tbuckley/cabot-search huggingface dataset:
Effectiveness of home exercise on pain and disability from osteoarthritis of the knee: a randomised controlled trial
Authors: S. C O'Reilly, K. R Muir, M. Doherty
Journal: Annals of the Rheumatic Diseases (1999)

To assess the effect of a home based exercise programme, designed to improve quadriceps strength, on knee pain and disability.191 men and women with knee pain aged 40-80 were recruited from the community and randomised to exercise (n = 113) or no intervention (n = 78). The exercise group performed strengthening exercises daily for six months. The primary outcome measure was change in knee pain (Western Ontario McMaster Osteoarthritis index (WOMAC)). Secondary measures included visual analogue scales (VAS) for pain on stairs and walking and WOMAC physical function scores.WOMAC pain score reduced by 22.5% in the exercise group and by 6.2% in the control group (between group difference p < 0.05, unpaired t test). VAS scores for pain also reduced in the exercise group compared with the control group (p < 0.05). Physical function scores reduced by 17.4% in the exercise group and were unchanged in controls (p < 0.05).A simple programme of home quadriceps exercises can significantly improve self reported knee pain and function.
Relation of Gemfibrozil Treatment and Lipid Levels With Major Coronary Events
Authors: Sander J. Robins, Dorothea Collins, Janet T. Wittes, Vasilios Papademetriou, Prakash C. Deedwania, Ernst J. Schaefer, Judith R. McNamara, Moti L. Kashyap, Jerome M. Hershman, Laura F. Wexler, Hanna Bloomfield Rubins, None for the VA-HIT Study Group
Journal: JAMA (2001)

ContextA low plasma level of high-density lipoprotein cholesterol (HDL-C) is a major risk factor for coronary heart disease (CHD). A secondary prevention study, the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), demonstrated that CHD events were significantly reduced during a median follow-up of 5.1 years by treating patients with the fibric acid derivative gemfibrozil when the predominant lipid abnormality was low HDL-C.ObjectiveTo determine if the reduction in major CHD events with gemfibrozil in VA-HIT could be attributed to changes in major plasma lipid levels.DesignMulticenter, randomized, double-blind, placebo-controlled trial conducted from September 1991 to August 1998.SettingThe Department of Veterans Affairs Cooperative Studies Program, in which 20 VA medical centers were participating sites.ParticipantsA total of 2531 men with a history of CHD who had low HDL-C levels (mean, 32 mg/dL [0.83 mmol/L] ) and low low-density lipoprotein cholesterol (LDL-C) levels (mean, 111 mg/dL [2.88 mmol/L]).InterventionParticipants were randomly assigned to receive gemfibrozil, 1200 mg/d (n = 1264), or matching placebo (n = 1267).Main Outcome MeasureRelation of lipid levels at baseline and averaged during the first 18 months of gemfibrozil treatment with the combined incidence of nonfatal myocardial infarction and CHD death.ResultsConcentrations of HDL-C were inversely related to CHD events. Multivariable Cox proportional hazards analysis showed that CHD events were reduced by 11% with gemfibrozil for every 5-mg/dL (0.13-mmol/L) increase in HDL-C (P = .02). Events were reduced even further with gemfibrozil beyond that explained by increases in HDL-C values, particularly in the second through fourth quintiles of HDL-C values during treatment. During gemfibrozil treatment, only the increase in HDL-C significantly predicted a lower risk of CHD events; by multivariable analysis, neither triglyceride nor LDL-C levels at baseline or during the trial predicted CHD events.ConclusionsConcentrations of HDL-C achieved with gemfibrozil treatment predicted a significant reduction in CHD events in patients with low HDL-C levels. However, the change in HDL-C levels only partially explained the beneficial effect of gemfibrozil.
Inhibition of Experimental Abdominal Aortic Aneurysm in the Rat by Use of Decoy Oligodeoxynucleotides Suppressing Activity of Nuclear Factor κB and ets Transcription Factors
Authors: Hideki Nakashima, Motokuni Aoki, Takashi Miyake, Tomio Kawasaki, Masahiro Iwai, Nobuo Jo, Masako Oishi, Kazusaburo Kataoka, Shigetsugu Ohgi, Toshio Ogihara, Yasufumi Kaneda, Ryuichi Morishita
Journal: Circulation (2003)

Background— Two phenomena, inflammation and matrix degradation, contribute to the progression of abdominal aortic aneurysm (AAA). Importantly, the inflammation is regulated by the transcription factor nuclear factor (NF)–κB, whereas the destruction and degradation of elastin fibers by matrix metalloproteinases (MMP) are regulated by ets. Thus, we developed a novel strategy to treat AAA by simultaneous inhibition of both NF-κB and ets by using chimeric decoy oligodeoxynucleotides (ODN). Methods and Results— AAA was induced in rats by transient aortic perfusion with elastase, whereas transfection of decoy ODN was performed by wrapping a delivery sheet containing decoy ODN around the aorta. Gel-mobility shift assay at 7 days after treatment demonstrated that both NF-κB and ets binding activity were simultaneously inhibited by chimeric decoy ODN. Transfection of chimeric decoy ODN resulted in significant inhibition of the progression of AAA such as aneurysmal dilation at 4 weeks after treatment as compared with control, accompanied by a reduction of MMP expression. Moreover, the destruction of elastin fibers was inhibited in the aorta transfected with chimeric decoy ODN. Importantly, transfection of chimeric decoy ODN demonstrated potent inhibition of aneurysmal dilatation compared with NF-κB decoy ODN alone, whereas scrambled decoy ODN had no effects. Interestingly, the migration of macrophages was significantly inhibited by chimeric decoy ODN. Conclusions— We demonstrated that inhibition of the progression of AAA was achieved by a novel strategy with chimeric decoy ODN used against NF-κB and ets in rat model. NF-κB and ets are considered to play an important role in the pathogenesis of AAA.
S26 Recurrent respiratory tract infections and specific antibody deficiency in children
Authors: M. T. C. Lim, K. Jeyarajah, H. Pandya, M. Browning, E. Gaillard
Journal: Thorax (2010)

<h3>Introduction</h3> Specific Antibody Deficiency (SAD) is associated with recurrent childhood lower respiratory tract infections (LRTI). SAD in children as a clinical entity is poorly defined, and has been described as a primary immunodeficiency of unknown origin. SAD can be identified by measuring antibodies to childhood vaccines, and a failure to respond to booster immunisations. The prevalence of SAD and its clinical significance in children is poorly understood. <h3>Objectives</h3> The aim of this study is to determine the extent of SAD in children followed with recurrent respiratory tract infections at a tertiary paediatric respiratory centre. <h3>Methods</h3> All patients with recurrent LRTI9s attending our complex paediatric respiratory clinic over a 12-month period were studied. Results of specific antibody levels to pneumococcus and the response to booster vaccines were reviewed. <h3>Results</h3> 102 children with recurrent respiratory infections were seen during this period (age range 10 months to 18 years, median age 4 years 10 months). Sixty-four children had specific IgG antibody levels to pneumococcus vaccine serotypes tested, of which 45 (70%) had low antibody levels. Of these, 27 patients received either Prevenar (a polysaccharide conjugated vaccine containing seven serotypes) or Pneumovax II booster vaccines (a polysaccharide vaccine containing 23 pneumococcal serotypes), and were subsequently retested for their specific IgG antibody levels. Adequate levels of antibodies tested post-booster were mounted in only 13 patients (48%). <h3>Conclusions</h3> The prevalence of SAD in children with troublesome recurrent LRTI9s is high and may be under-diagnosed. Pneumococcal vaccine booster response is variable in these children. The clinical significance of SAD and the response to booster immunisation warrants further study.
Rational Design of Human DNA Ligase Inhibitors that Target Cellular DNA Replication and Repair
Authors: Xi Chen, Shijun Zhong, Xiao Zhu, Barbara Dziegielewska, Tom Ellenberger, Gerald M. Wilson, Alexander D. MacKerell, Alan E. Tomkinson
Journal: Cancer Research (2008)

Abstract Based on the crystal structure of human DNA ligase I complexed with nicked DNA, computer-aided drug design was used to identify compounds in a database of 1.5 million commercially available low molecular weight chemicals that were predicted to bind to a DNA-binding pocket within the DNA-binding domain of DNA ligase I, thereby inhibiting DNA joining. Ten of 192 candidates specifically inhibited purified human DNA ligase I. Notably, a subset of these compounds was also active against the other human DNA ligases. Three compounds that differed in their specificity for the three human DNA ligases were analyzed further. L82 inhibited DNA ligase I, L67 inhibited DNA ligases I and III, and L189 inhibited DNA ligases I, III, and IV in DNA joining assays with purified proteins and in cell extract assays of DNA replication, base excision repair, and nonhomologous end-joining. L67 and L189 are simple competitive inhibitors with respect to nicked DNA, whereas L82 is an uncompetitive inhibitor that stabilized complex formation between DNA ligase I and nicked DNA. In cell culture assays, L82 was cytostatic whereas L67 and L189 were cytotoxic. Concordant with their ability to inhibit DNA repair in vitro, subtoxic concentrations of L67 and L189 significantly increased the cytotoxicity of DNA-damaging agents. Interestingly, the ligase inhibitors specifically sensitized cancer cells to DNA damage. Thus, these novel human DNA ligase inhibitors will not only provide insights into the cellular function of these enzymes but also serve as lead compounds for the development of anticancer agents. [Cancer Res 2008;68(9):3169–77]
Drug survival of the first and second course of anti-tumour necrosis factor agents in juvenile idiopathic arthritis
Authors: P Tynjälä, P Vähäsalo, V Honkanen, P Lahdenne
Journal: Annals of the Rheumatic Diseases (2008)

Objectives: To evaluate drug survival (continuation rates on drug) of anti-tumour necrosis factor (TNF) agents in juvenile idiopathic arthritis (JIA) and predictors for treatment discontinuation. Methods: A retrospective observational study on JIA patients taking etanercept (n = 105) or infliximab (n = 104) with at least one year follow-up. Kaplan–Meier curves and log-rank statistics were used to compare treatments and a proportional hazards model to assess risk factors for discontinuation. Results: Etanercept versus infliximab treatment survival at 12 months was 83% versus 80%, at 24 months 68% versus 68%, at 36 months 64% versus 53%, at 48 months 61% versus 48% (p = 0.194), respectively. Reasons for discontinuing the first biological treatment were inefficacy (etanercept 28% vs infliximab 20%, p = 0.445), adverse events (7% vs 22%, p = 0.002) or inactive disease (10% vs 16%, p = 0.068). Women (hazard ratio (HR) 2.8, 95% CI 1.3 to 5.8), patients with systemic JIA (HR 7.8, 95% CI 1.7 to 34.9) or those taking infliximab (HR 2.0, 95% CI 1.2 to 3.3) were at higher risk of treatment discontinuation. One-third of the patients were switched to the second anti-TNF therapy, which was discontinued less frequently than the first. At 12 months treatment survival of etanercept was 60%, infliximab 58% and adalimumab 66% as the second-line anti-TNF therapy. Conclusions: Although infliximab was discontinued more often than etanercept because of adverse events, during a 48-month follow-up the overall treatment survival of etanercept and infliximab as the first biological agent in JIA was comparable. A switch from one anti-TNF agent to another appears a reasonable therapeutic option.
Elevated Circulating Level of Ghrelin in Cachexia Associated With Chronic Heart Failure
Authors: Noritoshi Nagaya, Masaaki Uematsu, Masayasu Kojima, Yukari Date, Masamitsu Nakazato, Hiroyuki Okumura, Hiroshi Hosoda, Wataru Shimizu, Masakazu Yamagishi, Hideo Oya, Hideki Koh, Chikao Yutani, Kenji Kangawa
Journal: Circulation (2001)

Background Ghrelin is a novel growth hormone (GH)-releasing peptide, isolated from the stomach, that may also cause a positive energy balance by stimulating food intake and inducing adiposity. We sought to investigate the pathophysiology of ghrelin in the cachexia associated with chronic heart failure (CHF). Methods and Results Plasma ghrelin was measured in 74 patients with CHF and 12 control subjects, together with potentially important anabolic and catabolic factors, such as GH and tumor necrosis factor (TNF-α). Patients with CHF were divided into two groups, those with cachexia (n=28) and those without cachexia (n=46). Plasma ghrelin did not significantly differ between all CHF patients and controls (181±10 versus 140±14 fmol/mL, P =NS). However, plasma ghrelin was significantly higher in CHF patients with cachexia than in those without cachexia (237±18 versus 147±10 fmol/mL, P &lt;0.001). Circulating GH, TNF-α, norepinephrine, and angiotensin II were also significantly higher in CHF patients with cachexia than in those without cachexia. Interestingly, plasma ghrelin correlated positively with GH ( r =0.28, P &lt;0.05) and TNF-α ( r =0.31, P &lt;0.05) and negatively with body mass index ( r =−0.35, P &lt;0.01). Conclusions Plasma ghrelin was elevated in cachectic patients with CHF, associated with increases in GH and TNF-α and a decrease in body mass index. Considering ghrelin-induced positive energy effects, increased ghrelin may represent a compensatory mechanism under catabolic-anabolic imbalance in cachectic patients with CHF.
THE NEOPLASTIC POTENTIALITIES OF MOUSE EMBRYO TISSUES
Authors: William E. Smith
Journal: The Journal of Experimental Medicine (1950)

The lung tissue of mouse embryos of the C strain proliferates to some extent after implantation in adult hosts of the same breed and rapidly differentiates, forming a parenchyma remarkably like the normal. The grafts persist long. When methylcholanthrene dissolved in olive oil has been introduced with them much more growth of them occurs. The carcinogen induces a pronounced metaplasia of the epithelium of the bronchial tree, and the altered cells are often aggressive, multiplying, invading, and largely replacing the parenchyma about them. So closely do they resemble malignant elements in aspect and behavior that it is frequently difficult to tell whether carcinomatous change is not actually present. Genuine tumors soon arise, multiple benign adenomas sometimes appearing within 3 weeks, and indubitable carcinomas a few weeks later. Not a few of the cancers are of transitional cell type, that is to say are expressive of an intermediate stage in the metaplasia. Under the influence of methylcholanthrene the cells lining the alveolar spaces of the graft sometimes undergo metaplasia also, with result in stratified squamous epithelium. It follows that there is reason to doubt the current assumption that all squamous cell carcinomas of the lung necessarily arise from the bronchial tree. The findings, taken with others previously reported, make it difficult to suppose, furthermore, that the generality of lung tumors can be due to neoplastic viruses entering the organism in postnatal life and having no broader scope than those thus far discovered.
Age and alarm symptoms do not predict endoscopic findings among patients with dyspepsia: a multicentre database study
Authors: M. B. Wallace, V. L. Durkalski, J. Vaughan, Y. Y. Palesch, E. D. Libby, P. S. Jowell, N. J. Nickl, S. M. Schutz, Joseph Leung, P. B. Cotton
Journal: Gut (2001)

<h3>INTRODUCTION</h3> Symptoms of dyspepsia are common but most patients do not have major upper gastrointestinal pathology. Endoscopy is recommended for dyspeptic patients over the age of 45, or those with certain "alarm" symptoms. We have evaluated the effectiveness of age and "alarm" symptoms for predicting major endoscopic findings in six practising endoscopy centres. <h3>METHODS</h3> Clinical variables of consecutive patients with dyspepsia symptoms undergoing upper endoscopy examinations were recorded using a common endoscopy database. Patients who had no previous upper endoscopy or barium radiography were included. Stepwise multivariate logistic regression was used to identify predictors of endoscopic findings. The accuracy of these for predicting endoscopic findings was evaluated with receiver operating characteristic analysis. The sensitivity and specificity of age thresholds from 30 to 70 years were evaluated. <h3>RESULTS</h3> Major pathology (tumour, ulcer, or stricture) was found at endoscopy in 787/3815 (21%) patients with dyspepsia. Age, male sex, bleeding, and anaemia were found to be significant but weak independent predictors of endoscopic findings. A multivariate prediction rule based on these factors had poor predictive accuracy (c statistic=0.62). Using a simplified prediction rule of age ⩾45 years or the presence of any "alarm" symptom, sensitivity was 87% and specificity was 26%. Increasing or decreasing the age cut off did not significantly improve the predictive accuracy. <h3>CONCLUSIONS</h3> Age and the presence of "alarm" symptoms are not effective predictors of endoscopic findings among patients with dyspepsia. Better clinical prediction strategies are needed to identify patients with significant upper gastrointestinal pathology.
Isolation and Characterization of Circulating Tumor Cells from Patients with Localized and Metastatic Prostate Cancer
Authors: Shannon L. Stott, Richard J. Lee, Sunitha Nagrath, Min Yu, David T. Miyamoto, Lindsey Ulkus, Elizabeth J. Inserra, Matthew Ulman, Simeon Springer, Zev Nakamura, Alessandra L. Moore, Dina I. Tsukrov, Maria E. Kempner, Douglas M. Dahl, Chin-Lee Wu, A. John Iafrate, Matthew R. Smith, Ronald G. Tompkins, Lecia V. Sequist, Mehmet Toner, Daniel A. Haber, Shyamala Maheswaran
Journal: Science Translational Medicine (2010)

Rare circulating tumor cells (CTCs) are present in the blood of patients with metastatic epithelial cancers but have been difficult to measure routinely. We report a quantitative automated imaging system for analysis of prostate CTCs, taking advantage of prostate-specific antigen (PSA), a unique prostate tumor-associated marker. The specificity of PSA staining enabled optimization of criteria for baseline image intensity, morphometric measurements, and integration of multiple signals in a three-dimensional microfluidic device. In a pilot analysis, we detected CTCs in prostate cancer patients with localized disease, before surgical tumor removal in 8 of 19 (42%) patients (range, 38 to 222 CTCs per milliliter). For 6 of the 8 patients with preoperative CTCs, a precipitous postoperative decline (<24 hours) suggests a short half-life for CTCs in the blood circulation. Other patients had persistent CTCs for up to 3 months after prostate removal, suggesting early but transient disseminated tumor deposits. In patients with metastatic prostate cancer, CTCs were detected in 23 of 36 (64%) cases (range, 14 to 5000 CTCs per milliliter). In previously untreated patients followed longitudinally, the numbers of CTCs declined after the initiation of effective therapy. The prostate cancer-specific TMPRSS2-ERG fusion was detectable in RNA extracted from CTCs from 9 of 20 (45%) patients with metastatic disease, and dual staining of captured CTCs for PSA and the cell division marker Ki67 indicated a broad range for the proportion of proliferating cells among CTCs. This method for analysis of CTCs will facilitate the application of noninvasive tumor sampling to direct targeted therapies in advanced prostate cancer and warrants the initiation of long-term clinical studies to test the importance of CTCs in invasive localized disease.
Functional Prostacyclin Synthase Promoter Polymorphisms. Impact in Pulmonary Arterial Hypertension
Authors: Robert S. Stearman, Amber R. Cornelius, Xiao Lu, David S. Conklin, Mark J. Del Rosario, Anita M. Lowe, Mihret T. Elos, Lynsey M. Fettig, Randall E. Wong, Naoko Hara, Joy D. Cogan, John A. Phillips, Matthew R. Taylor, Brian B. Graham, Rubin M. Tuder, James E. Loyd, Mark W. Geraci
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary artery pressure, vascular remodeling, and ultimately right ventricular heart failure. PAH can have a genetic component (heritable PAH), most often through mutations of bone morphogenetic protein receptor 2, and idiopathic and associated forms. Heritable PAH is not completely penetrant within families, with approximately 20% concurrence of inactivating bone morphogenetic protein receptor 2 mutations and delayed onset of PAH disease. Because one of the treatment options is using prostacyclin analogs, we hypothesized that prostacyclin synthase promoter sequence variants associated with increased mRNA expression may play a protective role in the bone morphogenetic protein receptor 2 unaffected carriers.To characterize the range of prostacyclin synthase promoter variants and assess their transcriptional activities in PAH-relevant cell types. To determine the distribution of prostacyclin synthase promoter variants in PAH, unaffected carriers in heritable PAH families, and control populations.Polymerase chain reaction approaches were used to genotype prostacyclin synthase promoter variants in more than 300 individuals. Prostacyclin synthase promoter haplotypes' transcriptional activities were determined with luciferase reporter assays.We identified a comprehensive set of prostacyclin synthase promoter variants and tested their transcriptional activities in PAH-relevant cell types. We demonstrated differences of prostacyclin synthase promoter activities dependent on their haplotype.Prostacyclin synthase promoter sequence variants exhibit a range of transcriptional activities. We discovered a significant bias for more active prostacyclin synthase promoter variants in unaffected carriers as compared with affected patients with PAH.
Fragmented Sleep Accelerates Tumor Growth and Progression through Recruitment of Tumor-Associated Macrophages and TLR4 Signaling
Authors: Fahed Hakim, Yang Wang, Shelley X.L. Zhang, Jiamao Zheng, Esma S. Yolcu, Alba Carreras, Abdelnaby Khalyfa, Haval Shirwan, Isaac Almendros, David Gozal
Journal: Cancer Research (2014)

Abstract Sleep fragmentation (SF) is a highly prevalent condition and a hallmark of sleep apnea, a condition that has been associated with increased cancer incidence and mortality. In this study, we examined the hypothesis that sleep fragmentation promotes tumor growth and progression through proinflammatory TLR4 signaling. In the design, we compared mice that were exposed to sleep fragmentation one week before engraftment of syngeneic TC1 or LL3 tumor cells and tumor analysis four weeks later. We also compared host contributions through the use of mice genetically deficient in TLR4 or its effector molecules MYD88 or TRIF. We found that sleep fragmentation enhanced tumor size and weight compared with control mice. Increased invasiveness was apparent in sleep fragmentation tumors, which penetrated the tumor capsule into surrounding tissues, including adjacent muscle. Tumor-associated macrophages (TAM) were more numerous in sleep fragmentation tumors, where they were distributed in a relatively closer proximity to the tumor capsule compared with control mice. Although tumors were generally smaller in both MYD88−/− and TRIF−/− hosts, the more aggressive features produced by sleep fragmentation persisted. In contrast, these more aggressive features produced by sleep fragmentation were abolished completely in TLR4−/− mice. Our findings offer mechanistic insights into how sleep perturbations can accelerate tumor growth and invasiveness through TAM recruitment and TLR4 signaling pathways. Cancer Res; 74(5); 1329–37. ©2014 AACR.