tbuckley/cabot-search huggingface dataset:
<scp>PDK</scp>1/Akt/<scp>PDE</scp>4D axis identified as a target for asthma remedy synergistic with β<sub>2</sub><scp>AR</scp> agonists by a natural agent arctigenin
Authors: R. Fang, Q. Cui, J. Sun, X. Duan, X. Ma, W. Wang, B. Cheng, Y. Liu, Y. Hou, G. Bai
Journal: Allergy (2015)

Abstract Background Asthma is a heterogenetic disorder characterized by chronic inflammation with variable airflow obstruction and airway hyper‐responsiveness. As the most potent and popular bronchodilators, β 2 adrenergic receptor (β 2 AR ) agonists bind to the β 2 AR s that are coupled via a stimulatory G protein to adenylyl cyclase, thereby improving cAMP accumulation and resulting in airway smooth muscle relaxation. We previously demonstrated arctigenin had a synergistic function with the β 2 AR agonist, but the target for this remained elusive. Method Chemical proteomics capturing was used to enrich and uncover the target of arctigenin in human bronchial smooth muscle cells, and reverse docking and molecular dynamic stimulation were performed to evaluate the binding of arctigenin and its target. In vitro enzyme activities and protein levels were demonstrated with special kits and Western blotting. Finally, guinea pig tracheal muscle segregation and ex vivo function were analysed. Results Arctigenin bound to PDK 1 with an ideal binding free energy −25.45 kcal/mol and inhibited PDK 1 kinase activity without changing its protein level. Additionally, arctigenin reduced PKB /Akt‐induced phosphorylation of PDE 4D, which was first identified in this study. Attenuation of PDE 4D resulted in cAMP accumulation in human bronchial smooth muscle. The inhibition of PDK 1 showed a synergistic function with β 2 AR agonists and relaxed the constriction of segregated guinea pig tracheal muscle. Conclusions The PDK 1/Akt/ PDE 4D axis serves as a novel asthma target, which may benefit airflow obstruction.
Media influence on suicide
Authors: A. Howe
Journal: BMJ (2003)

EDITOR-The alarming escalation of charcoal burning suicide in Hong Kong supports Hawton and Williams's call for guidelines on the reporting of suicide.1 We previously reported on the emergence of this new method of suicide in Hong Kong.2In November 1998 a 35 year old woman committed suicide by burning charcoal in a barbeque grill in her sealed and cramped apartment.Compared with jumping, which accounts for most local suicide deaths, suicide by burning charcoal was romanticised as an easy and comfortable way of dying.The incident was pictorially reported in the media.Two months after its appearance charcoal burning became the third commonest method of suicide in Hong Kong, where carbon monoxide poisoning was previously uncommon.2In 2001 it replaced hanging as the second commonest method of suicide, accounting for 25% of all deaths from suicide.People committing suicide by charcoal burning were often middle aged and were portrayed as debt
Correlation of miR-422a, miR-21 and miR-155 analysis with hMSH2 and hMLH1 mRNA expression profiles in non-small cell lung carcinomas and their adjacent normal tissues
Authors: Dimitra Vageli, Sotirios G. Doukas, Theodora Kerenidi, George K. Koukoulis, Konstantinos I. Gourgoulianis, Zoe Daniil
Journal: European Respiratory Journal (2013)

Background: In a recent study has been shown that hMLH1 gene has an additional function in tumorgenesis as a general stimulating factor for miRNA biogenesis. Additionally, a correlation of elevated miR-21 with hMSH2 mRNA levels has been reported in lung cancer cell lines . 

Aim: To correlate miR-422a, miR-21 and miR-155 levels with hMSH2 and hMLH1, mRNA expression profiles in NSCLCs and their adjacent normal tissues (ANTs).

Materials and methods: Quantitation of mature miR-422a, miR-21 and miR-155 was performed in 11 NSCLCs and ANTs, using control-miRNA RNU6. miRNA levels were defined as ratios of target-miRNA/U6 and relative expression as ratios of miRNAs levels in NSCLCs/ANTs. MMR mRNA levels had been established in advance.

Results: There was a significant correlation between hMLH1 mRNA levels and miR-422a, miR-21 levels. We also found a significant relationship between cases with elevated hMLH1 and those with elevated miR-21, miR-422a miR-155, compared with cases with low miR-422a, miR-21, miR-155 levels ( p <0.004, p< 0.001, p <0.003, respectively). Cases with elevated miR-422a and miR-21 show more often low hMSH2 levels, than cases with low miR-422a and miR-21 levels ( p <0.004 p< 0.001, respectively). 70% of NSCLCs had reduced miR-422a ratios compare to ANTs. Finally, NSCLCs of stage III expressed higher miR-21 levels ( p <0.05).

Conclusions: Our findings 1) support hMLH1 function as a stimulator factor of miRNAs, 2) are in line with miR-422a and miR21 role as regulators of hMSH2 expression, 3) support a tumor-suppressor role of miR-422a and 4) highlight miR-21 marker as an index of tumor progression in lung cancer.
Antimicrobial activity evaluations of gatifloxacin, a new fluoroquinolone: contemporary pathogen results from a global antimicrobial resistance surveillance program (SENTRY, 1997)
Authors: Ronald N. Jones, Matthew A.T. Croco, Michael A. Pfaller, Mondell L. Beach, Kari C. Kugler
Journal: Clinical Microbiology and Infection (1999)
Mesenchymal stem cells down-regulate inflammation but not airway hyperresponsiveness in experimental asthma
Authors: Luis Antonio Mariñas-Pardo, Isabel Mirones-Aguilar, Óscar Amor-Carro, Rebeca Fraga-Iriso, Beatriz Lema-Costa, Isabel Cubillo-Moreno, Miguel Άngel Rodríguez-Milla, Javier García-Castro, David Ramos-Barbόn
Journal: European Respiratory Journal (2011)

Introduction: Mesenchymal stem cells (MSCs) have immunomodulatory properties. MSCs may have a potential to down-regulate airway inflammation in asthma, but may as well serve as building blocks for unwanted airway remodeling. Here we tested the effect of MSCs in experimental asthma.

Methods: MSCs from peritoneal adipose tissue of donor mice were transduced to express green fluorescent protein (GFP). Experimental asthma was induced in recipient mice by repeated intranasal instillation of house dust mite (HDM) extract. These mice subsequently received 3×105 MSCs intravenously (HDM-MSC group). Control groups consisted of HDM-instilled miced that received MSC vehicle (HDM-noMSC group), or PBS-instilled mice that received MSCs (PBS-MSC group). Airway responsiveness to methacholine, bronchoalveolar lavage (BAL) leukocytes and the presence of GFP+ MSCs in the lung were analyzed 3 days after the MSC or vehicle injection.

Results: HDM-MSC mice showed: (i) unchanged airway hyperresponsiveness to methacholine compared with HDM-noMSC mice; (ii) BAL leukocyte counts decreased to the PBS-MSC group baseline; and (iii) GFP+ MSCs present in lung parenchyma but not in the conductive airway wall.

Conclusion: In experimental asthma, a single MSC infusion effectively decreases airway inflammation but leaves airway hyperresponsiveness untouched. MSCs infused for therapeutic aims may not home to the airway wall. Whether clinicaly relevant outcomes in terms of lung function can be expected from MSC therapy in severe asthma needs further studies.

Funded by the Fondo de Investigaciόn Sanitaria of Spain & European Regional Development Fund, a GlaxoSmithKline Collaborative Research Trial and SEPAR.
Varenicline is useful for smoking cessation
Authors: Paul Cadden
Journal: Thorax (2007)

▴ Smoking cessation with varenicline, a selective α4β2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up. Nides M, Oncken C, Gonzales D, et al . Arch Intern Med2006;166:1561–8.

[OpenUrl][1][CrossRef][2][PubMed][3]



Current smoking cessation therapies, including nicotine replacement therapy, bupropion and nortriptyline, report up to 30% quit rates at 1 year if used in conjunction with behavioural counselling.

Varenicline is a new drug that is a partial nicotine receptor agonist and antagonist designed specifically to aid smoking cessation by modulating central dopamine release.

The …

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 [2]: /lookup/external-ref?access_num=10.1001/archinte.166.15.1561&link_type=DOI
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Selective Ablation of Acute Myeloid Leukemia Using Antibody-Targeted Chemotherapy: A Phase I Study of an Anti-CD33 Calicheamicin Immunoconjugate
Authors: E.L. Sievers, F.R. Appelbaum, R.T. Spielberger, S.J. Forman, D. Flowers, F.O. Smith, K. Shannon-Dorcy, M.S. Berger, I.D. Bernstein
Journal: Blood (1999)
Tryptophan Induced Eosinophilia-Myalgia Syndrome: Clinical and Microscopic Findings
Authors: R W Groves, K J Simpson, S Koblar, C Pitzalis, R J Hay
Journal: Journal of the Royal Society of Medicine (1992)

Case report A 26-year-old man gave a 4 month history of dyspnoea, weakness and limb swelling associated with transient erythema. Subsequently he developed sclerotic plaques involving the arms, legs and abdomen. There was no history ofRaynaud's phenomenon. He was a keen weightlifter and had taken vitamin sachets containing L-tryptophan 0.5 g, ornithine 0.5 g and arginine 1 g twice daily for the preceding 4 months as an adjunct to fitness training. On examination there was shiny tethering of the skin of the lower legs, which spared the feet. On the abdom.m1 and arms there were scleroderma-like plaques and contractures of the fingers, ankles and knees were noted. The nail folds were normal. There was severe, predominantly distal, weakness and wasting of the limbs with areflexia and sensory loss. He was unable to stand or walk. Investigations revealed marked peripheral eosinophilia: Figure 2. Electron micrograph of dermal fibroblast. There are longitudinal 'stress fibres' typical of myofibroblast differentiation. Note also the electron dense inclusion bodies (arrow)
A prospective study: Are CTPAs requested appropriately and if not do they diagnose alternative pathologies?
Authors: Sophia Antoniou, Hsiu Tung, Shelley Srivastava
Journal: European Respiratory Journal (2014)

Introduction   Computerised Tomography Pulmonary Angiogram (CTPA) is routinely used to investigate suspected pulmonary embolism (PE).  PEs are clinically difficult to diagnose and associated with significant morbidity and mortality. Clinical concern and the increased availability of CTPA may mean more patients receive unnecessary radiation: a CTPA is approximately 750 chest radiographs[1]. In addition, detection of other pathology by CTPA often has minimal clinical impact[2].   Aims   To investigate our compliance with NICE guidelines in ordering CTPAs, and whether detecting alternative diagnoses justifies their use.   Methods   This prospective study, in a London teaching hospital, reviewed data in all medical and oncology patients who had a CTPA in January 2014. Clinical diagnoses and risk scores were recorded according to national guidelines.   Results   A CTPA was carried out on 49 patients (66% female); 10 had confirmed PE (20%). In 31 (63%), guidelines were not followed: 27 did not have D-dimers. Of those with PE, 40% were detected despite low Wells Scores. In 19 (39%), an alternative diagnosis explaining the symptoms was shown: 8 on CTPA, but only 6 resulted in a management change. Incidental findings were made in 6 requiring follow-up.   Conclusions   PEs remain difficult to diagnose. Clinical skills may not be accurate, our detection rate was 20%, and 40% had a low Wells score. A better scoring system may be required. In addition, alternative diagnoses for CTPA do not appear to alter management in the majority. More research is required in diagnosing PE to minimise radiation and contrast risks, and ensure CTPAs are of maximum clinical benefit.  [1] BMJ 2011;342:d947  [2] Chest 2013;144(6):1893-9.
The effects of oral care on FeNO measurement in asthmatic patients
Authors: Mitsuhiro Kamimura, Yoichiro Hamamoto, Atsuto Mouri, Munehisa Hukusumi, Tatsuya Ibe
Journal: European Respiratory Journal (2014)

[Background] The fractional exhaled NO (FeNO) is widely measured as an indicator of bronchial inflammation in asthmatic patients. However, No is also produced in the oral cavity, though it is minor component of total FeNO. In oral cavity, nitrate in saliva is reduced into NO by anaerobes and acid circumstance. Thus, the amount of oral NO production might depend on local condition. We evaluated the influence of oral care on the measurement of FeNO in patients with asthma.  [Patients and Methods] Sixty-two patients with asthma were enrolled in the study. At their visit to the out-patient department of the hospital, FeNO was measured before and after the oral care by 3 minutes teeth brushing and gargling with water. NIOX MINO was used for FeNO measurement.  [Results] In total cases, before the oral care, FeNO was 26.7+/-27.1ppb and after the oral care, 25.0 +/- 27.5ppb. The FeNO decreased by 1.73+/-0.95 (-31∼+23, p=P=0.0090 Wilcoxon signed-rank test) after the oral care.In the group in which the FeNO level is above 20ppb before the oral care (n=28), FeNO decreased by 3.14+/-1.98 (P=0.0120) and above 30ppb (n=15), 5.467+/-3.10 (P=0.0123) after the oral care. The Higher the FeNO level before the oral care, the larger the decrease of the FeNO level. The decrease of FeNO by the oral care significantly co-related with higher age (p=0.0243).  [Conclusions] FeNO decreased significantly by the oral care. In total cases, its impact is limited but there would be high oral NO producers among those with higher age and with those with higher FeNO level at the baseline. The oral origin NO should be taken into count when FeNO level is not co-related with the symptom activities.
Causes of pleural effusion in Belarus: Results of video assisted thoracoscopic pleural biopsy
Authors: Dzmitry Katovich, Alena Skrahina, Hennadz Hurevich
Journal: European Respiratory Journal (2013)

Background.  About one million new cases of pleural effusion (PE) has been diagnosed annually in the world. PE is often the first or single syndrome of certain diseases and it can be the manifestation of more than 50 various diseases. The causes of pleural effusion have large variety in different regions.  Purpose of the study was to evaluate the causes of PE in Belarus.   Patients and methods.  In Belarussian Republican Research and Practical Centre for Pulmonology and Tuberculosis (TB) during the period from 2002 to 2011 600 video assisted thoracoscopies (VATS) have been performed in patients (men - 71% women - 29%) with pleural effusion for diagnostics purpose. Right-sided localisation observed in 55%, left-sided - in 41% and bilateral involvement - in 4% cases.   Results.  There are the following results of pleural biopsies: TB – 243 cases (40.5%), non-specific inflammation (other infections or inflamation of unknown origin) – 314 cases (52.3%), tumors and metastasis – 43 cases (7.2%).   Conclusion:  TB is the leading cause of pleural effusion in Belarus among the patienst with PE of unknow diagnosis.
Inhaled Formoterol Diminishes Insulin-Induced Hypoglycemia in Type 1 Diabetes
Authors: Renata D. Belfort-DeAguiar, Sarita Naik, Janice Hwang, Barbara Szepietowska, Robert S. Sherwin
Journal: Diabetes Care (2015)

OBJECTIVE Hypoglycemia is one of the major factors limiting implementation of tight glycemic control in patients with type 1 diabetes and is associated with increased morbidity and mortality during intensive insulin treatment. β-2 Adrenergic receptor (AR) agonists have been reported to diminish nocturnal hypoglycemia; however, whether long-acting inhaled β-2 AR agonists could potentially be used to treat or prevent hypoglycemia has not been established. RESEARCH DESIGN AND METHODS Seven patients with type 1 diabetes and seven healthy control subjects received inhaled formoterol (48 μg), a highly specific β-2 AR agonist, or a placebo during a hyperinsulinemic-hypoglycemic clamp study to evaluate its capacity to antagonize the effect of insulin. In a second set of studies, five subjects with type 1 diabetes received inhaled formoterol to assess its effect as a preventive therapy for insulin-induced hypoglycemia. RESULTS During a hyperinsulinemic-hypoglycemic clamp, compared with placebo, inhaled formoterol decreased the glucose infusion rate required to maintain plasma glucose at a target level by 45–50% (P &amp;lt; 0.05). There was no significant effect on glucagon, epinephrine, cortisol, or growth hormone release (P = NS). Furthermore, in volunteers with type 1 diabetes 1 h after increasing basal insulin delivery twofold, glucose levels dropped to 58 ± 5 mg/dL, whereas hypoglycemia was prevented by inhaled formoterol (P &amp;lt; 0.001). CONCLUSIONS Inhalation of the β-2 AR–specific agonist formoterol may be useful in the prevention or treatment of acute hypoglycemia and thus may help patients with type 1 diabetes achieve optimal glucose control more safely.
Endothelial-derived nitric oxide inhibits sodium transport by affecting apical membrane channels in cultured collecting duct cells.
Authors: B A Stoos, O A Carretero, J L Garvin
Journal: Journal of the American Society of Nephrology (1994)

Previously, it has been shown that the addition of bradykinin (Bk) to M-1 cortical collecting duct cells in the presence of endothelial cells decreased short-circuit current (Isc), a measure of net active transport. This effect is presumably due to the release of endothelium-derived nitric oxide (EDNO), because the decrease in Isc could be blocked with Nw-nitro-L-arginine. To show that the inhibition of Isc was due to EDNO rather than prostaglandins, the ability of a cyclooxygenase inhibitor to block the inhibition was examined. When Bk was added to cocultures in the presence of meclofenamate (10(-5) M), Isc decreased from 62 +/- 12 to 44.5 +/- 7 muA/cm2, not significantly different from that in the absence of meclofenamate. To determine if the effect was due to an alteration of sodium absorption, Bk (10(-9) M) was added to cocultures, resulting in a decrease in Na flux from 28 +/- 3.1 to 20 +/- 2.2 nEq/min (P < 0.05), with Isc decreasing from 25 +/- 2.4 to 20 +/- 3.6 nEq/min (P < 0.05). To examine if the inhibition was due to blockade at the apical membrane sodium channel or the basolateral Na+/K+ ATPase, the cation-selective ionophore nystatin was used. Nystatin reversed the effect of EDNO on Isc. The effects of EDNO on Na+/K+ ATPase were also measured directly. Under maximum rate conditions, the Na+/K+ ATPase activity of control and Bk-treated cocultures was 5.2 +/- 0.3 and 6.8 +/- 1.0 nmol/min per square centimeter, respectively (not significantly different).(ABSTRACT TRUNCATED AT 250 WORDS)
Laboratory and clinical parameters in predicting risk of future exacerbations in both non-smoking and smoking COPD patients
Authors: Anatoli Tahanovich, Aliaksei Kadushkin
Journal: European Respiratory Journal (2014)

Background.  The majority of developed prediction models for future exacerbations included smoking patients with COPD, but they may be not representative for non-smoking COPD patient population.   Aim.  The aim of the study was to evaluate the significance of measuring the levels of cytokines, immunoglobulins, the percentages of lymphocyte subpopulations in peripheral blood as well as clinical parameters in order to assess the risk of future exacerbations in both non-smoking and smoking COPD patients.   Methods.  Twenty eight inflammatory biomarkers in peripheral blood and eight clinical parameters were quantified in 37 COPD patients and 41 healthy controls. The validation cohort consisted of 31 patients with COPD. Both groups of COPD patients and healthy subjects included both smokers and non-smokers. Patients with infrequent exacerbations were defined as those who had no or one exacerbation in a year. We determined frequent exacerbations as two or more exacerbations. Logistic regression analysis was used to develop the prediction model.   Results.  The final model to predict frequent exacerbations within a year included four variables: VEGF, C-reactive protein, number of exacerbations in the previous year and CAT score, with sensitivity of 94.4%, specificity of 80.0%, and a C-statistics of 0.85.   Conclusion.  Our newly developed prediction model can help clinicians to predict the risk of future exacerbations in individual non-smoking and smoking patients with COPD.
Abstract 693: Nox4 Mediates Cardiac Fibrosis while p47phox-based Nox2 is Required for the Inflammatory Response to Angiotensin II in Murine Cardiac Fibroblasts
Authors: Ioan Cucoranu, Calin B Chiribau, Roza E Clempus, Brandon Kitchel, George P Sorescu, Kathy K Griendling, Dan Sorescu
Journal: Circulation (2006)

Reactive oxygen species (ROS) mediate cardiac fibrosis induced by angiotensin II (Ang II) and NADPH oxidases (Nox) are a major source of ROS. In vitro, activation of Nox2 by Ang II requires the cyt...
Individual monitoring of procalcitonin and C-reactive protein levels as a criterion for cancel of antibiotic therapy in patients with severe community-acquired pneumonia
Authors: Kseniia Bielosludtseva, Tetyana Pertseva, Tetyana Kyreeva
Journal: European Respiratory Journal (2013)

According to procalcitonin (PCT) strategy antibiotic therapy (ABT) can be canceled at decreasing of individual PCT level more than in 80% from the initial one.

Aim: to justify the duration of ABT in patients (pts) with severe community acquired pneumonia (sCAP) based on monitoring of PCT and C-reactive protein (CRP).

Methods: 40 pts with verified sCAP (age–57,1±3,1 years, men–30, women–10), general data, SMRT-CO scale, serum levels of PCT and CRP on 1st day before ABT (step 1) and on 8–10th day of ABT (step 2).

Results: on step 1 the condition of all pts was serious, their PCT level was significantly above norm (17,8±4,22 ng/ml). On step 2 the status of all pts improved, although they had several residual symptoms, there individual PCT levels decreased more than in 85%. According to ABT strategy 2 groups (gr) were formed: 1–whom ABT was canceled on 8–10 day, 2–whom ABT was continued traditionally. Retrospectively it was determined that groups were homogeneous for clinical severity, PCT and CRP levels. All pts became healthy but the duration of ABT in gr 1 was 8,8±1,9 days and in gr 2 – 14,6±1,0 days (p <0,05). Serum levels of CRP in both gr decreased but didn’t exceed normal values.

Conclusions: 1) the presence of positive clinical and radiologic dynamics and the presence of 1-2 residual symptoms at sCAP the criterion for the cancel of ABT is significant (almost 2-fold) reduction of individual PCT level, which can significantly short the ABT and provide clinical and economic advantage without loss of efficacy; 2) whereas serum CRP normalized slowly, it’s monitoring cannot be a criterion to the ABT cancel.