tbuckley/cabot-search huggingface dataset:
<i>cag</i>A positive and negative <i>Helicobacter pylori</i>strains are simultaneously present in the stomach of most patients with non-ulcer dyspepsia: relevance to histological damage
Authors: N Figura, C Vindigni, A Covacci, L Presenti, D Burroni, R Vernillo, T Banducci, F Roviello, D Marrelli, M Biscontri, S Kristodhullu, C Gennari, D Vaira
Journal: Gut (1998)

Infection with Helicobacter pylori strains harbouring the cagA gene (cagA+) is associated with an increased risk of developing peptic ulcer and gastric cancer. The aim of this study was to assess whether H pylori isolates with different cagA status were present in patients with non-ulcer dyspepsia, and whether a variable cagA status is relevant to histological gastric mucosal damage and glandular cell proliferation.Well separated H pylori colonies (between 2 and 25) from primary plates, per gastric area, for each of 19 patients with non-ulcer dyspepsia were examined for cagA by hybridisation. Western blotting was used to examine both representative colonies for CagA expression and the patients' sera for antibody response to CagA. Glandular gastric cell proliferation was assessed immunohistochemically.Of the 747 colonies examined, 45.3% were cagA+. All colonies from four patients were cagA+, and all colonies from two patients were cagA-. In 13 patients (68%) both cagA+ and cagA- colonies were found. CagA expression of isolates corresponded to their cagA status. H pylori strains with different CagA molecular masses were present in three patients. Results based on all 19 patients studied showed that the prevalence of cagA+ colonies in areas with mucosal atrophy associated or not with intestinal metaplasia (67.9%) was significantly higher than in normal mucosa (44.7%) and mucosa from patients with chronic gastritis (44.0%) (p < 0.001). High levels of cell proliferation were associated with histological atrophy with or without intestinal metaplasia, but not with the possession of cagA by organisms colonising the same mucosal sites.Most patients with nonulcer dyspepsia are infected by both cagA+ and cagA- H pylori colonies. The cagA status of infecting organisms may play a role in the development of atrophy and intestinal metaplasia.
Observer variability of lung function measurements in 2–6-yr-old children
Authors: B. Klug, K.G. Nielsen, H. Bisgaard
Journal: European Respiratory Journal (2000)

The aim of this study was to assess the within-observer and between-observer variability of lung function measurements in children aged 2-6 yrs. Two observers examined 22 asthmatic children independently according to a predefined protocol. Each observer obtained duplicate measurements of respiratory resistance by the interrupter technique (Rint), respiratory resistance (Rrs,5) and reactance (Xrs,5) at 5 Hz by the impulse oscillation technique and the specific airway resistance (sRaw) by whole body plethysmography. The within-subject SD (SDw) was not significantly different in the two observers. The ratio SDw between observers/mean SDw within observers was 0.94, 1.25, 1.35 and 2.86 for Xrs,5, Rrs,5, sRaw and Rint, respectively, indicating greater between-observer variability of the latter. The systematic difference between observers assessed by the difference between observer means (expressed as a percentage of their mean value) was 11, 7, 6 and 2% for Xrs,5, sRaw, Rrs,5 and Rint, respectively. These differences were statistically significant, except that for Rint. In conclusion, specific airway resistance, impulse oscillation technique and respiratory resistance assessed by the interrupter technique measurements in young children are subject to influence by the observer, and the random variability between observers appears to be particularly great for respiratory resistance assessed by the interrupter technique. The authors suggest that the between-observer variability should be investigated when evaluating novel methods for testing lung function.
Boronic acid compounds as potential pharmaceutical agents
Authors: Wenqian Yang, Xingming Gao, Binghe Wang
Journal: Medicinal Research Reviews (2003)

Abstract Boronic acid compounds have been used, because of their unique structural features, for the development of potent enzyme inhibitors, boron neutron capture agents for cancer therapy, and as antibody mimics that recognize biologically important saccharides. Consequently, there has been a surge of interests in boronic acid compounds. This study reviews the recent development in this area during the last six years. © 2003 Wiley Periodicals, Inc. Med Res Rev, 23, No. 3, 346–368, 2003
Role of gap junctions in the propagation of the cardiac action potential
Authors: S Rohr
Journal: Cardiovascular Research (2004)

Gap junctions play a pivotal role for the velocity and the safety of impulse propagation in cardiac tissue. Under physiologic conditions, the specific subcellular distribution of gap junctions together with the tight packaging of the rod-shaped cardiomyocytes underlies anisotropic conduction, which is continuous at the macroscopic scale. However, when breaking down the three-dimensional network of cells into linear single cell chains, gap junctions can be shown to limit axial current flow and to induce ‘saltatory’ conduction at unchanged overall conduction velocities. In two- and three-dimensional tissue, these discontinuities disappear due to lateral averaging of depolarizing current flow at the activation wavefront. During gap junctional uncoupling, discontinuities reappear and are accompanied by slowed and meandering conduction. Critical gap junctional uncoupling reduces conduction velocities to a much larger extent than does a reduction of excitability, which suggests that the safety for conduction is higher at any given conduction velocity for gap junctional uncoupling. In uniformly structured tissue, gap junctional uncoupling is accompanied by a parallel decrease in conduction velocity. However, this is not necessarily the case for non-uniform structures like tissue expansion where partial uncoupling paradoxically increases conduction velocity and has the capacity to remove unidirectional conduction blocks. Whereas the impact of gap junctions on impulse conduction is generally assessed from the point of view of cell coupling among cardiomyocytes, it is possible that other cell types within the myocardium might be coupled to cardiomyocytes as well. In this context, it has been shown that fibroblasts establish successful conduction between sheets of cardiomyocytes over distances as long as 300 μm. This might not only explain electrical synchronization of heart transplants but might be of importance for cardiac diseases involving fibrosis. Finally, the intriguing fact that sodium channels are clustered at the intercalated disc recently rekindled the provocative question of whether gap junctions alone are responsible for impulse propagation or whether electric field mechanisms might account for conduction as well. Whereas computer simulations show the feasibility of conduction in the absence of gap junctional coupling, a definite answer to this question must await further investigations into the biophysical properties of the intercalated disc.
Cyclin-Dependent Kinase 7/9 Inhibitor SNS-032 Abrogates FIP1-like-1 Platelet-Derived Growth Factor Receptor α and Bcr-Abl Oncogene Addiction in Malignant Hematologic Cells
Authors: Yongbin Wu, Chun Chen, Xiaoyong Sun, Xianping Shi, Bei Jin, Ke Ding, Sai-Ching Jim Yeung, Jingxuan Pan
Journal: Clinical Cancer Research (2012)

The "gate-keeper" mutations T674I platelet-derived growth factor receptor α (PDGFRα) in hypereosinophilic syndrome (HES) and T315I Bcr-Abl in chronic myeloid leukemia (CML) are resistant to imatinib and the second-generation small-molecule tyrosine kinase inhibitors (TKI). However, to combat acquired resistance to imatinib, an alternative approach is to decrease the expression of the addicted gene to efficiently kill resistant malignant hematologic cells. The purpose of this study was to evaluate the strategy of shutting down the transcription and expression of FIP1-like-1 (FIP1L1)-PDGFRα and Bcr-Abl with SNS-032, an inhibitor of cyclin-dependent kinase 7 (CDK7) and CDK9 in phase I clinical trials.The effects of SNS-032 on PDGFRα and Bcr-Abl signaling pathways, apoptosis, and cell cycling were analyzed in TKI-resistant cells of HES and CML. The in vivo antitumor activity of SNS-032 was assessed with xenografted BaF3-T674I FIP1L1-PDGFRα and KBM5-T315I Bcr-Abl cells in nude mouse models.SNS-032 inhibited the phosphorylation on Ser5 and Ser2 of RNA polymerase II. SNS-032 decreased both the mRNA and protein levels of FIP1L1-PDGFRα and Bcr-Abl and inhibited the proliferation of malignant cells expressing FIP1L1-PDGFRα or Bcr-Abl. It also decreased the phosphorylation of downstream molecules. It induced apoptosis by triggering both the mitochondrial pathway and the death receptor pathway.This CDK7/9 inhibitor potently inhibits FIP1L1-PDGFRα-positive HES cells and Bcr-Abl-positive CML cells regardless of their sensitivity to imatinib. SNS-032 may have potential in treating hematologic malignancy by abrogating oncogene addiction.
Hazards of the sauna.
Authors: S E Josse
Journal: BMJ (1977)

Pyorala et al4 suggested the possibility that this decreased anticoagulant tolerance was not due to a retardation of the metabolism of the anticoagulant drugs.Their results suggested that C17-alkylated steroids affect the turnover of vitamin-K-dependent clotting factors, an impairment of synthesis being a likely mechanism.It was thought possible that C17alkylated steroids might diminish the stores of this vitamin available for metabolic competition with anticoagulant agents.
Airway resistance in COPD
Authors: Marion Heiß-Neumann, Dorothe Burggraf, Matthias Wjst, Loems Ziegler-Heitbrock
Journal: European Respiratory Journal (2012)

Chronic obstructive lung disease is characterized by airflow limitation, usually assessed by forced expiratory maneuvers (FEV1 and FVC). These maneuvers reflect a complex, dynamic relationship between patient effort, muscle strength, elastic recoil as well as airway resistance, which plays a dominant role in airflow limitation.

Within the Emphysema versus Airway Disease study (EvA) we examine postbronchodilator values for total resistance, in- and expiratory resistance (Rin, Rex) and specific resistance (sR) in COPD patients (n= 509; GOLD stage I-III, no current smoking).

Mean postbronchodilator values for total airway resistance are higher in patients compared to controls (0.35 vs 0.19 kPa*sec/L).

Looking at Rin versus Rex, the increase in patients is mainly due to a higher Rex (mean 0.50 versus 0.22 kPa*sec/L) compared to Rin (0.25 vs 0.15 kPa*sec/L).

Specific resistance, which is adjusted for volume to avoid errors because of hyperinflation, is elevated as well (1.64 vs 0.71 kPa*sec). All reported differences in mean values are highly significant with p < 1*E-15.

Mean values for Rex and sR are remarkably elevated in COPD and show a good association with GOLD stages, so they may be preferred for monitoring of COPD since they are obtained with tidal breathing.

Supported by EU FP7 project # 200605.
Various biomarkers of oxidative stress in patients with uncontrolled asthma
Authors: M.A. Abdullaeva, E. Kh. Anaev, N.B. Karmen, L.V. Tokareva, T.N. Anokhina
Journal: European Respiratory Journal (2013)

The  aim  of this study was to measure the dynamics of various biomarkers of oxidative stress in patients with uncontrolled asthma after 2 weeks of standard treatment.   Methods:  33 patients with moderate-to-severe uncontrolled asthma were recruited in the study (20 male, age 48.6±8.4 yrs, ACT   Results:  There were significantly improved clinical signs of asthma and pulmonary ventilation parameters after treatment. The intensity of cough, dyspnea and relief medication decreased (p 1  and FEV 1 /FVC ratio increased by 16%, 60% and 38% respectively (p   Conclusion:  The dynamics of various biomarkers of oxidative stress in patients with uncontrolled asthma is a reliable method for assessing and monitoring airway inflammation.
Blockade of cardiac sodium channels by lidocaine. Single-channel analysis.
Authors: A O Grant, M A Dietz, F R Gilliam, C F Starmer
Journal: Circulation Research (1989)

The mechanism of interaction of lidocaine with cardiac sodium channels during use-dependent block is not well defined. We examined the blockade of single cardiac sodium channels by lidocaine and its hydrophobic derivative RAD-242 in rabbit ventricular myocytes. Experiments were performed in cell-attached and inside-out patches. Use-dependent block was assessed with trains of ten 200-msec pulses with interpulse intervals of 500 msec and test potentials of -60 to -40 mV. Single-channel kinetics sometimes showed time-dependent change in the absence of drug. During exposure to 80 microM lidocaine, use-dependent block during the trains was associated with a decrease in the average number of openings per step. At -60 mV, mean open time was not significantly changed (control, 1.4 +/- 0.6 msec; lidocaine, 1.2 +/- 0.3 msec, p greater than 0.05). Greater block developed during trains of 200-msec pulses compared with trains of 20-msec pulses at the same interpulse interval at test potentials during which openings were uncommon later than 20 msec (-50 and -40 mV). Prolonged bursts of channels showing slow-gating kinetics were observed both in control and the presence of 80 microM lidocaine. However, lidocaine may decrease the late sodium current by altering the kinetics of slow gating. The hydrophobic lidocaine derivative RAD-242, which has a 10-fold greater lipid solubility than lidocaine, decreased the peak averaged current during pulse train stimulation by 60% without a change in the mean open time. Our results suggest that the major effect of lidocaine during use-dependent block involves the interaction with a nonconducting state of the sodium channel followed by a failure to open during subsequent depolarization.
The Metastasis-Associated Gene <i>CD24</i> Is Regulated by Ral GTPase and Is a Mediator of Cell Proliferation and Survival in Human Cancer
Authors: Steven C. Smith, Gary Oxford, Zhong Wu, Matthew D. Nitz, Mark Conaway, Henry F. Frierson, Garret Hampton, Dan Theodorescu
Journal: Cancer Research (2006)

Abstract Ral GTPases are important mediators of transformation, tumorigenesis, and cancer progression. We recently identified the metastasis-associated protein CD24, a glycosyl phosphatidyl inositol–linked surface protein, as a downstream target of Ral signaling by profiling the expression of RalA/B–depleted bladder carcinoma cells. Because CD24 is highly expressed in bladder and many other tumor types, we sought to determine if this protein plays an essential role in maintaining the malignant phenotype. Here, we show that loss of CD24 function in cell lines derived from common tumor types is associated with decreased rates of cell proliferation, clonogenicity in soft agar, changes in the actin cytoskeleton, and induction of apoptosis. Given these phenotypes, we evaluated a human bladder cancer tissue microarray by immunohistochemistry for CD24 to determine if CD24 is a prognostic cancer biomarker. Multivariate analysis showed that increased CD24 expression correlated with shorter patient disease-free survival (P = 0.07). In conclusion, we show that CD24 is a novel and functionally relevant Ral-regulated target and a potentially important prognostic marker. We suggest that these insights may lead to future therapeutic approaches that seek to eliminate CD24 function in cancer cells. (Cancer Res 2006; 66(4): 1917-22)
Is Pulsatile Blood Flow No Longer Essential?
Authors: Leslie W. Miller
Journal: Circulation (2009)

T he heart's natural provision of pulsatile blood flow has been regarded as an essential requirement for normal organ function, especially critical organs such as the kidney, liver, and brain.However, in this issue of Circulation, Russell and colleagues 1 have demonstrated that this tenet of medicine is no longer accurate.Their study examined the long-term impact of nonpulsatile blood flow as provided by a new generation of so-called continuous-flow left ventricular assist devices (LVADs), in this case the Heartmate II LVAD (Thoratec Corp, Pleasanton, Calif), on end-organ function in patients with refractory heart failure awaiting a heart transplant.These pumps draw blood from the left ventricle via a drainage cannula placed in the LV apex on a continuous basis and propel the blood by a rotary pump back into the circulation in a nonphasic flow pattern 2 through a return cannula connected to the aorta.The major findings of the Heartmate II clinical trial, including both the primary cohort 2 and a larger number of patients enrolled in the continuousaccess protocol, 3 have previously been reported.
Neutral endopeptidase (EC 3.4.24.11) downregulates the onset of intestinal inflammation in the nematode infected mouse
Authors: G Barbara
Journal: Gut (2003)

<b>Background and aims:</b> Substance P (SP) release from sensory nerves induces neurogenic inflammation. Neutral endopeptidase (NEP) degrades SP, thereby limiting its proinflammatory effects. Intestinal inflammation following <i>Trichinella spiralis</i> infection markedly downregulates NEP, resulting in diminished SP degradation, with unknown functional consequences. We hypothesised that diminished expression of NEP would exacerbate <i>T spiralis</i> induced enteritis. <b>Methods:</b> NEP knockout (NEP−/−) and wild-type (NEP+/+) mice were infected with <i>T spiralis</i> and studied at 6, 12, 24, and 48 hours post infection (PI). Tissue inflammation was quantified by computerised cell counting and myeloperoxidase activity (MPO). The leucocyte adhesion molecule, intercellular adhesion molecule 1 (ICAM-1), and SP were assessed by immunohistochemistry. <b>Results:</b> Before infection, the lack of NEP was not associated with changes in mucosal cellularity or MPO activity. Twelve hours PI, NEP−/− mice showed a 2.5-fold increase in MPO activity at a time when values in NEP+/+ mice were still within normal limits. MPO activity and cellularity peaked at 24 hours PI. This was accompanied by increased staining for both ICAM-1 and SP in NEP−/− mice. Infusion of rhNEP to NEP−/− mice significantly reduced MPO activity 24 hours PI. <b>Conclusions:</b> These findings demonstrate that NEP downregulates the early onset of nematode intestinal inflammation and that increased bioavailability of SP and overexpression of ICAM-1 in NEP−/− mice likely play a role in the earlier onset of intestinal inflammation.
Volume changes in sarcoplasmic reticulum of rat hearts perfused with hypertonic solutions.
Authors: E Page, J Upshaw-Earley
Journal: Circulation Research (1977)

To explore whether morphometry of intracellular membrane-limited subcompartments can be used to follow physiological volume changes in such subcompartments in hearts rapidly fixed by perfusion fixation, we have measured osmotically induced volume changes in electron micrographs of longitudinally oriented sarcoplasmic reticulum (LSR) and terminal cisterns (TC) of rat left ventricular myocardial cells. Vascular perfusion with solutions whose osmolality varied from 0.67 to 1.88 isomolal showed that in the hyperosmolal range LSR volume decreased linearly. Approximately 79% of LSR luminal volume participated in the osmotic rey unresponsive. By contrast, we found that the TC responded by dilation when hearts were perfused with hypersomolal NaCl, NaI, LiCl, or sucrose. Furthermore, with hyperosmolal NaCl the dilation developed within 1 minute; its rate and extent of development were concentration-dependent; it manifested an obligate association with prior or concomitant T-tubular dilation and was not readily reversible. We conclude that (1) the technique sensitively measures in situ changes of LSR volume; (2) most of LSR luminal water is osmotically responsive, but a significant fraction may not be; (3) exposure to hyperosomolal solutions may bring about (perhaps irreversible) structural changes in the diadic membrane complex, leading to changes in its solute permeability.
Outcome of Induction and Postremission Therapy in Younger Adults With Acute Myeloid Leukemia With Normal Karyotype: A Cancer and Leukemia Group B Study
Authors: Sherif S. Farag, Amy S. Ruppert, Krzysztof Mrózek, Robert J. Mayer, Richard M. Stone, Andrew J. Carroll, Bayard L. Powell, Joseph O. Moore, Mark J. Pettenati, Prasad R.K. Koduru, Judith Stamberg, Maria R. Baer, AnneMarie W. Block, James W. Vardiman, Jonathan E. Kolitz, Charles A. Schiffer, Richard A. Larson, Clara D. Bloomfield
Journal: Journal of Clinical Oncology (2004)

Evaluate the outcome of induction and postremission therapy in adults younger than 60 years with normal cytogenetics acute myeloid leukemia (AML).In 490 patients, induction included cytarabine and daunorubicin (AD) or cytarabine and escalated doses of daunorubicin and etoposide +/- PSC-833 (ADE/ADEP). Intensification included one cycle of high-dose cytarabine (HDAC) followed by etoposide/cyclophosphamide and mitoxantrone/diaziquone (group I), three HDAC cycles (group II), four intermediate-dose cytarabine (IDAC) or HDAC cycles (group III), or one HDAC/etoposide cycle and autologous stem-cell transplantation (ASCT; group IV).Of 350 patients receiving AD, 73% achieved complete remission (CR), compared with 82% of 140 receiving ADE/ADEP (P = .04). Splenomegaly was associated with a lower CR rate (P < .001), and ADE/ADEP, with a higher CR rate in younger patients (P = .005). The 5-year disease-free survival (DFS) rate was 28% each for intensification groups I and II, compared with 41% and 45% for groups III and IV, respectively (P = .02). The 5-year cumulative incidence of relapse (CIR) was 62% and 67% for groups I and II, respectively, compared with 54% and 44% for groups III and IV, respectively (P = .049). The type of postremission intensification remained significant for DFS and CIR in multivariable analysis.In younger adults with normal cytogenetics AML, splenomegaly predicts a lower CR rate, and the postremission strategies of either four cycles of I/HDAC or one cycle of HDAC/etoposide followed by ASCT are associated with improved DFS and reduced relapse compared with therapies that include fewer cycles of cytarabine or no transplantation.
The Old and the Restless
Authors: Susanna M. Lewis, Gillian E. Wu
Journal: The Journal of Experimental Medicine (2000)

Estimates put the origin of V(D)J recombination at ∼450 million years ago (for reviews, see references 1, 2). It has been speculated that it all started with a chance occurrence, the integration of a mobile element into a gene encoding an Ig domain ([3][1]). The acquisition of the V(D)J