tbuckley/cabot-search huggingface dataset:
Wnt Signaling and Aging-Related Heart Disorders
Authors: Atsuhiko T. Naito, Ichiro Shiojima, Issei Komuro
Journal: Circulation Research (2010)

Aging is associated with various heart diseases, and this may be attributable, in part, to the prolonged exposure of the heart to cardiovascular risk factors. However, aging is also associated with heart disorders such as diastolic dysfunction that are not necessarily linked to the risk factors for cardiovascular diseases. Recent studies have demonstrated a mechanistic link between Wnt signaling and premature aging or aging-related phenotypes. As a part of the review series on Wnt signaling and the cardiovascular system, we discuss here the possible involvement of Wnt signaling in aging-associated heart diseases or heart disorders.
Platelet-derived growth factor AA and AB dimers are present in normal human epithelial lining fluid
Authors: M Allam, N Martinet, H Gallati, P Vaillant, M Hosang, Y Martinet
Journal: European Respiratory Journal (1993)

Normal lung architecture is related to the presence of mesenchymal cells (fibroblasts and smooth muscle cells), and to the production by these cells of extracellular matrix. The turnover of mesenchymal cells is under a fine regulation due, at least in part, to the local presence of different mediators acting on their cell cycle. Since normal human alveolar macrophages obtained by bronchoalveolar lavage (BAL) spontaneously release platelet-derived growth factor (PDGF), a cytokine with chemotactic and growth activity on mesenchymal cells, we evaluated normal human epithelial lining fluid (ELF) for the presence of PDGF. Active only as a dimer, PDGF is a glycoprotein composed of two chains (A and B) and, thus, can be present in three forms: AA, AB, and BB dimers. Interestingly, normal ELF contains PDGF AA dimers, and to a lesser extent AB dimers, while no significant level of BB dimers is detected. Furthermore, ELF PDGF is biologically active and responsible for a significant part of the chemotactic activity and the "competence" growth activity for mesenchymal cells present in normal ELF. These findings suggest that ELF PDGF has a role in normal lung structure maintenance and tissue repair.
Estrogen-Independent Proliferation Is Present in Estrogen-Receptor<i>HER2</i>-Positive Primary Breast Cancer After Neoadjuvant Letrozole
Authors: Matthew J. Ellis, Yu Tao, Oliver Young, Sharon White, Alan D. Proia, Julliette Murray, Lorna Renshaw, Dana Faratian, Jeremy Thomas, Mitch Dowsett, Andreas Krause, Dean B. Evans, William R. Miller, J. Michael Dixon
Journal: Journal of Clinical Oncology (2006)

To investigate the impact of human epidermal growth factor receptor (HER) 1 and HER2 gene amplification on endocrine therapy responsiveness, a fluorescence in situ hybridization (FISH) study was conducted on tumor samples from 305 postmenopausal patients with stage II and III estrogen receptor (ER) -positive (ER > or = 10%) breast cancers treated on two independent neoadjuvant endocrine therapy trials.FISH analysis focused on HER1 and/or HER2 immunohistochemistry (IHC) -positive patients and a random selection of HER1/2 IHC-negative patients. HER2 FISH status was correlated with response and changes in the proliferation marker Ki67.HER1 was rarely amplified (< 1%), and HER2 amplification was observed in 9.2% of patients. Letrozole response by clinical measurement (71% HER2 FISH positive v 71% HER2 FISH negative), mammogram (44% HER2 FISH positive v 47% HER2 FISH negative), or ultrasound (47% HER2 FISH positive v 54% HER2 FISH negative) was not impaired by HER2 FISH-positive status. In contrast, HER2 FISH-positive tumors showed higher histologic grade (P = .009), higher pretreatment Ki67 (P = .005), and less Ki67 suppression after letrozole when compared with HER2 FISH-negative tumors (P = .0001). Similar observations regarding Ki67 were made in a smaller cohort of tamoxifen-treated tumors.Neoadjuvant letrozole is clinically effective in ER-positive HER2 FISH-positive tumors, indicating sensitivity to short-term estrogen deprivation. However, continued proliferation despite ongoing letrozole or tamoxifen treatment in the majority of ER-positive HER2 FISH-positive samples (88%) could imply therapeutic resistance that may manifest later in the clinical course of the disease. Discordance between clinical and biomarker findings in this study serves to emphasize the need for surrogate end point validation in neoadjuvant endocrine trials through correlation with information on long-term outcomes.
Regulation of Cholesterol Biosynthesis
Authors: H Rudney, R C Sexton
Journal: Annual Review of Nutrition (1986)

THE CHOLESTEROL BIOSYNTHETIC PATHWAy. . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . 245 Introduction   . . . . . . .   ........   245 Overview of Polyisoprenoid Synthesis and the Role of HMG-CoA Reductase ......... 246 Endogenous and Exogenous Factors Regulating HMG-CoA Reductase Activity . . .. . . 248 Post-mevalonate Regulation of Polyisoprenoid and Cholesterol Synthesis .... .... ..... 251 Oxysterols as Regulators of Cholesterol Synthesis  .. .... .. 254 DIETARY FACTORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... . . . 258 Rates of Cholesterogenesis in Various Tissues   . . . . . ... . ... 258 Eff ects of Dietary Fats on Hepatic Cho/esterogenesis  ... 259 Effects of Vitamin A Active Substances   ..   260 Effects of Vitamin D A ctive Substances   . . . . .. . . ... . .... 261 Role of Cholesterogenesis in Hepatic VLDL Production  ... . . . . . . ... ...... 263 Diurnal Variations in Hepatic Cholesterogenesis   ........ .... .. . .   264 CONCLUSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . 265
P209 Impact of Patient Satisfaction with Their Maintenance Inhaler on Treatment Compliance and Health Outcomes in Chronic Obstructive Pulmonary Disease: An Analysis of Real-World Clinical Practise in Europe: Abstract P209 Table 1
Authors: H Chrystyn, M Small, G Milligan, V Higgins, E Garcia Gil, C Karakurum
Journal: Thorax (2012)

<h3>Introduction and objective</h3> Compliance with prescribed treatment is often suboptimal in patients with chronic obstructive pulmonary disease (COPD). This analysis examined the relationships between inhaler satisfaction, compliance and health outcomes. <h3>Methods</h3> Data were analysed from a large, cross-sectional survey of real-world clinical practise conducted in five European countries. Respiratory specialists and primary care physicians provided information on six consecutive patients with COPD (aged ≥40 years with history of smoking). The same patients were then asked to voluntarily complete a self-assessment form. Physicians scored patient compliance with prescribing instructions (5-point Likert scale: 1='not at all compliant'; 5='fully compliant') and patients rated overall satisfaction with their maintenance inhaler (7point Likert scale: 1='not at all satisfied'; 7='very satisfied'). Health outcomes assessments included exacerbations, the modified Medical Research Council dyspnoea scale, the EuroQoL (EQ-5D) instrument and the Jenkins Sleep Questionnaire. Sequential regression was used to analyze the relationship between inhaler attributes and overall satisfaction. Least-squares regression and additive models were used to analyze the relationships between inhaler satisfaction, compliance and health outcomes. <h3>Results</h3> Data were included for 1443 patients for whom self-completed and matched physician-completed record forms were available. The majority of patients (71.8%) were male; mean age was 65.2 years. Very few patients (0.7%) were 'not at all compliant' with their physician's prescribing instructions, whilst 33.3% were 'fully compliant'. Most patients (75.1%) were more satisfied with their inhaler than not; 6.6% were 'very satisfied'. Key attributes influencing satisfaction related to durability, ergonomics and ease of use. There was a significant association between inhaler satisfaction and compliance (χ2 − df=89.7; p&lt;0.001). Other factors related to greater compliance, though to a lesser degree, were fewer maintenance drugs (χ2 − df=17.7; p&lt;0.001) and male gender (χ2 − df=2.9; p&lt;0.05). Severity of breathlessness, age and ethnicity were not significantly associated with compliance (p&gt;0.05). Higher compliance scores were significantly associated with better health outcomes (Table). There was also a direct association between inhaler satisfaction and better health outcomes (exacerbations and EQ-5D, p&lt;0.001). <h3>Conclusions</h3> Inhaler satisfaction appears to be significantly associated with COPD treatment compliance, and patients with greater compliance experience better health outcomes, including less frequent exacerbations.
Healthcare-associated, community-acquired and hospital-acquired bacteraemic urinary tract infections in hospitalized patients: a prospective multicentre cohort study in the era of antimicrobial resistance
Authors: J.P. Horcajada, E. Shaw, B. Padilla, V. Pintado, E. Calbo, N. Benito, R. Gamallo, M. Gozalo, J. Rodríguez-Baño
Journal: Clinical Microbiology and Infection (2012)
Risks of the unregulated market in human breast milk
Authors: Sarah Steele, Jeanine Martyn, Jens Foell
Journal: BMJ (2015)

Urgent need for regulation

As healthcare workers we routinely emphasise the nutritional superiority of breast milk for infant feeding to new and expectant mothers. Some women, though, find themselves unable to breast feed. Although some of them turn to clinicians and health visitors for advice, as many as three quarters of new mothers now look to the internet for guidance.1 Online these women find emotive, moralising discourse around breast feeding and often fear inducing warnings that formula is inferior to human milk for infant feeding.

They may also find sites that facilitate the buying, selling, and trading of breast milk, as well as high profile media sites featuring celebrities who are engaged in this trade. In the absence of warnings about the dangers of buying milk online, this option might seem healthy and beneficial—the better choice if one can’t breast feed oneself.2 What mothers, and many healthcare workers, don’t realise is that this market is dangerous, putting infant health at risk.

The online market in human milk, growing fastest in …
Impact of Positive Positron Emission Tomography on Prediction of Freedom From Progression After Stanford V Chemotherapy in Hodgkin's Disease
Authors: Ranjana Advani, Lauren Maeda, Philip Lavori, Andrew Quon, Richard Hoppe, Sheila Breslin, Saul A. Rosenberg, Sandra J. Horning
Journal: Journal of Clinical Oncology (2007)

To correlate [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) status after chemotherapy, but before radiation, with outcome in patients treated with the Stanford V regimen.We analyzed retrospectively 81 patients with Hodgkin's disease who had serial [(18)F]FDG-PET scans performed at baseline and again at the completion of Stanford V chemotherapy, before planned radiotherapy. Patients with favorable stage I/II (nonbulky mediastinal disease) and those with bulky mediastinal disease or stage III/IV were scanned after 8 and 12 weeks of chemotherapy, respectively. Radiotherapy fields were determined before starting chemotherapy based on baseline computed tomography scans.After chemotherapy, six of 81 patients had residual [(18)F]FDG-PET-positive sites, all in sites for which radiotherapy was planned. Four of the six patients with positive [(18)F]FDG-PET scans after chemotherapy experienced relapse compared with just three of 75 patients with negative [(18)F]FDG-PET scans. At a median follow-up of 4 years, the freedom from progression (FFP) was 96% in postchemotherapy [(18)F]FDG-PET-negative patients versus 33% in [(18)F]FDG-PET-positive patients (P < .0003). In a bivariate Cox model, [(18)F]FDG-PET positivity after chemotherapy remained a highly significant predictor of progression-free survival even after controlling for bulky disease and International Prognostic Score more than 2.These data indicate that PET status after chemotherapy is strongly predictive of FFP with the Stanford V regimen despite the use of consolidative radiotherapy. These results have implications for the design of clinical trials adapted to functional imaging.
P231 Once-daily Tiotropium Respimat(R): Safety And Tolerability Results From Five Phase Iii Trials In Adults With Symptomatic Asthma
Authors: J. Haughney, M. Vandewalker, E. Meltzer, P. Paggiaro, M. Engel, A. Unseld, P. Moroni-Zentgraf, H. Kerstjens
Journal: Thorax (2014)

<h3>Background</h3> Tiotropium Respimat<sup>®</sup>, a once-daily long-acting anticholinergic agent, is effective as add-on to inhaled corticosteroids (ICS) ± a long-acting β2-agonist (LABA) in adults with symptomatic asthma. Safety and tolerability are key issues in the development of new therapies or established therapies in new disease areas. We present key safety data from five Phase III, randomised, double-blind, parallel-group trials that evaluated the efficacy and safety of once-daily tiotropium Respimat<sup>®</sup> versus placebo in adults with symptomatic asthma. Methods: Two 48-week trials of tiotropium Respimat<sup>®</sup> 5 µg (PrimoTinA-asthma<sup>®</sup>: NCT00776984, NCT00772538) in patients on high-dose ICS (≥800 µg budesonide or equivalent) + LABA; two 24-week trials of tiotropium Respimat<sup>®</sup> 5 µg and 2.5 µg (MezzoTinA-asthma<sup>®</sup>: NCT01172808, NCT01172821) in patients on moderate-dose ICS (400–800 µg budesonide or equivalent); one 12-week trial of tiotropium Respimat<sup>®</sup> 5 µg and 2.5 µg (GraziaTinA-asthma<sup>®</sup>: NCT01316380) in patients on low-dose ICS (200–400 µg budesonide or equivalent). All tiotropium doses were delivered via the Respimat<sup>®</sup> SoftMist™ inhaler. Results: 3476 patients were treated. Incidence of any adverse events (AEs), serious AEs and investigator-defined drug-related AEs was similar across treatment groups within each trial. AEs reported by ≥5% of patients were similar across all treatment groups within each trial (Table). The number of cardiovascular AEs was small in all five studies and comparable between tiotropium Respimat<sup>®</sup> and placebo. No deaths occurred in any trial. Conclusion: Once-daily tiotropium Respimat® is well tolerated and comparable with placebo in adult patients with symptomatic asthma receiving at least low- to high-dose ICS.
Interrelationships Between Automaticity and Conduction in Purkinje Fibers
Authors: DONALD H. SINGER, RALPH LAZZARA, BRAIN F. HOFFMAN
Journal: Circulation Research (1967)

Microelectrode studies of transmembrane potentials of canine Purkinje fibers show that phase-4 depolarization causes voltage-dependent changes in conduction and responsiveness similar to those occurring during repolarization at comparable levels of potential. Abnormalities ranged from simple slowing of conduction to decrement, unidirectional and bidirectional block, and unexcitability. Reentrant excitation also developed. Significant conduction disturbances usually appeared at -75 to -70 mv; decrement and advanced block at -65 to -60 mv, or below. Because the threshold potential of normal Purkinje cells is approximately -70 mv, depolarization to lower levels implies shifts in this variable toward 0. Determinations of threshold potential confirm such shifts. It may be further inferred that significant abnormalities would most likely occur in fibers in which threshold potential is shifted toward 0 or membrane responsiveness impaired. Alterations in conduction due to phase-4 depolarization provide a reasonable explanation for various peculiarities of cardiac rhythm, including occurrence of conduction disturbances and reentrant rhythms at low heart rates, exit and entry block about parasystolic foci, instability of peripheral Purkinje pacemaakers, and supernormal conduction. Circumstances that enhance phase-4 depolarization are common in diseased hearts, indicating that this mechanism may be a significant factor in human arrhythmias.
A CENTRAL ROLE FOR CENTRAL TOLERANCE
Authors: Bruno Kyewski, Ludger Klein
Journal: Annual Review of Immunology (2006)

Recent elucidation of the role of central tolerance in preventing organ-specific autoimmunity has changed our concepts of self/nonself discrimination. This paradigmatic shift is largely attributable to the discovery of promiscuous expression of tissue-restricted self-antigens (TRAs) by medullary thymic epithelial cells (mTECs). TRA expression in mTECs mirrors virtually all tissues of the body, irrespective of developmental or spatio-temporal expression patterns. This review summarizes current knowledge on the cellular and molecular regulation of TRA expression in mTECs, outlines relevant mechanisms of antigen presentation and modes of tolerance induction, and discusses implications for the pathogenesis of autoimmune diseases and other biological processes such as fertility, pregnancy, puberty, and tumor defense.
Specific Resistance of Body Tissues
Authors: HERMAN P. SCHWAN, CALVIN F. KAY
Journal: Circulation Research (1956)

The resistive properties of various tissues surrounding the heart were investigated in a number of living dogs. Alternating currents of a frequency varying between 10 and 10,000 c.p.s. have been used for this purpose. Technical problems associated with such measurements are analyzed. The results show that the resistive properties of most tissues are comparable and that the resistivity decreases slowly as the frequency increases.
Prognostic Importance of Hypodiploid Hemopoietic Precursors in Myelodysplastic Syndromes
Authors: Richard Clark, Stephen Peters, Terry Hoy, Stuart Smith, Katrina Whittaker, Allan Jacobs
Journal: New England Journal of Medicine (1986)

It has been suggested that a poor prognosis and the development of leukemia in patients with myelodysplasia may be related to chromosomal abnormalities. We measured the DNA content of bone marrow cells with flow cytometry in 19 hematologically normal subjects and in 70 patients who had recently been diagnosed as having myelodysplasia. Thirty-four of the patients were found to have aneuploidy. This was not related to the percentage of blast cells in the bone marrow, and there was no demarcation in terms of DNA content between patients with a high percentage of blast cells and those with a low percentage of such cells. Patients with hypodiploid marrow cells had a significantly shorter survival time than other patients (P = 0.001). Patients with hyperdiploid marrow and those whose marrow had a normal DNA content had similar survival times. Hypodiploidy appears to be a better indicator of poor survival than the marrow blast-cell count. Patients with sideroblastic anemia invariably had cells with a normal or high DNA content; none of these patients died during the study. Our data suggest that there is a relation between the loss of chromosomal material and progression toward a leukemic phenotype. It is tempting to speculate that this process may involve a loss of negative regulatory genes ("anti-oncogenes"). (N Engl J Med 1986; 314: 1472–5.)
Renal Dysfunction as a Predictor of Stroke and Systemic Embolism in Patients With Nonvalvular Atrial Fibrillation
Authors: Jonathan P. Piccini, Susanna R. Stevens, YuChiao Chang, Daniel E. Singer, Yuliya Lokhnygina, Alan S. Go, Manesh R. Patel, Kenneth W. Mahaffey, Jonathan L. Halperin, Günter Breithardt, Graeme J. Hankey, Werner Hacke, Richard C. Becker, Christopher C. Nessel, Keith A.A. Fox, Robert M. Califf
Journal: Circulation (2012)

Background— We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. Methods and Results— In ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), 14 264 patients with nonvalvular AF and creatinine clearance ≥30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non–central nervous system embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation), an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 patients (4.0%) experienced primary end-point events. Reduced creatinine clearance was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack. Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, as well as vascular disease of the heart and limbs (C-index 0.635). A model that included creatinine clearance (R 2 CHADS 2 ) improved net reclassification index by 6.2% compared with CHA 2 DS 2 VASc (C statistic=0.578) and by 8.2% compared with CHADS 2 (C statistic=0.575). The inclusion of creatinine clearance &lt;60 mL/min and prior stroke or transient ischemic attack in a model with no other covariates led to a C statistic of 0.590.Validation of R 2 CHADS 2 in an external, separate population improved net reclassification index by 17.4% (95% confidence interval, 12.1%–22.5%) relative to CHADS 2 . Conclusions— In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. Clinical Trial Registration— URL: http://www.ClinicalTrials.gov . Unique identifier: NCT00403767.
Cervical complications of rheumatoid arthritis
Authors: M J Kauppi
Journal: Annals of the Rheumatic Diseases (2004)

### Case history 1

A 47 year old housewife presented with a 3 year history of fleeting inflammatory pain and oedema affecting the small joints of the hands symmetrically. She had previously been given a diagnosis of rheumatoid arthritis (RA), and was receiving treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and prednisolone (10 mg/day).

For the past year she had experienced inflammatory neck pain with a recurrent sense of heaviness and muscle weakness in the upper and lower limbs. Her symptoms were present, especially, during prolonged flexion and were relieved in a favourable posture.

Examination showed symmetrical arthritis and tenderness of wrist and metacarpophalangeal (MCP) joints in both hands. A reduction of about 30% was seen in the anterior and lateral flexion of the cervical spine. Neurological examination results were, however, normal.

Laboratory tests showed high acute phase response and negative rheumatoid factor. Radiographs of the hands and feet disclosed osteopenia but no erosions. Further investigations included radiographs of the cervical spine (neutral and flexion position) (figs 1A and B) and an anterior atlantoaxial subluxation (aAAS) was seen. Magnetic resonance imaging (MRI; fig 1C) of the cervical spine showed the aAAS and also space-taking pathological soft tissue (synovitis pannus) around the dens of the axis. The pannus was in contact with the spinal cord, but there was still spinal fluid behind the cord.



 Figure 1  
 (A) Lateral view radiograph of the cervical spine (case 1) during flexion. Severe AAS is present (arrows show the anterior aspect of the dens of axis and the anterior arch of the atlas). (B) The AAS disappears during neutral posture. (C) Neutral position MRI examination of the cervical spine with the patient in a supine position. AAS is present, together with inflammatory tissue around the dens, but there is no compression of the spinal cord.



The patient was referred to a neurosurgeon …