tbuckley/cabot-search huggingface dataset:
Dynamic hyperinflation and flow limitation during methacholine-induced bronchoconstriction in asthma
Authors: C Tantucci, M Ellaffi, A Duguet, M Zelter, T Similowski, JP Derenne, J Milic-Emili
Journal: European Respiratory Journal (1999)

Although persistent activation of the inspiratory muscles and narrowing of the glottic aperture during expiration have been indicated as relevant mechanisms leading to dynamic hyperinflation in acute asthma, expiratory flow limitation (EFL) has recently been proposed as a possible triggering factor for increasing endexpiratory lung volume (EELV). To establish whether the attainment of maximal flow rate during tidal expiration could elicit dynamic elevation of EELV, breathing pattern, change in EELV by measuring inspiratory capacity (IC) and occurrence of EFL by the negative expiratory pressure (NEP) method were monitored in 10 stable asthmatic subjects during methacholine-induced, progressive bronchoconstriction in seated position. Change in dyspnoea was scored using the Borg scale. At maximum response forced expiratory volume in one second (FEV1) fell on average by 45+/-2% (p&lt;0.001 versus control), while IC decreased 29+/-2%, (by 0.89+/-0.07 L, (p&lt;0.01 versus control)). Only 2 subjects exhibited EFL at the end of methacholine challenge. In 7 subjects EELV started to increase before the occurrence of EFL. Dyspnoea, which increased from 0.2+/-0.1 to 5.5+/-1.0 (Borg scale) at maximum response (p&lt;0.001), was significantly related to the level of bronchoconstriction as assessed by change in (delta)FEV1 (r=0.72; p&lt;0.001) and to dynamic hyperinflation as measured by deltaIC (r=0.50; p&lt;0.001). However, for both deltaFEV1 and deltaIC the slope of the relationship with increasing dyspnoea was highly variable among the subjects. It is concluded that in acute methacholine-induced bronchoconstriction, dynamic hyperinflation may occur in the absence of expiratory flow limitation and that expiratory flow limitation does not represent the triggering factor to generate dynamic hyperinflation. In these circumstances, dyspnoea appears to be related to the increase in end-expiratory lung volume and not to the onset of expiratory flow limitation.
Beyond scoring: a modern interpretation of disease progression in chronic liver disease
Authors: Matteo Rosselli, Jane MacNaughtan, Rajiv Jalan, Massimo Pinzani
Journal: Gut (2013)

The progressive understanding of the natural history of chronic liver diseases (CLD) and the relative pathophysiological mechanisms have led to important improvements in the current management of these disorders. As for any cognitive course, this progress has been based on the establishment of identifiable endpoints. Along these lines, the introduction of staging systems based on the histopathological assessment of liver tissue fibrosis has allowed a reasonable understanding of what is defined as disease progression in CLD, and has facilitated the communication between clinicians and pathologists. However, there is increasing awareness that a simple semiquantitative fibrosis score does not adequately represent the complexity of the pathophysiological process leading to cirrhosis, and ultimately to life-threatening complications. Indeed, the categorisation in fibrosis stages is a clinical compromise that does not reflect the biological complexity of disease progression. This inadequacy becomes fully manifested in the stage defined ‘cirrhosis’, a phase of CLD often lasting several years, lacking appropriate clinical–pathological correlates.1 ,2

All these issues, and particularly those related to cirrhosis, are currently magnified by the increasing availability of potentially effective causative treatments (ie, antiviral agents for HCV and HBV CLD) with the emerging need of assessing/predicting disease stabilisation or even disease regression with relative accuracy. The aim of this article is to analyse this evolving area of hepatology, and focus on some relevant areas of research which will likely bring further advancement in the near future. In particular, the progression of CLD should be analysed according to aetiology-driven mechanisms, and by integrating the results of invasive and non-invasive methods with a clear mission towards the identification of predictive indexes guiding a more effective clinical management. Further complexity has been introduced by the recent description of the entity termed ‘acute on chronic liver failure’ (ACLF) which refers to a very rapid progression of …
Aberrant Promoter Hypermethylation of Multiple Genes in Gallbladder Carcinoma and Chronic Cholecystitis
Authors: Takao Takahashi, Narayan Shivapurkar, Erick Riquelme, Hisayuki Shigematsu, Jyotsna Reddy, Makoto Suzuki, Kuniharu Miyajima, Xian Zhou, B. Nebiyou Bekele, Adi F. Gazdar, Ignacio I. Wistuba
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Aberrant methylation of 5′ gene promoter regions is an epigenetic phenomenon that is a major mechanism for silencing of tumor suppressor genes in many cancer types. There is limited information about the molecular changes involved in the pathogenesis of gallbladder carcinoma (GBC), including methylation status. Experimental Design: We investigated the aberrant promoter methylation profile of 24 known or suspected tumor suppressor genes in 50 GBCs and compared those results with the findings in 25 chronic cholecystitis (CC) specimens without cancer. The methylation-specific polymerase chain reaction and combined restriction analysis methods were used to detect methylation, and the results were confirmed by sequencing of cloned polymerase chain reaction products. Results: In GBC, gene methylation frequencies varied from 0% to 80%. Ten genes demonstrated relatively high frequencies of aberrant methylation: SHP1 (80%), 3-OST-2 (72%), CDH13 (44%), P15INK4B (44%), CDH1 (38%), RUNX3 (32%), APC (30%), RIZ1 (26%), P16INK4A (24%), and HPP1 (20%). Eight genes (P73, RARβ2, SOCS-1, DAPK, DcR2, DcR1, HIN1, and CHFR) showed low frequencies (2–14%) of methylation, and no methylation of the remaining six genes (TIMP-3, P57, RASSF1A, CRBP1, SYK, and NORE1) was detected. In CC, methylation was detected for seven genes: SHP1 (88%), P15INK4B (28%), 3-OST-2 (12%), CDH1 (12%), CDH13 (8%), DcR2 (4%), and P16INK4A (4%). Significantly higher frequencies of methylation in GBC compared with CC were detected for eight genes (3-OST-2, CDH13, CDH1, RUNX3, APC, RIZ1, P16INK4A, and HPP1). Of those, four genes showed frequent methylation (&amp;gt;30%) in GBCs. The mean methylation index, an expression of the amount of methylated genes by case, was significantly higher in GBC (0.196 ± 0.013) compared with CC (0.065 ± 0.008; P &amp;lt; 0.001). Conclusions: Our study constitutes the most comprehensive methylation profile report available in GBC and demonstrates that this neoplasm has a distinct pattern of abnormal gene methylation. Whereas gallbladders from healthy individual were not available, our finding of methylation in CC cases without cancer suggests that this phenomenon represents an early event in the pathogenesis of GBC.
Epac Mediates β-Adrenergic Receptor–Induced Cardiomyocyte Hypertrophy
Authors: Mélanie Métrich, Alexandre Lucas, Monique Gastineau, Jane-Lise Samuel, Christophe Heymes, Eric Morel, Frank Lezoualc’h
Journal: Circulation Research (2008)

Cardiac hypertrophy is promoted by adrenergic overactivation and can progress to heart failure, a leading cause of mortality worldwide. Although cAMP is among the most well-known signaling molecules produced by beta-adrenergic receptor stimulation, its mechanism of action in cardiac hypertrophy is not fully understood. The identification of Epac (exchange protein directly activated by cAMP) proteins as novel sensors for cAMP has broken the dogma surrounding cAMP and protein kinase A. However, their role and regulation in the mature heart remain to be defined. Here, we show that cardiac hypertrophy induced by thoracic aortic constriction increases Epac1 expression in rat myocardium. Adult ventricular myocytes isolated from banded animals display an exaggerated cellular growth in response to Epac activation. At the molecular level, Epac1 hypertrophic effects are independent of its classic effector, Rap1, but rather involve the small GTPase Ras, the phosphatase calcineurin, and Ca(2+)/calmodulin-dependent protein kinase II. Importantly, we find that in response to beta-adrenergic receptor stimulation, Epac1 activates Ras and induces adult cardiomyocyte hypertrophy in a cAMP-dependent but protein kinase A-independent manner. Knockdown of Epac1 strongly reduces beta-adrenergic receptor-induced hypertrophic program. Finally, we report for the first time that Epac1 is mainly expressed in human heart as compared with Epac2 isoform and is increased in heart failure. Taken together, our data demonstrate that the guanine nucleotide exchange factor Epac1 contributes to the hypertrophic effect of beta-adrenergic receptor in a protein kinase A-independent fashion and may, therefore, represent a novel therapeutic target for the treatment of cardiac disorders.
Dietary Pattern Influences Breast Cancer Prognosis in Women Without Hot Flashes: The Women's Healthy Eating and Living Trial
Authors: Ellen B. Gold, John P. Pierce, Loki Natarajan, Marcia L. Stefanick, Gail A. Laughlin, Bette J. Caan, Shirley W. Flatt, Jennifer A. Emond, Nazmus Saquib, Lisa Madlensky, Sheila Kealey, Linda Wasserman, Cynthia A. Thomson, Cheryl L. Rock, Barbara A. Parker, Njeri Karanja, Vicky Jones, Richard A. Hajek, Minya Pu, Joanne E. Mortimer
Journal: Journal of Clinical Oncology (2008)

To determine whether a low-fat diet high in vegetables, fruit, and fiber differentially affects prognosis in breast cancer survivors with hot flashes (HF) or without HF after treatment.A secondary analysis was conducted on 2,967 breast cancer survivors, age 18 to 70 years, who were randomly assigned between 1995 and 2000 in a multicenter, controlled trial of a dietary intervention to prevent additional breast cancer events and observed through June 1, 2006. We compared the dietary intervention group with a group who received five-a-day dietary guidelines.Independent of HF status, a substantial between-group difference among those who did and did not receive dietary guidelines was achieved and maintained at 4 years in intake of vegetable/fruit servings per day (54% higher; 10 v 6.5 servings/d, respectively), fiber (31% higher; 25.5 v 19.4 g/d, respectively), and percent energy from fat (14% lower; 26.9% v 31.3%, respectively). Adjusting for tumor characteristics and antiestrogen treatment, HF-negative women assigned to the intervention had 31% fewer events than HF-negative women assigned to the comparison group (hazard ratio [HR] = 0.69; 95% CI, 0.51 to 0.93; P = .02). The intervention did not affect prognosis in the women with baseline HFs. Furthermore, compared with HF-negative women assigned to the comparison group, HF-positive women had significantly fewer events in both the intervention (HR = 0.77; 95% CI, 0.59 to 1.00; P = .05) and comparison groups (HR = 0.65; 95% CI, 0.49 to 0.85; P = .002).A diet with higher vegetable, fruit, and fiber and lower fat intakes than the five-a-day diet may reduce risk of additional events in HF-negative breast cancer survivors. This suggestive finding needs confirmation in a trial in which it is the primary hypothesis.
Infection and death from influenza A H1N1 virus in Mexico: a retrospective analysis
Authors: Santiago Echevarría-Zuno, Juan Manuel Mejía-Aranguré, Alvaro J Mar-Obeso, Concepción Grajales-Muñiz, Eduardo Robles-Pérez, Margot González-León, Manuel Carlos Ortega-Alvarez, Cesar Gonzalez-Bonilla, Ramón Alberto Rascón-Pacheco, Víctor Hugo Borja-Aburto
Journal: The Lancet (2009)
International network for capacity building for the control of emerging viral vector-borne zoonotic diseases: ARBO-ZOONET
Authors: J Ahmed, M Bouloy, O Ergonul, A. R. Fooks, J Paweska, V Chevalier, C Drosten, R Moormann, N Tordo, Z Vatansever, P Calistri, A Estrada-Peña, A Mirazimi, H Unger, H Yin, U Seitzer
Journal: Eurosurveillance (2009)

Arboviruses are arthropod-borne viruses, which include West Nile fever virus (WNFV), a mosquito-borne virus, Rift Valley fever virus (RVFV), a mosquito-borne virus, and Crimean-Congo haemorrhagic fever virus (CCHFV), a tick-borne virus. These arthropod-borne viruses can cause disease in different domestic and wild animals and in humans, posing a threat to public health because of their epidemic and zoonotic potential. In recent decades, the geographical distribution of these diseases has expanded. Outbreaks of WNF have already occurred in Europe, especially in the Mediterranean basin. Moreover, CCHF is endemic in many European countries and serious outbreaks have occurred, particularly in the Balkans, Turkey and Southern Federal Districts of Russia. In 2000, RVF was reported for the first time outside the African continent, with cases being confirmed in Saudi Arabia and Yemen. This spread was probably caused by ruminant trade and highlights that there is a threat of expansion of the virus into other parts of Asia and Europe. In the light of global warming and globalisation of trade and travel, public interest in emerging zoonotic diseases has increased. This is especially evident regarding the geographical spread of vector-borne diseases. A multi-disciplinary approach is now imperative, and groups need to collaborate in an integrated manner that includes vector control, vaccination programmes, improved therapy strategies, diagnostic tools and surveillance, public awareness, capacity building and improvement of infrastructure in endemic regions.
Clinical commissioning groups and councils must have single process for commissioning services for elderly, say MPs
Authors: A. O'Dowd
Journal: BMJ (2012)

Many drugs interfere with the assay of urinary 17-oxo and oxogenic steroids. Some propionic acid derivatives, in particular, tiaprofenic acid, have now been shown to affect this assay. Care should be taken when interpreting results in patients on these drugs.
Multicenter Phase II Trial of Chemoradiation With Oxaliplatin for Rectal Cancer
Authors: Claus Rödel, Torsten Liersch, Robert Michael Hermann, Dirk Arnold, Thomas Reese, Matthias Hipp, Alois Fürst, Nimrod Schwella, Michael Bieker, Gunter Hellmich, Hermann Ewald, Jörg Haier, Florian Lordick, Michael Flentje, Heiko Sülberg, Werner Hohenberger, Rolf Sauer
Journal: Journal of Clinical Oncology (2006)

To evaluate the activity and safety of preoperative radiotherapy (RT) and concurrent capecitabine and oxaliplatin (XELOX-RT) plus four cycles of adjuvant XELOX in patients with rectal cancer.One hundred ten patients with T3/T4 or N+ rectal cancer were entered onto the trial in 11 investigator sites and received preoperative RT (50.4 Gy in 28 fractions). Capecitabine was administered concurrently at 1,650 mg/m2 on days 1 to 14 and 22 to 35, and oxaliplatin was administered at 50 mg/m2 on days 1, 8, 22, and 29. Surgery was scheduled 4 to 6 weeks after completion of XELOX-RT. Four cycles of adjuvant XELOX (capecitabine 1,000 mg/m2 bid on days 1 to 14; oxaliplatin 130 mg/m2 on day 1) were administered. The main end points were activity as assessed by the pathologic complete response (pCR) rate and the feasibility of postoperative XELOX chemotherapy.After XELOX-RT, 103 of 104 eligible patients underwent surgery; pCR was achieved in 17 patients (16%), one patient had ypT0N1 disease, and 53 patients showed tumor regression of more than 50% of the tumor mass. R0 resections were achieved in 95% of patients, and sphincter preservation was accomplished in 77%. Full-dose preoperative XELOX-RT was administered in 96%. Grade 3 or 4 diarrhea occurred in 12% of patients. Postoperative complication occurred in 43% of patients. Sixty percent of patients received all four cycles of adjuvant XELOX, with sensory neuropathy (18%) and diarrhea (12%) being the main grade 3 or 4 toxicities.Preoperative XELOX-RT plus four cycles of adjuvant XELOX is an active and feasible treatment. This regimen is proposed for phase III evaluation comparing standard fluorouracil-based treatment with XELOX- based multimodality treatment.
Effects of Budesonide/Formoterol (BUD/FM) Deliverd By Pressurized Metered-Dose Inhaler (pMDI) on Symptoms In African Americans and Caucasians With Moderate and Severe Asthma With and Without Fixed Airway Obstruction (FAO)
Authors: Donald P. Tashkin, Bradley E. Chipps, Frank Trudo
Journal: Journal of Allergy and Clinical Immunology (2014)
Combined Levothyroxine Plus Liothyronine Compared With Levothyroxine Alone in Primary Hypothyroidism
Authors: Patrick W. Clyde, Amir E. Harari, Eric J. Getka, K. M. Mohamed Shakir
Journal: JAMA (2003)

Standard therapy for patients with primary hypothyroidism is replacement with synthetic thyroxine, which undergoes peripheral conversion to triiodothyronine, the active form of thyroid hormone. Within the lay population and in some medical communities, there is a perception that adding synthetic triiodothyronine, or liothyronine, to levothyroxine improves the symptoms of hypothyroidism despite insufficient evidence to support this practice.To evaluate the benefits of treating primary hypothyroidism with levothyroxine plus liothyronine combination therapy vs levothyroxine monotherapy.Randomized, double-blind, placebo-controlled trial conducted from May 2000 to February 2002 at a military treatment facility that serves active duty and retired military personnel and their family members. The trial included a total of 46 patients aged 24 to 65 years with at least a 6-month history of treatment with levothyroxine for primary hypothyroidism.Patients received either their usual dose of levothyroxine (n = 23) or combination therapy (n = 23), in which their usual levothyroxine dose was reduced by 50 micro g/d and substituted with liothyronine, 7.5 micro g, taken twice daily for 4 months.Scores on a hypothyroid-specific health-related quality-of-life (HRQL) questionnaire, body weight, serum lipid levels, and 13 neuropsychological tests measured before and after treatment.Serum thyrotropin levels remained similar and within the normal range in both treatment groups from baseline to 4 months. Body weight and serum lipid levels did not change. The HRQL questionnaire scores improved significantly in both the control group (23%; P<.001) and the combination therapy group (12%; P =.02), but these changes were statistically similar (P =.54). In 12 of 13 neuropsychological tests, outcomes between groups were not significantly different; the 1 remaining test (Grooved Peg Board) showed better performance in the control group.Compared with levothyroxine alone, treatment of primary hypothyroidism with combination levothyroxine plus liothyronine demonstrated no beneficial changes in body weight, serum lipid levels, hypothyroid symptoms as measured by a HRQL questionnaire, and standard measures of cognitive performance.
The ubiquitin?proteasome system may be involved in the pathogenesis of hypertrophic cardiomyopathy
Authors: H VOSBERG
Journal: Cardiovascular Research (2005)

Cardiac morbidity results in the majority of cases from conditions that do not arise in the myocardium itself, but rather in response to extra-myocardial challenges associated with systemic, vascular, or other dysfunctions.A few, not particularly frequent cardiac disorders, however, can be traced to an impairment from within the myocardium.Many, if not most, of these conditions have a genetic cause.Mutations in numerous genes have been identified, most notably in genes coding for proteins involved in contraction and force development, electrical conductance, and in structure and maintenance of the cyto-and nucleoskeleton.Particularly well studied among the genuinely myocardial disorders have been the cardiomyopathies, clinically well known for decades and characterized by distorted force production affecting either diastole (relaxation) or systole (contraction).Impaired diastole and systole are hallmarks of hypertrophic-(HCM) and dilated cardiomyopathy (DCM), respectively.HCM-the topic of this commentary-has been intensively studied with respect to both inherited causes [1] and disease mechanisms [2].Established clinical features of HCM are unspecific cardiac symptoms in young adults, asymmetric myocardial hypertrophy with or without leftventricular outflow obstruction, slow progression, but a high risk of sudden cardiac death [3].Transmission is dominant, with penetrance being variable.Molecular genetic analysis began in the late 1980s and has produced a wealth of information about mutations in a large number of genes since then.In short, more than 200 mutations were found in 12 genes coding for sarcomeric proteins acting as bmolecular
Bone Morphogenic Protein-7 Inhibits Monocyte-Stimulated TGF-β1 Generation in Renal Proximal Tubular Epithelial Cells
Authors: Xiao Liang Zhang, Wisam Selbi, Carol de la Motte, Vincent Hascall, Aled O. Phillips
Journal: Journal of the American Society of Nephrology (2004)

It has been demonstrated that bone morphogenic protein-7 (BMP-7) stimulates formation of hyaluronan (HA)-based cables on the cell surface of renal proximal tubular cells and that these cables mediate monocyte binding. Furthermore, interaction of monocytes with proximal tubule cell (PTC) surface intracellular adhesion molecule (ICAM) stimulates the synthesis of TGF-beta1. This study examined the effect of BMP-7 on monocyte-stimulated TGF-beta1 synthesis under conditions of basal and stimulated ICAM expression. Monocyte (U937 cells)-dependent stimulation of TGF-beta1 promoter activity and protein synthesis was reduced by addition of BMP-7 for 24 h before addition of U937 cells. Removal of cell surface HA or inhibition of monocyte interaction with HA using antibody to CD44 prevented this effect of BMP-7. These data suggest that BMP-7 enhances HA-dependent binding and reduces ICAM-dependent binding, which is known to stimulate TGF-beta1 synthesis. This hypothesis was examined further by stimulation of PTC ICAM expression by TNF-alpha. After TNF-alpha stimulation, monocyte-dependent TGF-beta1 synthesis increased. This was abrogated by inhibition of ICAM-CD18 interactions. TNF-alpha stimulation alone did not increase TGF-beta1 synthesis. TNF-alpha stimulation of PTC in the presence of BMP-7 failed to increase monocyte-dependent TGF-beta1 stimulation. Although stimulation of PTC by BMP-7 alone decreased cell surface ICAM expression, it did not affect TNF-alpha-induced ICAM expression. The effect of BMP-7 on TGF-beta1 synthesis in TNF-alpha-stimulated cells was abrogated by disruption of CD44-HA interactions, suggesting that it was due to increased monocyte binding to HA on the cell surface.
Genomic DNA k-mer spectra: models and modalities
Authors: Benny Chor, David Horn, Nick Goldman, Yaron Levy, Tim Massingham
Journal: Genome biology (2009)

The empirical frequencies of DNA k-mers in whole genome sequences provide an interesting perspective on genomic complexity, and the availability of large segments of genomic sequence from many organisms means that analysis of k-mers with non-trivial lengths is now possible. We have studied the k-mer spectra of more than 100 species from Archea, Bacteria, and Eukaryota, particularly looking at the modalities of the distributions. As expected, most species have a unimodal k-mer spectrum. However, a few species, including all mammals, have multimodal spectra. These species coincide with the tetrapods. Genomic sequences are clearly very complex, and cannot be fully explained by any simple probabilistic model. Yet we sought such an explanation for the observed modalities, and discovered that low-order Markov models capture this property (and some others) fairly well. Multimodal spectra are characterized by specific ranges of values of C+G content and of CpG dinucleotide suppression, a range that encompasses all tetrapods analyzed. Other genomes, like that of the protozoa Entamoeba histolytica, which also exhibits CpG suppression, do not have multimodal k-mer spectra. Groupings of functional elements of the human genome also have a clear modality, and exhibit either a unimodal or multimodal behaviour, depending on the two above mentioned values.