tbuckley/cabot-search huggingface dataset:
Mortality and causes of death in Crohn's disease: results from 20 years of follow-up in the IBSEN study
Authors: Øistein Hovde, Iril Kempski-Monstad, Milada Cvancarova Småstuen, Inger Camilla Solberg, Magne Henriksen, Jørgen Jahnsen, Njål Stray, Bjørn A Moum
Journal: Gut (2013)

Population-based studies have shown a slightly decreased life expectancy in patients with Crohn's disease (CD). The primary aim of the present study was to evaluate mortality and causes of death 20 years after the diagnosis in a well defined population-based cohort of CD patients in Norway.The Inflammatory Bowel South-Eastern Norway study has prospectively followed all patients diagnosed with CD in the period between 1 January 1990 and 31 December 1993 in four geographically well-defined areas. All patients (n=237) were age and sex matched with 25 persons from the same county selected at random from the general population. Data on death and causes of deaths were collected from the Norwegian Causes of Death Register. All causes and cause-specific mortality (gastrointestinal cancer, cancer and heart disease) were modelled with Cox regression model stratified by matched sets. Results are expressed as HRs with 95% CIs.There was no significant difference between CD patients and controls in overall mortality (HR=1.35, 95% CI 0.94 to 1.94, p=0.10). Furthermore, there were no marked differences in deaths from gastrointestinal cancer, other cancers or cardiovascular diseases in the CD group compared with the controls. In the CD group, 13.9% had died compared with 12.7% in the control group (p=0.578).In our population-based inception cohort followed for 20 years, there was no increased mortality or more deaths from cancer compared with the general population.
Safety of anticoagulation use and bevacizumab in patients with glioma
Authors: Phioanh (Leia) Nghiemphu, Richard M. Green, Whitney B. Pope, Albert Lai, Timothy F. Cloughesy
Journal: Neuro-Oncology (2008)

Bevacizumab in combination with chemotherapy is now being studied for the treatment of malignant gliomas. However, the risk of intracranial hemorrhage has limited its use in patients requiring full anticoagulation for venous thrombosis. To assess the safety of using anticoagulation with bevacizumab, we conducted a retrospective review of our patients who were treated with bevacizumab while receiving anticoagulation. We reviewed their medical records and imaging for signs of hemorrhage. In total, we had 21 patients who received anticoagulation and bevacizumab concurrently for a median time of 72 days. Eighteen patients had adequate anticoagulation for venous thrombosis. There were no frank lobar hemorrhages in any patient. Three patients had small, intraparenchymal hemorrhages on MRI, but only one patient actually developed symptoms due to the hemorrhage. None of these patients had residual neurological deficits from the hemorrhages. Two more patients had evidence of a minor increase in signal on noncontrast T1-weighted sequence, presumed to be petechial hemorrhages, without any clinical sequelae or progression. In contrast, seven patients who had symptomatic hemorrhages from bevacizumab were not on any anticoagulation. In this retrospective review, anticoagulation did not lead to any major hemorrhages and does not appear to be a contraindication for starting bevacizumab therapy.
Host Genetics of HIV Acquisition and Viral Control
Authors: Patrick R. Shea, Kevin V. Shianna, Mary Carrington, David B. Goldstein
Journal: Annual Review of Medicine (2012)

Since the discovery of HIV as the cause of AIDS, numerous insights have been gained from studies of its natural history and epidemiology. It has become clear that there are substantial interindividual differences in the risk of HIV acquisition and course of disease. Meanwhile, the field of human genetics has undergone a series of rapid transitions that have fundamentally altered the approach to studying HIV host genetics. We aim to describe the field as it has transitioned from the era of candidate-gene studies and the era of genome-wide association studies (GWAS) to its current state in the infancy of comprehensive sequencing. In some ways the field has come full circle, having evolved from being driven almost exclusively by our knowledge of immunology, to a bias-free GWAS approach, to a point where our ability to catalogue human variation far outstrips our ability to biologically interpret it.
From the Cyclooxygenase-2 Inhibitor Celecoxib to a Novel Class of 3-Phosphoinositide-Dependent Protein Kinase-1 Inhibitors
Authors: Jiuxiang Zhu, Jui-Wen Huang, Ping-Hui Tseng, Ya-Ting Yang, Joseph Fowble, Chung-Wai Shiau, Yeng-Jeng Shaw, Samuel K. Kulp, Ching-Shih Chen
Journal: Cancer Research (2004)

Abstract The blockade of Akt activation through the inhibition of 3-phosphoinositide-dependent kinase-1 (PDK-1) represents a major signaling mechanism whereby celecoxib mediates apoptosis. Celecoxib, however, is a weak PDK-1 inhibitor (IC50, 48 μm), requiring at least 30 μm to exhibit discernable effects on the growth of tumor cells in vitro. Here, we report the structure-based optimization of celecoxib to develop PDK-1 inhibitors with greater potency in enzyme inhibition and growth inhibition. Kinetics of PDK-1 inhibition by celecoxib with respect to ATP suggest that celecoxib derivatives inhibit PDK-1 by competing with ATP for binding, a mechanism reminiscent to that of many kinase inhibitors. Structure-activity analysis together with molecular modeling was used to generate compounds that were tested for their potency in inhibiting PDK-1 kinase activity and in inducing apoptosis in PC-3 prostate cancer cells. Docking of potent compounds into the ATP-binding site of PDK-1 was performed for lead optimization, leading to two compounds, OSU-03012 and OSU-03013, with IC50 values in PDK-1 inhibition and apoptosis induction in the low μm range. Exposure of PC-3 cells to these agents led to Akt dephosphorylation and inhibition of p70 S6 kinase activity. Moreover, overexpression of constitutively active forms of PDK-1 and Akt partially protected OSU-03012-induced apoptosis. Screening in a panel of 60 cell lines and more extensive testing in PC-3 cells indicated that the mean concentration for total growth inhibition was ∼3 μm for both agents. Considering the conserved role of PDK-1/Akt signaling in promoting tumorigenesis, these celecoxib analogs are of translational relevance for cancer prevention and therapy.
Mutations within lncRNAs are effectively selected against in fruitfly but not in human
Authors: Wilfried Haerty, Chris P Ponting
Journal: Genome biology (2013)

Previous studies in Drosophila and mammals have revealed levels of long non-coding RNAs (lncRNAs) sequence conservation that are intermediate between neutrally evolving and protein-coding sequence. These analyses compared conservation between species that diverged up to 75 million years ago. However, analysis of sequence polymorphisms within a species' population can provide an understanding of essentially contemporaneous selective constraints that are acting on lncRNAs and can quantify the deleterious effect of mutations occurring within these loci. We took advantage of polymorphisms derived from the genome sequences of 163 Drosophila melanogaster strains and 174 human individuals to calculate the distribution of fitness effects of single nucleotide polymorphisms occurring within intergenic lncRNAs and compared this to distributions for SNPs present within putatively neutral or protein-coding sequences. Our observations show that in D.melanogaster there is a significant excess of rare frequency variants within intergenic lncRNAs relative to neutrally evolving sequences, whereas selection on human intergenic lncRNAs appears to be effectively neutral. Approximately 30% of mutations within these fruitfly lncRNAs are estimated as being weakly deleterious. These contrasting results can be attributed to the large difference in effective population sizes between the two species. Our results suggest that while the sequences of lncRNAs will be well conserved across insect species, such loci in mammals will accumulate greater proportions of deleterious changes through genetic drift.
Topographic detection of photorefractive keratectomy1,21The voluntary informed consent of the subjects used in this research was obtained, as required by SECNAVINST 3900.39E.2The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.
Authors: Steven C Schallhorn, Jennifer L Reid, Sandor E Kaupp, Christopher L Blanton, Larry Zoback, Harold Goforth, Charles W Flowers, Peter J McDonnell
Journal: Ophthalmology (1998)
STUDIES ON CIRCULATING IMMUNE COMPLEXES
Authors: Charles G. Cochrane, David Hawkins
Journal: The Journal of Experimental Medicine (1968)

The relationship between certain physicochemical properties of circulating immune complexes and their ability to localize in vessel walls during a state of increased permeability was studied. The ability to become deposited was related to the large size of complexes, rather than to their net charge or to a specific affinity between complexes and structures of vessel walls. Soluble complexes with sedimentation rates greater than 19S were capable of being entrapped along the vessel wall membranes, while complexes smaller than this were not. These large complexes were removed rapidly from the circulation, while smaller complexes persisted. Minimal levels of total complexes in the circulation necessary for detectable vascular localization were found to be as low as 15 microg antibody N/ml plasma. In experimental serum sickness, a disease known to be induced by circulating immune complexes, the development of vascular and glomerular lesions occurred almost exclusively in rabbits having large (greater than 19S) circulating immune complexes. Animals with smaller complexes did not show deposition of complexes in glomeruli or development of glomerulonephritis. Their incidence of vasculitis was markedly reduced.
Paradoxical survival of elderly men with high blood pressure.
Authors: R. D. Langer, T. G. Ganiats, E. Barrett-Connor
Journal: BMJ (1989)

A recent study in Finland found a paradoxical graded positive association between blood pressure and survival in people aged 85 and over 1 . Other studies have shown a lack of association between hypertension and mortality in elderly people but not this unexpected advantage in terms of survival, possibly because they had too few very old subjects 2-4 . We tested this relation in another cohort
The Role of Protein Traffic in the Progression of Renal Diseases
Authors: Piero Ruggenenti, Giuseppe Remuzzi
Journal: Annual Review of Medicine (2000)

Progression to irreversible renal parenchymal damage and end-stage renal disease is the final common pathway of chronic proteinuric nephropathies and is relatively independent of the type of initial insult. In animals, a reduction in nephron mass exposes the remaining nephrons to adaptive hemodynamic changes that are intended to sustain renal function but may be detrimental in the long term. High glomerular capillary pressure impairs glomerular permeability to proteins, which are then filtered in excessive quantities and reach the lumen of the proximal tubule. The secondary process of reabsorption of filtered proteins can contribute substantially to renal interstitial injury by activating intracellular events, including upregulation of vasoactive and inflammatory genes. The corresponding molecules formed in excessive amounts by the renal tubules cause an interstitial inflammatory reaction that normally precedes renal scarring and correlates with declining function. In several clinical studies, the increase in urinary protein excretion correlated with the tendency of the renal disease to progress more than it correlated with the underlying renal disease itself. Whenever urinary protein excretion is reduced, the decline in the glomerular filtration rate (GFR) slows or stops. Thus, to the extent that angiotensin-converting enzyme inhibitors lower the rate of urinary protein excretion, they effectively limit the progressive decline in GFR. If treatment is sufficiently prolonged, the GFR decline can be effectively halted or reversed, even in patients with remarkably severe disease, and remission is now achievable in some patients.
Chromatin accessibility, p300, and histone acetylation define PML-RARα and AML1-ETO binding sites in acute myeloid leukemia
Authors: Sadia Saeed, Colin Logie, Kees-Jan Francoijs, Gianmaria Frigè, Mauro Romanenghi, Fiona G. Nielsen, Lianne Raats, Maryam Shahhoseini, Martijn Huynen, Lucia Altucci, Saverio Minucci, Joost H. A. Martens, Hendrik G. Stunnenberg
Journal: Blood (2012)
Hemodynamic Studies in Portal Hypertension
Authors: J J Fomon, W D Warren
Journal: Annual Review of Medicine (1969)

The hemodynamic alterations occurring in portal hypertension are com­ plex and difficult to evaluate. Investigation and understanding of the vas­ cular pathophysiology assume clinical importance because operative treat­ ment very often alters splanchnic blood flow suddenly and dramatically. I t is generally conceded that hepatic function is a major determinant in the degree of well being of patients with portal hypertension, especially after complications of portal hypertension are treated by portosystemic shunt. The concept that hepatic function is not the sole determining factor is em­ phasized by a number of clinical studies. Callow et al. (I), Conn & Linden­ muth (2) and Jackson et al. (3) have analyzed the results of shunt therapy in controlled, randomized studies. Survival rates in the surgical groups are not superior to those in the groups treated medically. In a review of the subject, Grace et al. (4) came to the same conclusion. Although survival rates were similar, modes of death differed. In the medically treated control group, hemorrhage from esophageal varices was the major cause while in patients undergoing portacaval shunt, liver failure was the most common cause of death. Johnson et al. (S) reported the results of nonshunting procedures in the control of esophageal varices. None of the long-term survivors were troubled with hepatic encephalopathy or liver failure. In bilharzial cirrhosis hepato­ cellular function usually remains good but Hassab (6) found that 20.6 per cent of such patients undergoing portacaval shunt developed encephalopathy. After nonshunting operations on 3SS patients with the same disease only one patient developed encephalopathy in the absence of bleeding. Mikkelsen et al. (7) reported on 36 patients, in 17 of whom the portal vein was patent, liver function was excellent and there was no evidence of liver disease on gross examination. Following portacaval shunts, 10 developed signs of encephalopathy and five died of liver failure. In those patients with spon­ taneously occluded portal veins these complications were infrequent. The foregoing clinical observations suggest that the sudden complete diversion of portal blood flow, as occurs following an end-to-side or side-to­ side (8, 9) portacaval shunt, may be detrimental to the liver under certain circumstances. This detrimental effect has been observed in dogs (10), spider monkeys (11), and man (12). Warren et al. (13, 14) studied hemo-
IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells
Authors: Carolina Schinke, Orsolya Giricz, Weijuan Li, Aditi Shastri, Shanisha Gordon, Laura Barreyro, Tushar Bhagat, Sanchari Bhattacharyya, Nandini Ramachandra, Matthias Bartenstein, Andrea Pellagatti, Jacqueline Boultwood, Amittha Wickrema, Yiting Yu, Britta Will, Sheng Wei, Ulrich Steidl, Amit Verma
Journal: Blood (2015)
Modulation of Ventricular Repolarization by a Premature Stimulus
Authors: Kenneth R. Laurita, Steven D. Girouard, David S. Rosenbaum
Journal: Circulation Research (1996)

Recent evidence suggests that ion channels governing the response of action potential duration (APD) to a premature stimulus (ie, APD restitution) are heterogeneously dispersed throughout the heart. However, because of limitations of conventional electrophysiological recording techniques, the effects of restitution in single cells on ventricular repolarization at the level of the intact heart are poorly understood. Using high-resolution optical mapping with voltage-sensitive dyes, we measured APD restitution kinetics at 128 simultaneous sites on the epicardial surface (1 cm 2 ) of intact guinea pig hearts (n=15). During steady state baseline pacing, APD gradients that produced a spatial dispersion of repolarization were observed. Mean APD was shortened monotonically from 186±19 ms during baseline pacing (S 1 -S 1 cycle length, 393±19 ms) to 120±4 ms as single premature stimuli were introduced at progressively shorter coupling intervals (shortest S 1 -S 2 , 190±15 ms). In contrast, premature stimuli caused biphasic modulation of APD dispersion (defined as the variance of APD measured throughout the mapping field). Over a broad range of increasingly premature coupling intervals, APD dispersion decreased from 70±29 ms 2 to a minimum of 10±7 ms 2 at a critical S 1 -S 2 interval (216±18 ms), and then, at shorter premature coupling intervals, APD dispersion increased sharply to 66±25 ms 2 . Modulation of APD dispersion by premature stimuli was attributed to coupling interval–dependent changes in the magnitude and direction of ventricular APD gradients, which, in turn, were explained by systematic heterogeneities of APD restitution across the epicardial surface. There was a characteristic pattern in the spatial distribution of cellular restitution such that faster restitution kinetics were closely associated with longer baseline APD. This relationship explained the reversal of APD between single cells, inversion of APD gradients across the heart, and ECG T-wave inversion during closely coupled premature stimulation. Therefore, because of the heterogeneous distribution of cellular restitution kinetics across the epicardial surface, a single premature stimulus profoundly altered the pattern and synchronization of ventricular repolarization in the intact ventricle. This response has important mechanistic implications in the initiation of arrhythmias that are dependent on dispersion of repolarization.
Changes of alveolar oxygen tension in chronic obstructive pulmonary disease (COPD) and effect of variable oxygen tension on hypoxia inducible factor (HIF)-1α system of alveolar epithelial cells
Authors: Balazs Odler, Erna Sziksz, Leonora Himer, Gabor Horvath, Anna Onody, Adam Vannay, Gyorgy Losonczy, Attila J. Szabo, Veronika Muller
Journal: European Respiratory Journal (2013)

In COPD airway obstruction causes hypoventilated areas in the lung leading to alveolar hypoxia. HIF-1 α plays an important role in the response to hypoxia and protection of cells against harmful effects. Role of alveolar oxygen tension and HIF-1α in the development of COPD are unknown.

Heathly volunteers (n=7) and 9 patients with COPD were enrolled into clinical examinations including lung function test and blood gas analysis. Mass spectrometry was used to measure exhaled O2 on the level of functional reserve capacity (FRC) and residual volume (RV). HIF1α mRNA and protein expression of alveolar epithelial cells (A549) were analyzed by RT-PCR and flow cytometry using hypoxia (FiO2: 20,9% (control); 13±1%; 6±1%; 1±1%).

Exhaled O2 on the level of FRC did not change,(C:15.6±1.2 vs. COPD: 15,8±1.4 %), while on the level of RV the alveolar FiO2 was significantly decreased (C: 13,6±1,8 vs. COPD: 11.6±2.1%, p<0.05) in patients with COPD and the value correlated to pO2 and showed negative correlation to RV. HIF-1α mRNA and protein expression significantly increased in mild hypoxia, extreme hypoxia did not change the mRNA expression. Hypoxia significantly increased the A549 cell count in all treated groups (FiO2 13±1%: 13,33x105; FiO2 6±1%:13,2x105; FiO2 1±1%: 12,86x105 vs. control FiO2 20,9%: 7,73x105; p<0.01).

In COPD the exhaled O2 level is decreased in parellel to hyperinflation, demonstrating that there are more severe hypoxic areas in the lungs compare to physiological conditions. Mild hypoxia increases HIF1α mRNA and protein expression, while in severe hypoxia these changes are absent.
Effect of cycling cadence on subsequent 3 km running performance in well trained triathletes
Authors: T Bernard, F Vercruyssen, F Grego, C Hausswirth, R Lepers, J-M Vallier, J Brisswalter
Journal: British Journal of Sports Medicine (2003)

Objectives: To investigate the effect of three cycling cadences on a subsequent 3000 m track running performance in well trained triathletes. Methods: Nine triathletes completed a maximal cycling test, three cycle-run succession sessions (20 minutes of cycling + a 3000 m run) in random order, and one isolated run (3000 m). During the cycling bout of the cycle-run sessions, subjects had to maintain for 20 minutes one of the three cycling cadences corresponding to 60, 80, and 100 rpm. The metabolic intensity during these cycling bouts corresponded approximately to the cycling competition intensity of our subjects during a sprint triathlon (&gt; 80% V̇ o 2 max). Results: A significant effect of the prior cycling exercise was found on middle distance running performance without any cadence effect (625.7 (40.1), 630.0 (44.8), 637.7 (57.9), and 583.0 (28.3) seconds for the 60 rpm run, 80 rpm run, 100 rpm run, and isolated run respectively). However, during the first 500 m of the run, stride rate and running velocity were significantly higher after cycling at 80 or 100 rpm than at 60 rpm (p&lt;0.05). Furthermore, the choice of 60 rpm was associated with a higher fraction of V̇ o 2 max sustained during running compared with the other conditions (p&lt;0.05). Conclusions: The results confirm the alteration in running performance completed after the cycling event compared with the isolated run. However, no significant effect of the cadence was observed within the range usually used by triathletes.
Spa therapy in the treatment of knee osteoarthritis: a large randomised multicentre trial
Authors: R. Forestier, H. Desfour, J.-M. Tessier, A. Francon, A. M. Foote, C. Genty, C. Rolland, C.-F. Roques, J.-L. Bosson
Journal: Annals of the Rheumatic Diseases (2009)

To determine whether spa therapy, plus home exercises and usual medical treatment provides any benefit over exercises and usual treatment, in the management of knee osteoarthritis.Large multicentre randomised prospective clinical trial of patients with knee osteoarthritis according to the American College of Rheumatology criteria, attending French spa resorts as outpatients between June 2006 and April 2007. Zelen randomisation was used so patients were ignorant of the other group and spa personnel were not told which patients were participating. The main endpoint criteria were patient self-assessed. All patients continued usual treatments and performed daily standardised home exercises. The spa therapy group also received 18 days of spa therapy (massages, showers, mud and pool sessions). MAIN ENDPOINT: The number of patients achieving minimal clinically important improvement (MCII) at 6 months, defined as > or =19.9 mm on the visual analogue pain scale and/or > or =9.1 points in a normalised Western Ontario and McMaster Universities osteoarthritis index function score and no knee surgery.The intention to treat analysis included 187 controls and 195 spa therapy patients. At 6 months, 99/195 (50.8%) spa group patients had MCII and 68/187 (36.4%) controls (chi(2)=8.05; df=1; p=0.005). However, no improvement in quality of life (Short Form 36) or patient acceptable symptom state was observed at 6 months.For patients with knee osteoarthritis a 3-week course of spa therapy together with home exercises and usual pharmacological treatments offers benefit after 6 months compared with exercises and usual treatment alone, and is well tolerated.