tbuckley/cabot-search huggingface dataset:
Intra-articular hyaluronan injections in the treatment of osteoarthritis of the knee: a randomised, double blind, placebo controlled multicentre trial. Hyaluronan Multicentre Trial Group.
Authors: L S Lohmander, N Dalen, G Englund, M Hamalainen, E M Jensen, K Karlsson, M Odensten, L Ryd, I Sernbo, O Suomalainen, A Tegnander
Journal: Annals of the Rheumatic Diseases (1996)

OBJECTIVE: To assess the effects of intra-articular injections of hyaluronan on symptoms of knee osteoarthritis (OA). METHODS: Two hundred and forty patients with symptomatic, radiological knee OA were randomly assigned to treatment with weekly injections for five weeks with either 25 mg of high molecular weight hyaluronan or vehicle. Results were evaluated at weeks 1, 2, 3, 4, 5, 13, and 20 by visual analogue scales (pain, function, motion, activity), algofunctional index, and global evaluation by patient and investigator. Analysis was by "intention to treat9, "per protocol9, and area under the curve principles on unstratified patient groups and for patients stratified into four groups of equal size by age and baseline algofunctional index. RESULTS: No serious side effects were reported. At 20 weeks both treatment groups were improved compared with baseline, with no difference between unstratified groups treated with placebo or hyaluronan. Comparison of treatment groups stratified by age and baseline algofunctional index revealed a significant difference in favour of hyaluronan over placebo (pain, activity, algofunctional index, global evaluations by patient and investigator) for patients older than 60 years and with a baseline algofunctional index greater than 10. There was no clinically relevant difference between the two treatments for the other three stratified subgroups of younger age or fewer symptoms. Similar results were obtained by area under the curve, intention to treat, and per protocol analysis. CONCLUSIONS: Patients older than 60 years with knee osteoarthritis and with significant symptoms corresponding to an index of severity of knee disease of 10 or more, comprise the group most likely to benefit from treatment with intra-articular hyaluronan injections.
Molecular Mechanisms in Progressive Idiopathic Pulmonary Fibrosis
Authors: Mark P. Steele, David A. Schwartz
Journal: Annual Review of Medicine (2012)

There is clear evidence that environmental exposures and genetic predisposition contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Cigarette smoking increases the risk of developing IPF several-fold, as do other exposures such as metal-fume and wood-dust exposure. Occupations that increase the risk of IPF are agricultural work, hairdressing, and stone polishing, supporting the role of environmental exposure in disease pathogenesis. Genetic predisposition to IPF is evident from its familial aggregation and the fact that pulmonary fibrosis develops in several rare genetic disorders. Mutations in surfactant proteins lead to pulmonary fibrosis and are associated with endoplasmic reticulum stress in alveolar type II epithelial cells. Mutations in telomerase have been found in several families with IPF, and shortened telomeres are found in sporadic cases of IPF. A common variant in mucin 5B predisposes to both familial and sporadic IPF and is present in the majority of cases, indicating sporadic IPF occurs in those with genetic predisposition.
Sensitive detection of human papillomavirus type 16 E7-specific T cells by ELISPOT after multiple in vitro stimulations of CD8+ T cells with peptide-pulsed autologous dendritic cells.
Authors: Nathalie Cools, Peter Ponsaerts, Marc Lenjou, Griet Nijs, Dirk R Van Bockstaele, Viggo FI Van Tendeloo, Zwi N Berneman
Journal: Molecular Cancer (2006)

Cervical cancer is the second most common gynecological cancer amongst women world-wide. Despite optimized protocols, standard treatments still face several disadvantages. Therefore, research aims at the development of immune-based strategies using tumor antigen-loaded dendritic cells for the induction of cellular anti-tumor immunity. In this study, we used dendritic cells loaded with the HLA-A2-restricted HPV type 16 E711–20 peptide in order to induce an in vitro CD8+ T cell response. For this purpose, peptide-pulsed dendritic cells were co-cultured with autologous CD8+ T cells. After 5 weekly stimulations with peptide-pulsed mature dendritic cells, cultured T cells were analyzed for antigen specificity by an IFN-γ ELISPOT assay. Using this ELISPOT assay, we were able to detect E7-specific IFN-γ-secreting CD8+ T cells in 5/5 healthy donors. We show that peptide-pulsed mature dendritic cells are able to stimulate a HPV type 16 E7 peptide-specific immune response in vitro. These experiments describe an efficient culture protocol for antigen-specific T cells for use in pre-clinical vaccination research and confirm the need for sensitive T cell assays for detection of tumor-specific immune responses in vitro.
Regulation of Coronary Arterial BK Channels by Caveolae-Mediated Angiotensin II Signaling in Diabetes Mellitus
Authors: Tong Lu, Dai-Min Zhang, Xiao-Li Wang, Tongrong He, Ru-Xing Wang, Qiang Chai, Zvonimir S. Katusic, Hon-Chi Lee
Journal: Circulation Research (2010)

The large conductance Ca(2+)-activated K(+) (BK) channel, a key determinant of vascular tone, is regulated by angiotensin II (Ang II) type 1 receptor signaling. Upregulation of Ang II functions and downregulation of BK channel activities have been reported in diabetic vessels. However, the molecular mechanisms underlying Ang II-mediated BK channel modulation, especially in diabetes mellitus, have not been thoroughly examined.The aim in this study was to determine whether caveolae-targeting facilitates BK channel dysfunction in diabetic vessels.Using patch clamp techniques and molecular biological approaches, we found that BK channels, Ang II type 1 receptor, G(alphaq/11) (G protein q/11 alpha subunit), nonphagocytic NAD(P)H oxidases (NOX-1), and c-Src kinases (c-Src) were colocalized in the caveolae of rat arterial smooth muscle cells and the integrity of caveolae in smooth muscle cells was critical for Ang II-mediated BK channel regulation. Most importantly, membrane microdomain targeting of these proteins was upregulated in the caveolae of streptozotocin-induced rat diabetic vessels, leading to enhanced Ang II-induced redox-mediated BK channel modification and causing BK channel and coronary dysfunction. The absence of caveolae abolished the effects of Ang II on vascular BK channel activity and preserved BK channel function in diabetes.These results identified a molecular scheme of receptor/enzyme/channel/caveolae microdomain complex that facilitates the development of vascular BK channel dysfunction in diabetes.
The Challenge of Predicting and Preventing Sudden Cardiac Death Immediately After Myocardial Infarction
Authors: N. A. Mark Estes
Journal: Circulation (2009)

3][4] Despite optimal therapy, the risk of SCD is highest in the first 30 days among patients with left ventricular dysfunction. 4Thus, earlier implementation of strategies for the prevention of sudden death immediately after a STEMI is needed.
Human rhinovirus subtypes and association with respiratory symptoms during the first year of life in healthy children
Authors: Loretta Müller, Ines Mack, Nicolas Regamey, Caroline Tapparel, Laurent Kaiser, Urs Frey, Philipp Latzin
Journal: European Respiratory Journal (2014)

Background: Human rhinovirus (RV) is one of the most common respiratory viruses affecting children. Despite its known role in asthma development, its clinical impact in infants is unclear. In particular, little is known about the association of particular RV subtypes with respiratory symptoms in early life. We therefore investigated prevalence of RV subtypes and its association with respiratory symptoms in otherwise healthy infants.

Methods: In a subsample of 20 infants from a prospective birth cohort, we analyzed RV colonization in nasal swabs on a weekly basis during the first year of life. RV-positive samples were further sequenced to determine RV subtypes. Respiratory health was assessed weekly by standardized telephone interviews with the parents.

Results: RV was detected in 261 out of 825 (32%) nasal swabs obtained in the 20 infants. RV type A and C were equally frequent (39%), followed by RV-B (12%) and untypable samples (10%). 76 different RV subtypes were identified (30xA, 8xB, 36xC); 22 RV subtypes were identified more than four times. Half of the RV-positive episodes were accompanied by respiratory symptoms. Association between RV subtypes and symptoms was heterogeneous. The two most frequent subtypes (A78/A16) were identified 18/9x in 7/4 infants and symptomatic in 53/75% episodes. The seasonal RV colonization pattern differed among RV types, e.g. 63% in spring and 21% in fall for RV-A and 29% in spring and 46% in fall for RV-C.

Conclusions: Distribution of RV subtypes among infants is highly heterogeneous, varies between seasons and is differently associated with respiratory symptoms.
Developmental changes in guanine nucleotide regulatory proteins in the rat myocardial alpha 1-adrenergic receptor complex.
Authors: H M Han, R B Robinson, J P Bilezikian, S F Steinberg
Journal: Circulation Research (1989)

During development, the cardiac alpha 1-adrenergic chronotropic response changes from positive in the neonate to negative in the adult. The negative chronotropic effect of alpha 1-adrenergic stimulation in the adult depends on maturation of sympathetic innervation and the presence of a pertussis toxin (PT)-sensitive guanine nucleotide-binding (G) protein. To examine the possibility of a developmental change in coupling of a PT-sensitive G protein to the alpha 1-adrenergic receptor, radioligand binding experiments with the iodinated alpha 1-selective radioligand [125I]-I-2-[beta-(4-hydroxyphenyl)ethylaminomethyl]tetralone ([ 125I]-IBE 2254) were performed on membranes prepared from control and PT-treated neonatal and adult rat hearts. Scatchard analysis showed fewer alpha 1-adrenergic receptors in the adult than in the neonate (168 +/- 10 fmol/mg protein in the neonate vs. 124 +/- 13 fmol/mg protein in the adult), but similar affinities (equilibrium dissociation constant 124 +/- 29 pM in the neonate vs. 140 +/- 34 pM in the adult). PT treatment did not alter the results. In both the neonate and adult, 5'-guanylylimidodiphosphate [Gpp(NH)p, 500 microM] shifted the l-epinephrine competition curve to the right and increased the slope factor toward unity. PT had no effect on the l-epinephrine competition curve in the neonate. However, in the adult PT itself caused a partial shift in the agonist competition curve, reducing but not eliminating the effect of Gpp(NH)p. Consistent with the results from the binding experiments, PT did not have any effect on the alpha 1-adrenergic-mediated positive chronotropic response in the neonate, whereas in the adult the alpha 1-adrenergic-mediated negative chronotropic response was completely converted to a positive one after PT treatment. These results indicate the presence of a PT-insensitive G protein in the neonatal and adult rat heart and the acquisition of a PT-sensitive G protein linked to the negative chronotropic response during development.
Intracellular electrical activity in circular muscle of canine colon.
Authors: M M Chambers, Y J Kingma, K L Bowes
Journal: Gut (1984)

In vivo and extracellular in vitro studies of colon muscle have led to a great deal of disagreement on the characteristics of slow wave activity. As intracellular recordings of electrical activity in single cells give clear records which are easier to analyse, we used this method to study the slow wave activity of the circular muscle of three different parts of the canine colon. Mucosa was removed from segments of proximal, mid and distal canine colon and specimens from each segment were mounted in an organ bath perfused with oxygenated Krebs9 solution. Membrane potential, amplitude and frequency of slow waves were measured using intracellular electrodes. Slow wave activity was present at a single, continuous frequency of 4-6 cpm in the circular muscle at all the sites studied in canine colon. There was no significant frequency gradient along the colon: the membrane potential and amplitude of slow waves did not differ significantly in the three parts of the colon.
Relationship between the inflammatory infiltrate in bronchial biopsy specimens and clinical severity of asthma in patients treated with inhaled steroids.
Authors: J. K. Sont, J. Han, J. M. van Krieken, C. E. Evertse, R. Hooijer, L. N. Willems, P. J. Sterk
Journal: Thorax (1996)

BACKGROUND: Current guidelines on the management of asthma advocate the use of anti-inflammatory treatment in all but mild disease. They define disease control in terms of clinical criteria such as lung function and symptoms. However, the relationship between the clinical control of the disease and inflammation of the airways is not clear. A cross sectional study was therefore undertaken to investigate the relationship between airways inflammation and measures of clinical control and bronchial hyperresponsiveness in asthmatic patients treated with inhaled steroids. METHODS: Twenty six atopic adults (19-45 years) with mild to moderate asthma (baseline forced expiratory volume in one second (FEV1) &gt; or = 50% predicted, concentration of histamine causing a 20% fall in FEV1 (PC20) 0.02-7.6 mg/ml) on regular treatment with inhaled steroids entered the study. Diary card recordings during the two weeks before a methacholine challenge test and bronchoscopic examination were used to determine peak flow variability, symptom scores, and use of beta 2 agonists. Biopsy specimens were taken by fibreoptic bronchoscopy from the carina of the right lower and middle lobes, and from the main carina. Immunohistochemical staining was performed on cryostat sections with monoclonal antibodies against: eosinophil cationic protein (EG1, EG2), mast cell tryptase (AA1), CD45, CD22, CD3, CD4, CD8, CD25, and CD45RO. The number of positively stained cells in the lamina propria was counted twice by using an interactive display system. RESULTS: There were no differences in cell numbers between the three sites from which biopsy specimens were taken. The PC20 for methacholine was inversely related to the average number of total leucocytes, EG1+, and EG2+ cells, mast cells, CD8+, and CD45RO+ cells in the lamina propria. These relationships were similar for each of the biopsy sites. Symptom scores, beta 2 agonist usage, FEV1, and peak flow variability were not related to any of the cell counts. CONCLUSIONS: Infiltration of inflammatory cells in the lamina propria of the airways seems to persist in asthmatic outpatients despite regular treatment with inhaled steroids. The number of infiltrating leucocytes such as mast cells, (activated) eosinophils, CD8+, and CD45RO+ cells in bronchial biopsy specimens from these patients appears to be reflected by airway hyperresponsiveness to methacholine, but not by symptoms or lung function. These findings may have implications for the adjustment of anti-inflammatory treatment of patients with asthma.
Safe treatment of thiopurine S-methyltransferase deficient Crohn's disease patients with azathioprine
Authors: B A Kaskas
Journal: Gut (2002)

Thiopurine S-methyltransferase (TPMT) deficient patients develop life threatening haematotoxicity (for example, pancytopenia) when treated with a standard dose of azathioprine (AZA) and 6-mercaptopurine (6-MP) due to excessive accumulation of cytotoxic metabolites. At present, it is generally recommended that these patients should not receive AZA or 6-MP treatment for inflammatory bowel disease. We report for the first time that Crohn's disease patients with TPMT deficiency can be successfully treated with AZA. We illustrate this with three cases where treatment has been successful and toxicity has been avoided by carefully titrating the drug dose. Thus very low TPMT activity demands pharmacogenetically guided <i>dosing</i>.
Krüppel-like factor 5 is a crucial mediator of intestinal tumorigenesis in mice harboring combined Apc Min and KRASV 12mutations
Authors: Mandayam O. Nandan, Amr M. Ghaleb, Beth B. McConnell, Nilesh V. Patel, Sylvie Robine, Vincent W. Yang
Journal: Molecular Cancer (2010)

Abstract Background Both mutational inactivation of the adenomatous polyposis coli ( APC ) tumor suppressor gene and activation of the KRAS oncogene are implicated in the pathogenesis of colorectal cancer. Mice harboring a germline Apc Min mutation or intestine-specific expression of the KRAS V 12 gene have been developed. Both mouse strains develop spontaneous intestinal tumors, including adenoma and carcinoma, though at a different age. The zinc finger transcription factor Krüppel-like factor 5 (KLF5) has previously been shown to promote proliferation of intestinal epithelial cells and modulate intestinal tumorigenesis. Here we investigated the in vivo effect of Klf5 heterozygosity on the propensity of Apc Min / KRAS V 12 double transgenic mice to develop intestinal tumors. Results At 12 weeks of age, Apc Min / KRAS V 12 mice had three times as many intestinal tumors as Apc Min mice. This increase in tumor number was reduced by 92% in triple transgenic Apc Min / KRAS V 12 / Klf5 +/- mice. The reduction in tumor number in Apc Min / KRAS V 12 / Klf5 +/- mice was also statistically significant compared to Apc Min mice alone, with a 75% decrease. Compared with Apc Min / KRAS V 12 , tumors from both Apc Min / KRAS V 12 / Klf5 +/- and Apc Min mice were smaller. In addition, tumors from Apc Min mice were more distally distributed in the intestine as contrasted by the more proximal distribution in Apc Min / KRAS V 12 and Apc Min / KRAS V 12 / Klf5 +/- mice. Klf5 levels in the normal-appearing intestinal mucosa were higher in both Apc Min and Apc Min / KRAS V 12 mice but were attenuated in Apc Min / KRAS V 12 / Klf5 +/- mice. The levels of β-catenin, cyclin D1 and Ki-67 were also reduced in the normal-appearing intestinal mucosa of Apc Min / KRAS V 12 / Klf5 +/- mice when compared to Apc Min / KRAS V 12 mice. Levels of pMek and pErk1/2 were elevated in the normal-appearing mucosa of Apc Min / KRAS V 12 mice and modestly reduced in Apc Min / KRAS V 12 / Klf5 +/- mice. Tumor tissues displayed higher levels of both Klf5 and β-catenin, irrespective of the mouse genotype from which tumors were derived. Conclusions Results of the current study confirm the cumulative effect of Apc loss and oncogenic KRAS activation on intestinal tumorigenesis. The drastic reduction in tumor number and size due to Klf5 heterozygosity in Apc Min / KRAS V 12 mice indicate a critical function of KLF5 in modulating intestinal tumor initiation and progression.
Endoscopic ultrasound-guided fine-needle marking of lymph nodes
Authors: M. Larsen, C. Fristrup, T. Pless, A. Ainsworth, H. Nielsen, C. Hovendal, M. Mortensen
Journal: Endoscopy (2009)

See also: Commentaire de travail de M. H. Larsen et al., pp. 133Endoscopy 2010; 42(02): 183-184DOI: 10.1055/s-0031-1291836
Effects of Tamoxifen on Benign Breast Disease in Women at High Risk for Breast Cancer
Authors: E. Tan-Chiu, J. Wang, J. P. Costantino, S. Paik, C. Butch, D. L. Wickerham, B. Fisher, N. Wolmark
Journal: JNCI Journal of the National Cancer Institute (2003)

In 1998 the National Surgical Adjuvant Breast and Bowel Project (NSABP) demonstrated that tamoxifen treatment reduced the incidence of both invasive and noninvasive breast cancer in women at high risk for the disease. We examined the effect of tamoxifen treatment on the incidence of benign breast disease and the number of breast biopsies in the same group of women.We examined the medical records of 13 203 women with follow-up who participated in the NSABP Breast Cancer Prevention Trial. Included in this analysis were women who had undergone a breast biopsy and who had histologic diagnoses of adenosis, cyst, duct ectasia, fibrocystic disease, fibroadenoma, fibrosis, hyperplasia, or metaplasia. The relative risk (RR) for each histologic diagnosis was estimated for women who received tamoxifen and for women who received placebo. We also tallied the number of biopsies that women in the placebo and tamoxifen groups underwent.Overall, tamoxifen treatment reduced the risk of benign breast disease by 28% (RR = 0.72, 95% confidence interval [CI] = 0.65 to 0.79). Tamoxifen therapy resulted in statistically significant reductions in the risk of adenosis (RR = 0.59, 95% CI = 0.47 to 0.73), cyst (RR = 0.66, 95% CI = 0.58 to 0.75), duct ectasia (RR = 0.72, 95% CI = 0.53 to 0.97), fibrocystic disease (RR = 0.67, 95% CI = 0.58 to 0.77), hyperplasia (RR = 0.60, 95% CI = 0.50 to 0.71), and metaplasia (RR = 0.51, 95% CI = 0.41 to 0.62). Tamoxifen therapy also reduced the risk for fibroadenoma (RR = 0.77, 95% CI = 0.56 to 1.04) and fibrosis (RR = 0.86, 95% CI = 0.72 to 1.03). Compared with the placebo group, the tamoxifen group had 29% (95% CI = 23% to 34%) fewer biopsies (1048 versus 1469) and 19% fewer women who underwent a biopsy (811 versus 1019). This resulted in a 29% reduction in the risk of biopsy in women treated with tamoxifen (RR = 0.71, 95% CI = 0.66 to 0.77). This risk reduction occurred predominantly in women younger than 50 years.Women in this study who received tamoxifen, especially younger women (i.e., <50 years), had a reduced incidence of clinically detected benign breast disease and underwent fewer breast biopsies.
Role of inspiratory capacity on exercise tolerance in COPD patients with and without tidal expiratory flow limitation at rest
Authors: O. Diaz, C. Villafranca, H Ghezzo, G Borzone, A Leiva, J Milic-Emil, C Lisboa
Journal: European Respiratory Journal (2000)

Expiratory flow limitation promotes dynamic hyperinflation during exercise in chronic obstructive pulmonary disease (COPD) patients with a consequent reduction in inspiratory capacity (IC), limiting their exercise tolerance. Therefore, the exercise capacity of patients with tidal expiratory flow limitation (FL) at rest should depend on the magnitude of IC. The presented study was designed to evaluate the role of FL on the relationship between resting IC, other respiratory function variables and exercise performance in COPD patients. Fifty-two patients were included in the study. Negative expiratory pressure (NEP) uptake (VO2,max) were measured during an incremental symptom-limited cycle exercise. Twenty-nine patients were FL at rest. The IC was normal in all non-FL patients, while in most FL subjects it was decreased. Both WRmax and VO2,max were lower in FL patients (p&lt;0.001, each). A close relationship of WRmax and O2,max to IC was found (r=0.73 and 0.75, respectively; p&lt;0.0001, each). In the whole group, stepwise regression analysis selected IC and forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) (% predicted) as the only significant contributors to exercise tolerance. Subgroup analysis showed that IC was the sole predictor in FL patients, and FEV1/FVC in non-FL patients. Detection of flow limitation provides useful information on the factors that influence exercise capacity in chronic obstructive pulmonary disease patients. Accordingly, in patients with flow limitation, inspiratory capacity appears as the best predictor of exercise tolerance, reflecting the presence of dynamic hyperinflation.