tbuckley/cabot-search huggingface dataset:
In Vivo Diagnosis of Small-Cell Lung Cancer by Endocytoscopy
Authors: Helmut Neumann, Michael Vieth, Markus F. Neurath, Florian S. Fuchs
Journal: Journal of Clinical Oncology (2010)

In Vivo Diagnosis of Small-Cell Lung Cancer by EndocytoscopySmall-cell lung cancers (SCLCs) represent approximately 13% of all newly diagnosed lung cancers and are characterized by an aggressive course with early locoregional and distant metastases.Prognosis is poor, ranging from 20 months in limited disease to 8 months in extensive disease.Various studies 1,2 have shown that disease stage is the most powerful prognostic factor of SCLC.Therefore, different scoring systems that include physical, biochemical, and radiologic markers have been established. 1,2Despite ongoing developments in bronchoscopy, including innovative powerful endoscopes with new optical enhancement techniques such as narrow band imaging or autofluorescence bronchoscopy, final diagnosis of SCLC remained a field of histopathology.Recently, endocytoscopy was introduced, enabling microscopic imaging of the mucosal layer of the gut at magnifications up to ϫ1,400. 3Endocytoscopy is based on a contact light microscope which enables real-time visualization of cellular structures of the superficial epithelial layer.Currently, endoscopy-based and probe-based systems are available.Probe-based systems consist of handheld miniprobes, which are capable of being inserted through the accessory channel of a standard endoscope.The device provides magnification imaging at ϫ570 or ϫ1,400 on a 19-inch monitor from an optical sampling site of about 0.5 mm in diameter. 3ifferent studies suggest that endocytoscopy has the potential for in vivo evaluation of duodenal mucosa in celiac disease. 4,5Furthermore, endocytoscopy was able to detect tissue abnormalities in normal mucosa surrounding colorectal cancer and to identify neoplasia in A B C D Fig 1.
Intact vesicles of canine cardiac sarcolemma: evidence from vectorial properties of Na+, K+-ATPase.
Authors: H R Besch, L R Jones, A M Watanabe
Journal: Circulation Research (1976)

Most biological membranes are functionally asymmetric. To study biochemical control of cardiac transsarcolemmalion fluxes, it would be of obvious advantage to use isolated vesicles of sarcolemma which retains the low passive permeability characteristics of intact sarcolemma because in such vesicles the membrane should exhibit its normal asymmetric character with respect to enzymic activities. The purpose of this investigation was to attempt identify such vesicles in a cardiac microsomal (membrane vesicular) preparation. We studied activation by Na+ and K+ of Na+, K+-ATPase and its associated K+-phosphatase activities, using as substrates ATP or p-nitrophenylphosphate (pNPP) in the presence of Mg2+. Optimal concentrations of K+ alone (10 mM) stimulated p-nitrophenylphosphatase (pNPPase) activity 1.8-fold, and over 80% of the increase could be inhibited by ouabain. Optimal Na+ plus K+ concentrations (100 mM and 10 mM, respectively) stimulated the rate of ATP hydrolysis 2-fold, but only 11 +/- 1.1% of the increased activity was ouabain-sensitive. Optimal pretreatment with sodium dodecyl sulfate (SDS) (0.3 mg/ml) rendered both activities completely sensitive to inhibition by ouabain and reduced the basal Mg2+-ATPase activity by 70-90%. The K+-stimulated pNPPase activity doubled after preincubation in SDS, but the ATPase activity stimulated by Na+ plus K+ fell by 50% under these conditions. A similar pattern of apparent activation was produced by preincubation with deoxycholate (DOC), except that basal Mg2+-dependent activities were resistant to destruction by this detergent. The incremental responses to activation by ions and substrates, and inhibition by oubain, are consistent with the hypothesis that permeability-intact vesicles of sarcolemma are present in the isolated preparation, and that detergent activation renders the vesicles highly permeable to the ions, substrates, and ouabain.
Recurrent abdominal pain in childhood
Authors: A Plunkett
Journal: Journal of the Royal Society of Medicine (2005)

Recurrent abdominal pain is a frequent presenting complaint in general practice, general paediatric clinics and paediatric gastroenterology clinics.Since its first description in 1958, 1 the condition has remained poorly understood with a multitude of factors being implicated in causation.The symptoms tend to be vague and investigations seldom show organic disease.Treatment strategies vary and have little basis in evidence.
Derepression of pathological cardiac genes by members of the CaM kinase superfamily
Authors: Timothy A. McKinsey
Journal: Cardiovascular Research (2006)

In response to pathologic stresses such as hypertension or myocardial infarction, the heart undergoes a remodeling process that is characterized by myocyte hypertrophy, myocyte death and fibrosis, resulting in impaired cardiac function and heart failure. Cardiac remodeling is associated with derepression of genes that contribute to disease progression. This review focuses on evidence linking members of the Ca(2+)/calmodulin-dependent protein kinase (CaMK) superfamily, specifically CaMKII, protein kinase D (PKD) and microtubule associated kinase (MARK), to stress-induced derepression of pathological cardiac gene expression through their effects on class IIa histone deacetylases (HDACs).
Road traffic injury prevention
Authors: Barry Pless
Journal: BMJ (2004)

Road traffic injury preventionWHO report advocates input from public health and a systems approach "A 63-year-old woman was in critical condition last night after being struck by a car . . .as she crossed Sherbrooke St E shortly after 4 pm . . .It appears the pedestrian and motorist both had a green light, said Constable Lapointe.The driver was turning left when she struck the pedestrian.Police did not believe alcohol or excessive speed were factors in the accident.
Personalized Respiratory Medicine: Exploring the Horizon, Addressing the Issues. Summary of a BRN-AJRCCM Workshop Held in Barcelona on June 12, 2014
Authors: Alvar Agustí, Josep Maria Antó, Charles Auffray, Ferran Barbé, Esther Barreiro, Jordi Dorca, Joan Escarrabill, Rosa Faner, Laura I. Furlong, Judith Garcia-Aymerich, Joaquim Gea, Bertil Lindmark, Eduard Monsó, Vicente Plaza, Milo A. Puhan, Josep Roca, Juan Ruiz-Manzano, Laura Sampietro-Colom, Ferran Sanz, Luis Serrano, James Sharpe, Oriol Sibila, Edwin K. Silverman, Peter J. Sterk, Jacob I. Sznajder
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Section:ChooseTop of pageAbstract <<Definition and Historical...A Perspective of PM from ...Bottlenecks and Opportuni...Implications for the Indi...Summary and Proposals for...ReferencesCITING ARTICLES
Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease
Authors: Eva Lonn, Salim Yusuf, Malcolm J Arnold, Patrick Sheridan, Janice Pogue, Mary Micks, Matthew J McQueen, Jeffrey Probstfield, George Fodor, Claes Held, Jacques Genest
Journal: New England Journal of Medicine (2006)

In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels. We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease.We randomly assigned 5522 patients 55 years of age or older who had vascular disease or diabetes to daily treatment either with the combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 or with placebo for an average of five years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, and stroke.Mean plasma homocysteine levels decreased by 2.4 micromol per liter (0.3 mg per liter) in the active-treatment group and increased by 0.8 micromol per liter (0.1 mg per liter) in the placebo group. Primary outcome events occurred in 519 patients (18.8 percent) assigned to active therapy and 547 (19.8 percent) assigned to placebo (relative risk, 0.95; 95 percent confidence interval, 0.84 to 1.07; P=0.41). As compared with placebo, active treatment did not significantly decrease the risk of death from cardiovascular causes (relative risk, 0.96; 95 percent confidence interval, 0.81 to 1.13), myocardial infarction (relative risk, 0.98; 95 percent confidence interval, 0.85 to 1.14), or any of the secondary outcomes. Fewer patients assigned to active treatment than to placebo had a stroke (relative risk, 0.75; 95 percent confidence interval, 0.59 to 0.97). More patients in the active-treatment group were hospitalized for unstable angina (relative risk, 1.24; 95 percent confidence interval, 1.04 to 1.49).Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease. (ClinicalTrials.gov number, NCT00106886; Current Controlled Trials number, ISRCTN14017017.).
Canonical Androstenedione Reduction Is the Predominant Source of Signaling Androgens in Hormone-Refractory Prostate Cancer
Authors: Matthew Fankhauser, Yuen Tan, Geoff Macintyre, Izhak Haviv, Matthew K.H. Hong, Anne Nguyen, John S. Pedersen, Anthony J. Costello, Christopher M. Hovens, Niall M. Corcoran
Journal: Clinical Cancer Research (2014)

It has been recognized for almost a decade that concentrations of signaling androgens sufficient to activate the androgen receptor are present in castration-resistant prostate cancer tissue. The source of these androgens is highly controversial, with three competing models proposed. We, therefore, wished to determine the androgenic potential of human benign and malignant (hormone-naïve and treated) prostate tissue when incubated with various precursors and examine concomitant changes in enzyme expression.Freshly harvested prostate tissue [benign, hormone-naïve, and hormone-refractory prostate cancer (HRPC)] was incubated in excess concentrations of cholesterol, progesterone, DHEA, androstenedione, or testosterone for 96 hours, and steroid concentrations in the conditioned media measured by gas chromatography-mass spectroscopy. Changes in the expression of androgen synthetic and/or degradative enzymes were determined by expression microarray and qPCR. Significant changes were confirmed in an independent dataset.Of the precursor molecules tested, only incubation with androstenedione gave rise to significant concentrations of signaling androgens. Although this was observed in all tissue types, it occurred to a significantly greater degree in hormone-refractory compared with hormone-naïve cancer. Consistent with this, gene set enrichment analysis of the expression microarray data revealed significant upregulation of 17HSD17B activity, with overexpression of the canonical enzyme AKR1C3 confirmed by qPCR in the same samples and in a publicly available expression dataset. Importantly, we found no evidence to support a significant contribution from either the "backdoor" or "5-α dione" pathway.Reduction of androstenedione to testosterone by the canonical HSD17B AKR1C3 is the predominant source of signaling androgens in HRPC.
Long-term effects of a partially supervised conditioning programme in cystic fibrosis
Authors: H. Hebestreit, S. Kieser, S. Junge, M. Ballmann, A. Hebestreit, C. Schindler, T. Schenk, H-G. Posselt, S. Kriemler
Journal: European Respiratory Journal (2009)

Little is known about the long-term persistence of positive effects induced by a physical conditioning programme in cystic fibrosis. Therefore, this study determined the effects of a 6-month conditioning programme on peak oxygen uptake (primary outcome) and other markers of fitness, physical activity, anthropometry, lung function and quality of life (secondary outcomes), 18 and 24 months after the programme was initiated. Patients with cystic fibrosis aged 12–40 yrs were randomly assigned to an intervention (n = 23) and a control (n = 15) group. The intervention group consented to add 3 h of sports per week for ≥6 months to their previous activities. Controls were asked to maintain their level of activity for 12 months. Patients were seen at baseline and after 3, 6, 12, 18 and 24 months. There was no significant difference between groups at baseline. The intervention induced positive effects on peak oxygen uptake (difference in changes from baseline to the 18- and 24-month assessments between groups: 3.72±1.23 mL·min −1 ·kg −1 ; p&lt;0.01), maximal workload (0.37±0.11 W·kg −1 ; p&lt;0.01), vigorous physical activity (1.63±0.82 h·week −1 ; p&lt;0.05), forced vital capacity (6.06±2.87% predicted; p&lt;0.05) and perceived health (9.89±4.72; p&lt;0.05). A home-based partially supervised physical conditioning programme can improve physical fitness, lung function and perceived health long after the intervention has ended.
Treatment for High-Risk Patients With Early-Stage Non–Small-Cell Lung Cancer
Authors: Alexander V. Louie, Suresh Senan
Journal: Journal of Clinical Oncology (2014)

TO THEEDITOR: We read with interest the report of Fernando et al 1 describing local recurrence (LR) rates after sublobar resection in high-risk patients with an early stage non–small-cell lung cancer (ESNSCLC), either with or without brachytherapy. The authors are to be commended for completing this study, particularly as other randomized trials evaluating different treatment strategies in the same patient population have failed to accrue. 2 “High-risk” patients were clearly defined, and the report focused on LR-free survival, which was defined to include recurrence at the staple line (local progression), in the primary tumor lobe away from the staple line, and in ipsilateral hilar nodes. The use of brachytherapy did not influence LR or overall survival at 3 years. For patients with ES-NSCLC who refuse surgery, or who are unfit to undergo surgery, stereotactic ablative radiotherapy (SABR) is currently the preferred treatment modality. 3 However, it has been argued that the ability to perform more accurate nodal staging is an advantage for surgical approaches, as both the excision of nodal metastases and identification of candidates for adjuvant chemotherapy can improve overall survival. 4 Therefore, the authors should provide data on the adequacy of staging hilar and mediastinal nodes in patients treated in their study. Data from the American College of Surgeons Oncology Group (ACOSOG) Z4032 study protocol specified that serial computed tomography scans can inform readers on relapses in hilar and mediastinal nodal stations in a recent surgical cohort, and treatment patterns after relapse may be indicative of postsurgical fitness in this high-risk cohort. The argument for rigorous surgical staging in high-risk ESNSCLC may be called into question by findings that performance of nodal staging did not influence survival in patients with ES-NSCLC who underwent surgery in the International Early Lung cancer Action Program (I-ELCAP), 5 or in a Danish population study. 6 Although Fernando et al rightly point out the low surgical mortality observed in their study, it would be useful to note that the I-ELCAP study also reported a low surgical mortality (0.9%) in a screen-detected cohort treated by general thoracic surgeons at centers with specialized screening programs. 5 Nevertheless, a mediastinal nodal resection was performed in only 55% of patients who underwent a sublobar resection in the I-ELCAP study. 5 Besides the issue of nodal staging in this population, the high rates of intercurrent death of patients in ACOSOG Z4032 as a result of noncancer causes (intention-to-treat cohort: 51.1% from other disease; 8.0% unknown) highlights the importance of less invasive treatment options for individuals with a limited life expectancy. Only a minority of patients with lung cancer are treated in surgical trials, 7 and
Clinical Correlates of <i>NRAS</i> and <i>BRAF</i> Mutations in Primary Human Melanoma
Authors: Julie A. Ellerhorst, Victoria R. Greene, Suhendan Ekmekcioglu, Carla L. Warneke, Marcella M. Johnson, Carolyn P. Cooke, Li-E Wang, Victor G. Prieto, Jeffrey E. Gershenwald, Qingyi Wei, Elizabeth A. Grimm
Journal: Clinical Cancer Research (2010)

NRAS and BRAF mutations are common in cutaneous melanomas, although rarely detected mutually in the same tumor. Distinct clinical correlates of these mutations have not been described, despite in vitro data suggesting enhanced oncogenic effects. This study was designed to test the hypothesis that primary human cutaneous melanomas harboring mutations in NRAS or BRAF display a more aggressive clinical phenotype than tumors wild type at both loci.Microdissection of 223 primary melanomas was carried out, followed by determination of the NRAS and BRAF mutational status. Genotypic findings were correlated with features known to influence tumor behavior including age, gender, Breslow depth, Clark level, mitotic rate, the presence of ulceration, and American Joint Committee on Cancer (AJCC) staging.Breslow depth and Clark level varied significantly among the genotypes, with NRAS mutants showing the deepest levels and wild-type tumors the least depth. Ulceration also differed significantly among the genotypes, with BRAF mutants demonstrating the highest rate. In addition, tumors with mutated NRAS were more likely to be located on the extremities. Patients whose tumors carried either mutation presented with more advanced AJCC stages compared with patients with wild-type tumors, and specifically, were more likely to have stage III disease at diagnosis. Overall survival did not differ among the 3 groups.Distinct clinical phenotypes exist for melanomas bearing NRAS and BRAF mutations, whether considered together or separately, and are associated with features known to predict aggressive tumor behavior. The impact of these mutations is most evident at earlier stages of disease progression.
Replication of association of the interleukin 23 receptor rs1343151 variant with rheumatoid arthritis in Caucasian sample sets
Authors: Michael Chen-Xu, Ruth Topless, Cushla McKinney, Marilyn E Merriman, Amanda Phipps-Green, Nicola Dalbeth, Peter J Gow, Andrew A Harrison, John Highton, Peter B Jones, Michael Nissen, Malcolm D Smith, Andre van Rij, Greg T Jones, Luis Rodriguez-Rodriguez, Benjamin Fernandez-Gutierrez, María Teruel, Alejandro Balsa, Dora Pascual-Salcedo, Ana M Ortiz, Miguel A Gonzalez-Gay, Sophia Steer, Marthe Maehlen, Benedicte Lie, B Paul Wordsworth, Lisa K Stamp, Javier Martin, Tony R Merriman
Journal: Annals of the Rheumatic Diseases (2011)

The IL-23R region is associated with a number of non-infectious inflammatory conditions including inflammatory bowel disease, ankylosing spondylitis and psoriasis,1,–,3 and albeit with less consistent evidence, rheumatoid arthritis (RA).4,–,6 Association of rs1343151 (G→A) with RA, but not rs1004819/rs10489629/rs2201841 , has been reported in European and New Zealand sample sets;5 none of rs3212227/rs6887695/rs7530511 was associated in European and North American sample sets,6 and rs7517847 was not associated in meta-analysed European and New Zealand sample sets.4 Given the immunological evidence pointing to the importance of the Th17–IL-23 axis in inflammation and autoimmunity,7 and the unresolved question of whether or not IL-23R is associated with RA, we further investigated association of IL-23R with RA in white European Caucasian case–control sample sets (cases ascertained …
Treatment-Resistant Bipolar Depression: A STEP-BD Equipoise Randomized Effectiveness Trial of Antidepressant Augmentation With Lamotrigine, Inositol, or Risperidone
Authors: Andrew A. Nierenberg, Michael J. Ostacher, Joseph R. Calabrese, Terence A. Ketter, Lauren B. Marangell, David J. Miklowitz, Sachiko Miyahara, Mark S. Bauer, Michael E. Thase, Stephen R. Wisniewski, Gary S. Sachs
Journal: American Journal of Psychiatry (2006)

OBJECTIVE: Clinicians have few evidence-based options for the management of treatment-resistant bipolar depression. This study represents the first randomized trial of competing options for treatment-resistant bipolar depression and assesses the effectiveness and safety of antidepressant augmentation with lamotrigine, inositol, and risperidone. METHOD: Participants (N=66) were patients with bipolar I or bipolar II disorder enrolled in the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). All patients were in a current major depressive episode that was nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant. Patients were randomly assigned to open-label adjunctive treatment with lamotrigine, inositol, or risperidone for up to 16 weeks. The primary outcome measure was the rate of recovery, defined as no more than two symptoms meeting DSM-IV threshold criteria for a mood episode and no significant symptoms present for 8 weeks. RESULTS: No significant between-group differences were seen when any pair of treatments were compared on the primary outcome measure. However, the recovery rate with lamotrigine was 23.8%, whereas the recovery rates with inositol and risperidone were 17.4% and 4.6%, respectively. Patients receiving lamotrigine had lower depression ratings and Clinical Global Impression severity scores as well as greater Global Assessment of Functioning scores compared with those receiving inositol and risperidone. CONCLUSIONS: No differences were found in primary pairwise comparison analyses of open-label augmentation with lamotrigine, inositol, or risperidone. Post hoc secondary analyses suggest that lamotrigine may be superior to inositol and risperidone in improving treatment-resistant bipolar depression.
A proof-of-concept study evaluating the effect of ADX10059, a metabotropic glutamate receptor-5 negative allosteric modulator, on acid exposure and symptoms in gastro-oesophageal reflux disease
Authors: C Keywood, M Wakefield, J Tack
Journal: Gut (2009)

<h3>Background:</h3> In preclinical models, antagonism of metabotropic glutamate receptor 5 (mGluR5) reduces transient lower oesophageal sphincter relaxations (TLOSRs) and increases LOS pressure. This study evaluated the effect of ADX10059, a potent, selective, negative allosteric modulator of mGluR5, on oesophageal pH-metry and clinical symptoms in GORD. <h3>Methods:</h3> Two groups of patients with GORD (n = 12 per group) underwent 24-h oesophageal pH-metry on two sequential treatment days. The patients received oral placebo three times daily (tds) 30 min before a high-fat meal on Day 1 and oral ADX10059 50 mg (Group 1) or 250 mg (Group 2) tds 30 min before a high-fat meal on Day 2. The primary variable was acid exposure (%time pH&lt;4). Secondary variables included number and duration of reflux episodes, number and duration of symptomatic episodes and symptoms recorded in diaries. Comparisons were made for Day 2 (active) versus Day 1 (placebo) treatment and for Group 1 versus Group 2. <h3>Results:</h3> ADX10059 250 mg tds significantly decreased the percentage of time with pH&lt;4 from 7.2% to 3.6% (p = 0.01). ADX10059 250 mg tds reduced pH-metry-measured oesophageal acid exposure, throughout the 24 h period, nocturnally and postprandially, and significantly reduced the number and duration of symptomatic reflux episodes (p = 0.03). ADX10059 50 mg tds was not significantly superior to placebo. ADX10059 was generally well tolerated. <h3>Conclusion:</h3> The mGluR5 negative allosteric modulator ADX10059 reduced acid reflux which was associated with improvement in clinical symptoms in patients with GORD. ADX10059 appears to have a potential role in the clinical management of GORD.