weekly visits followed by 6 monthly maintenance visits. Assessments were conducted after each treatment phase and at a follow-up visit after 6 months of no treatment.Emotion-focused psychotherapy was less effective for symptoms of panic disorder than treatment with either cognitive behavior therapy or imipramine; results obtained with emotion-focused psychotherapy after the acute and maintenance phases were similar to those seen with placebo. Treatment expectations were not different among the different groups. Patients receiving emotion-focused psychotherapy had the highest completion rate.The results suggest that emotion-focused psychotherapy (a supportive form of psychotherapy) has low efficacy for the treatment of panic disorder. However, emotion-focused psychotherapy may be superior to medical management in helping patients stay in treatment.