tbuckley/cabot-search huggingface dataset:
Macrophage Reprogramming by Mycolic Acid Promotes a Tolerogenic Response in Experimental Asthma
Authors: Johanna E. Korf, Gwenda Pynaert, Kurt Tournoy, Tom Boonefaes, Antoon Van Oosterhout, Daisy Ginneberge, Anuschka Haegeman, Jan A. Verschoor, Patrick De Baetselier, Johan Grooten
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Mycolic acid (MA) constitutes a major and distinguishing cell wall biolipid from Mycobacterium tuberculosis. MA interferes with the lipid homeostasis of alveolar macrophages, inducing differentiation into foamy macrophages exhibiting increased proinflammatory function.We verified the interference of this altered macrophage function with inhaled antigen-triggered allergic airway inflammation and underlying Th2 lymphocyte reactivity.Using ovalbumin (OVA) as model allergen, C57BL/6 or BALB/C mice were sensitized by OVA-alum immunization. Experimental asthma, triggered subsequently by repetitive nebulized OVA inhalation, was assessed, using as readout parameters eosinophilia, peribronchial inflammation, and Th2 cytokine function.A single intratracheal treatment of sensitized mice with MA, inserted into liposomes as carriers, prevented the onset of OVA-triggered allergic airway inflammation and promoted unresponsiveness to a secondary set of allergen exposures. The development of this tolerant condition required an 8-d lapse after MA instillation, coinciding with the appearance of foamy alveolar macrophages. MA-conditioned CD11b(+)F4/80(+) macrophages, transferred to the airways, mimicked the tolerogenic function of instilled MA; however, without the 8-d lapse requirement. Indicative of a macrophage-mediated tolerogenic antigen-presenting function, major histocompatibility complex (MHC)-mismatched donor macrophages failed to promote tolerance. Furthermore, Treg markers were strongly increased and established tolerance was lost after in situ depletion of CD25(+) Treg cells. Contrary to the interleukin-10 dependence of tolerogenic dendritic cells, IFN-gamma deficiency but not interleukin-10 deficiency abrogated the tolerogenic capacity of MA-conditioned macrophages.These results document an innate-driven Mycobacterium tuberculosis MA-triggered immune regulatory mechanism in control of pulmonary allergic responses by converting macrophages into IFN-gamma-dependent tolerogenic antigen-presenting cells.
Bombesin Inhibits Alveolarization and Promotes Pulmonary Fibrosis in Newborn Mice
Authors: Khalid Ashour, Lin Shan, Jong Hwan Lee, William Schlicher, Keiji Wada, Etsuko Wada, Mary E. Sunday
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Bombesin-like peptides promote fetal lung development. Normally, levels of mammalian bombesin (gastrin-releasing peptide [GRP]) drop postnatally, but these levels are elevated in newborns that develop bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by arrested alveolarization. In premature baboons with BPD, antibombesin antibodies reduce lung injury and promote alveolarization.The present study tests whether exogenous bombesin or GRP given perinatally alters alveolar development in newborn mice.Mice were given peptides intraperitoneally twice daily on Postnatal Days 1-3. On Day 14 lungs were inflation-fixed for histopathologic analyses of alveolarization.Bombesin had multiple effects on Day 14 lung, when alveolarization was about half complete. First, bombesin induced alveolar myofibroblast proliferation and increased alveolar wall thickness compared with saline-treated control animals. Second, bombesin diminished alveolarization in C57BL/6 (but not Swiss-Webster) mice. We used receptor-null mice to explore which receptors might mediate these effects. Compared with wild-type littermates, bombesin-treated GRP receptor (GRPR)-null mice had increased interstitial fibrosis but reduced defects in alveolarization. Neuromedin B (NMB) receptor-null and bombesin receptor subtype 3-null mice had the same responses as their wild-type littermates. GRP had the same effects as bombesin, whereas neither NMB nor a synthetic bombesin receptor type 3 ligand had any effect. All effects of GRP were abrogated in GRPR-null mice.Bombesin/GRP can induce features of BPD, including interstitial fibrosis and diminished alveolarization. GRPR appears to mediate all effects of GRP, but only part of the bombesin effect on alveolarization, suggesting that novel receptors may mediate some effects of bombesin in newborn lung.
PATENT PLUS: a blinded, randomised and extension study of riociguat plus sildenafil in pulmonary arterial hypertension
Authors: Nazzareno Galiè, Katharina Müller, Andrea-Viviana Scalise, Ekkehard Grünig
Journal: European Respiratory Journal (2015)

PATENT PLUS evaluated the safety and efficacy of riociguat in combination with sildenafil in pulmonary arterial hypertension patients. Patients receiving sildenafil (20 mg three times daily) were randomised to placebo or riociguat (up to 2.5 mg three times daily) for 12 weeks. The primary outcome was maximum change in supine systolic blood pressure (SBP) from baseline within 4 h of dosing. Secondary objectives comprised additional blood pressure, heart rate and exploratory efficacy variables, and safety. Patients could enter a long-term extension (LTE), where all patients received riociguat plus sildenafil. There was no difference in maximum change in supine SBP from baseline within 4 h between the riociguat (n=12) (mean± sd baseline: –20.2±15.3 mmHg; week 12: –20.7±18.0 mmHg) and placebo groups (n=6) (–7.6±3.9 and –20.2±12.9 mmHg, respectively). Changes in standing SBP and supine or standing diastolic blood pressure were also not different. Combination therapy showed no favourable effects on exploratory clinical parameters, including haemodynamics and exercise capacity. In the LTE, there were high rates of discontinuation due to hypotension and three (18%) deaths (not considered study drug-related by the investigator). There were potentially unfavourable safety signals with sildenafil plus riociguat and no evidence of a positive benefit/risk ratio. Concomitant use of riociguat with phosphodiesterase-5 inhibitors is therefore contraindicated.
SERENADE: The Study Evaluating Rimonabant Efficacy in Drug-Naive Diabetic Patients
Authors: Julio Rosenstock, Priscilla Hollander, Soazig Chevalier, Ali Iranmanesh
Journal: Diabetes Care (2008)

The purpose of this study was to assess the glucose-lowering efficacy and safety of rimonabant monotherapy in drug-naive type 2 diabetic patients.The Study Evaluating Rimonabant Efficacy in Drug-Naive Diabetic Patients (SERENADE) was a 6-month, randomized, double-blind, placebo-controlled trial of 20 mg/day rimonabant in drug-naive patients with type 2 diabetes (A1C 7-10%). The primary end point was A1C change from baseline; secondary end points included body weight, waist circumference, and lipid profile changes.A total of 281 patients were randomly assigned; 278 were exposed to treatment, and 236 (84.9%) completed the study. Baseline A1C (7.9%) was reduced by -0.8% with rimonabant versus -0.3% with placebo (Delta A1C -0.51%; P = 0.0002), with a larger rimonabant effect in patients with baseline A1C >or=8.5% (Delta A1C -1.25%; P = 0.0009). Weight loss from baseline was -6.7 kg with rimonabant versus -2.8 kg with placebo (Delta weight -3.8 kg; P < 0.0001). Rimonabant induced improvements from baseline in waist circumference (-6 vs. -2 cm; P < 0.0001), fasting plasma glucose (-0.9 vs. -0.1 mmol/l; P = 0.0012), triglycerides (-16.3 vs. +4.4%; P = 0.0031), and HDL cholesterol (+10.1 vs. +3.2%; P < 0.0001). Adverse events of interest that occurred more frequently with rimonabant versus placebo were dizziness (10.9 vs. 2.1%), nausea (8.7 vs. 3.6%), anxiety (5.8 vs. 3.6%), depressed mood (5.8 vs. 0.7%), and paresthesia (2.9 vs. 1.4%).Rimonabant monotherapy resulted in meaningful improvements in glycemic control, body weight, and lipid profile in drug-naive type 2 diabetic patients. Further ongoing studies will better establish the benefit-to-risk profile of rimonabant and define its place in type 2 diabetes management.
Aldosterone Decreases UT-A1 Urea Transporter Expression via the Mineralocorticoid Receptor
Authors: Randy A. Gertner, Janet D. Klein, James L. Bailey, Dong-un Kim, Xiao H. Luo, Serena M. Bagnasco, Jeff M. Sands
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Adrenalectomy in rats is associated with urinary concentrating and diluting defects. This study tested the effect of adrenal steroids on the UT-A1 urea transporter because it is involved in the urine-concentrating mechanism. Rats were adrenalectomized and given normal saline for 14 d, after which they received (1) vehicle, (2) aldosterone, or (3) spironolactone plus aldosterone. Adrenalectomy alone significantly increased UT-A1 protein in the inner medullary tip after 7 d, whereas aldosterone repletion reversed the effect. Spironolactone blocked the aldosterone-induced decrease in UT-A1, indicating that aldosterone was working via the mineralocorticoid receptor. For verifying that glucocorticoids downregulate UT-A1 protein through a different receptor, three groups of adrenalectomized rats were prepared: (1) vehicle, (2) adrenalectomy plus dexamethasone, and (3) adrenalectomy plus dexamethasone and spironolactone. Dexamethasone significantly reversed UT-A1 protein abundance increase in the inner medullary tip of adrenalectomized rats. When spironolactone was given with dexamethasone, it did not affect the dexamethasone-induced decrease in UT-A1. There was no significant change in serum vasopressin level, aquaporin 2, or Na+-K+-2Cl− co-transporter NKCC2/BSC1 protein abundances or UT-A1 mRNA abundance in any of the groups. In conclusion, either mineralocorticoids or glucocorticoids can downregulate UT-A1 protein. The decrease in UT-A1 does not require both steroid hormones, and each works through a different receptor.
High-intensity interval exercise training improves daily physical activity levels in COPD
Authors: Eleni Kortianou, Zafeiris Louvaris, Stavroula Spetsioti, Maroula Vasilopoulou, Nikolaos Chynkiamis, Ioannis Nasis, Giorgos Kaltsakas, Nikos G. Koulouris, Ioannis Vogiatzis
Journal: European Respiratory Journal (2014)

There is controversy as to whether rehabilitative exercise training improves daily physical activity levels in COPD.   Aim : To examine the effects high-intensity interval training on activity levels in COPD.   Methods : 30 patients (FEV 1 : 53±20%pred) were randomly assigned in 2 groups: the intervention (n=20) and the control (n=10). The intervention group exercised at 100% WRpeak (alternating 30-s exercise with 30-s rest), 40 min/day, 3 times/week for 3 months. Physical activity was measured and averaged in all patients for 7 consecutive days using the DynaPort MoveMonitor triaxial accelerometer before and after the 3-month period.   Results : At baseline both groups exhibited comparable daily movement intensity levels but following rehabilitation only the intervention group significantly improved the average movement intensity (from 1.79±0.08 to 1.92±0.09 m/s 2 ) with no significant change in the control group (from 1.71±0.05 to 1.78±0.07 m/s 2 ). In the intervention group quadriceps muscle strength normalized by body mass increased significantly (from 3.5±0.15 to 4.2±0.20 N/Kg). Walking time was also significantly improved (from 54±9 to 68±8 min) but remained unchanged in the control group (from 50±8 to 52±7 min). In addition, for the intervention group significant associations were found between the improvement in walking time and i) that of the 6-min walk distance (r=0.58) as well as ii) the improvement in normalized muscle strength (r=0.52).   Conclusion : High-intensity interval exercise training improves daily physical activity levels in COPD along with indices of functional capacity.  This work was funded by Innovative Medicines Initiative Joint Undertaking (IMU-JU #115011) through Thorax Foundation.
Arsenic-induced interstitial myocardial fibrosis reveals a new insight into drug-induced long QT syndrome
Authors: Wenfeng Chu, Cui Li, Xuefeng Qu, Dan Zhao, Xuelian Wang, Xiangru Yu, Fulai Cai, Haihai Liang, Yong Zhang, Xin Zhao, Baoxin Li, Guofen Qiao, Deli Dong, Yanjie Lu, Zhimin Du, Baofeng Yang
Journal: Cardiovascular Research (2012)

Arsenic trioxide (ATO), an effective therapeutic agent for acute promyelocytic leukaemia, can cause sudden cardiac death due to long QT syndrome (LQTS). The present study was designed to determine whether ATO could induce cardiac fibrosis and explore whether cardiac fibroblasts (CFs) are involved in the development of LQTS by ATO. ATO treatment of guinea pigs caused substantial interstitial myocardial fibrosis and LQTS, which was accompanied by an increase in transforming growth factor β1(TGF-β1) secretion and a decrease in ether-à-go-go-related gene (HERG) and inward rectifying potassium channel (IK1) subunit Kir2.1 protein levels. ATO promoted collagen production and TGF-β1 expression and secretion in cultured CFs. Whole-cell patch clamp and western blotting showed that treatment with TGF-β1 markedly reduced HERG and IK1 current densities and downregulated HERG and Kir2.1 protein expression in HEK293 cells stably transfected with the human recombinant HERG channel and in cardiomyocytes (CMs). These changes were completely reversed by treatment with the protein kinase A (PKA) antagonist, H89. CM and CF co-cultures showed that ATO significantly increased TGF-β1 levels in the culture medium, whereas markedly reduced HERG and Kir2.1 protein levels were observed in CMs compared with ATO-treated CMs not co-cultured with CFs. Finally, in vivo administration of LY364947, a pharmacological antagonist of TGF-β signalling, dramatically prevented interstitial fibrosis and LQTS and abolished aberrant expression of TGF-β1, HERG, and Kir2.1 in ATO-treated guinea pigs. ATO-induced TGF-β1 secretion from CFs aggravates QT prolongation, suggesting that modulation of TGF-β signalling may provide a novel strategy for the treatment of drug-induced LQTS.
Additional value of K‐ras point mutations in bronchial wash fluids for diagnosis of peripheral lung tumours
Authors: V.A.M.C. Somers, A.M.J. van Henten, G.P.M. ten Velde, J-W. Arends, F.B.J.M. Thunnissen
Journal: European Respiratory Journal (1999)

The purpose of this study was to examine the additional diagnostic value of K-ras point mutations in the clinical diagnosis of peripheral lung tumours. To this end, bronchial wash fluids obtained during bronchoscopy from patients suspected of having lung cancer were studied. Only those patients were investigated for whom the cytological diagnosis was not conclusive for malignancy. As a control group, patients without lung cancer were investigated. The method of "point mutation detection using the exonuclease amplification coupled capture technique" (Point-EXACCT) for analysis of K-ras codon 12 was performed in bronchial wash fluids and the corresponding tumour tissue, if available. K-ras point mutations were identified in 4 out of 19 (21%) bronchial wash fluids from patients without a decisive diagnosis of malignancy. The diagnosis of malignancy was further based on cytological examination of bronchial brush specimens, perthoracic needle aspiration, histological investigation of biopsy and resection specimens, needle aspiration of a lymph node in the neck and pleural fluid examination. Four of the patients who were K-ras-positive yielded positive malignant tissue via bronchoscopy even though the bronchial wash was negative for malignancy. The bronchial wash was positive for K-ras in two of the four patients whose tumour tissue demonstrated the K-ras mutations. Analysis of bronchial wash fluids from 11 patients without lung cancer revealed no K-ras codon 12 mutations. In conclusion, K-ras point mutations can be identified in bronchial wash fluids obtained during bronchoscopic procedures. K-ras can be used as a biomarker in the clinical diagnosis of lung cancer and may serve as an adjunct to cytology in lung cancer diagnosis.
Description of sleep disordered breathing in children with Prader-Willi syndrome
Authors: Martino Pavone, Valeria Caldarelli, Sonia Khirani, Marina Colella, Adriana Ramirez, Guillaume Aubertin, Frédéric Brioude, Nicole Beydon, Michèle Boulé, Lisa Giovannini-Chami, Renato Cutrera, Brigitte Fauroux
Journal: European Respiratory Journal (2013)

Introduction

Sleep disordered breathing (SDB) is common in patients with Prader-Willi syndrome (PWS) and has to be evaluated before growth hormone (GH), ENT surgery and/or noninvasive mechanical ventilation (NIV).

Objectives

To describe the baseline sleep disorders in children with PWS.

Methods

Anthropometrics, polygraphic (PG) and gas exchange data were obtained from three centers (France, Italy).

Results

Ninety two patients, mean age 8.4 ± 10.7 years (range 0.3-44 years), were included. The mean body mass index was 26 ± 16 kg/m2, apnea-hypopnea index (AHI) 6 ± 18 events/h, central apnea index 1 ± 1 events/h, minimal SpO2 86.7 ± 6.6%, percentage of time with SpO2<90% 1.5 ± 4.0%, 4% desaturation index 6 ± 20 /h, and mean and maximal transcutaneous carbon dioxide (n=19) 42.9 ± 6.8 mmHg and 47.4 ± 8.0 mmHg, respectively.

An AHI >1.5 events/hour, a minimal SpO2  1.4/hour was observed in 58%, 73%, and 57% of patients, respectively. PG was normal according to the 3 above criteria in only 16% of patients. A correlation was observed between age and minimal SpO2 (r=-0.318, p=0.005) and percentage of SpO2 <90% (r=0.323, p=0.003), and between body mass index and minimal SpO2 (r=-0.278, p=0.013) and percentage of SpO2 <90% (r=0.304, p=0.005). GH was started in 48 patients, NIV in 16 patients, and 10 patients had ENT surgery.

Conclusion

This large multicenter study confirms the high prevalence and severity of SDB in patients with PWS, underlining the importance of a systematic sleep study before any intervention.
Etanercept Treatment in Children With New-Onset Type 1 Diabetes: Pilot Randomized, Placebo-Controlled, Double-Blind Study
Authors: Lucy Mastrandrea, Jihnhee Yu, Torsten Behrens, John Buchlis, Christine Albini, Shannon Fourtner, Teresa Quattrin
Journal: Diabetes Care (2009)

We thank Dr. Peters (1) for his thoughtful comments regarding our study (2). Dr. Peters suggests that etanercept may effect the partial remission period of type 1 diabetes by mediating declines in autoantibodies, GAD-65 in particular. Clinical data supports the concept that titer and number of autoantibodies correlates with accelerated β-cell demise and a lower likelihood of clinical remission compared with individuals who tested negative for diabetes-associated …
Assessing asthma control: questionnaires and exhaled nitric oxide provide complementary information
Authors: C. Lopes, J. Fonseca, L. Delgado, A. Moreira, R. Barros, P. Moreira, M. da G. Castelo-Branco
Journal: European Respiratory Journal (2008)

To the Editor: 

Current asthma guidelines propose the use of quantitative composite measures of asthma control for assessment and follow-up 1. The use of inflammatory markers within the definition of control in asthma guidelines has been recently suggested 2. Sputum eosinophilia has been proposed as a useful surrogate marker of airway inflammation 3 but it is time-consuming and unfeasible in many clinical settings. In contrast, exhaled nitric oxide fraction ( F eNO) is easily measured, well correlated with eosinophilic airway inflammation 4 and has been used in routine asthma care 5. However, to be included in the assessment of asthma control it should provide additional information. Factor analysis is a statistical method used to uncover which sets of variables form coherent subsets that are relatively independent of one another, and to obtain a small number of factors …
Exposure to smoking in films and own smoking among Scottish adolescents: a cross-sectional study
Authors: K. Hunt, M. Henderson, D. Wight, J. D. Sargent
Journal: Thorax (2011)

<h3>Background</h3> Evidence of high exposure of UK youth to images of smoking in films has led to calls for an 18 rating for films with smoking to reduce smoking in youth. However, the only study to date in the UK to test for an association showed no relation between film-smoking exposure and smoking among young adults. <h3>Objective</h3> To assess whether there is an association between exposure to film images of smoking and own smoking among UK adolescents and whether repeated viewings of films has an impact. <h3>Design</h3> Cross-sectional study. <h3>Participants</h3> 1999 pupils aged 15–16 years from 13 Scottish schools. <h3>Outcome</h3> Smoked tobacco in the past year. <h3>Exposure measure</h3> Film-smoking exposure was assessed using the Beach method; account for repeated viewings of films was then used to modify estimated exposure. Covariates included: media usage, parental restriction on and context of TV/film viewing, family connectedness, parental monitoring and friends9 smoking. <h3>Results</h3> Most (71%) students had not smoked in the past year. About half reported no parental restrictions on TV/film viewing. Many reported repeated viewings of films; accounting for this more than doubled exposure estimates and strengthened the association with smoking. Adolescents with high exposure to film smoking were more likely to have smoked than those with low exposure (adjusted odds ratio (AOR) 2.08, 95% CI 1.22 to 3.55). Additionally, adolescents who reported parental rules about TV/film watching were less likely to smoke (AOR 0.37 (0.27 to 0.52)) than those who did not. Adolescents who mainly watched films with friends had higher exposure to film smoking and were more likely to smoke (AOR 2.19 (1.10 to 4.38)). <h3>Conclusions</h3> Exposure to film smoking is associated with smoking among Scottish adolescents. These data lend support to calls for an 18 rating for films with images of smoking.
Immune regulation and colitis: suppression of acute inflammation allows the development of chronic inflammatory bowel disease
Authors: B Eksteen
Journal: Gut (2004)

Persistent colitis is the result of a balance between local inflammation and regulatory networks. Regulatory T cells have potent anti-inflammatory effects and are likely to be important in the pathogenesis of chronic inflammatory bowel disease

The success of the gastrointestinal immune system depends on a balance between mounting effective immune responses to pathogenic antigens while suppressing potentially damaging responses against commensal organisms or food antigens. Both the innate and acquired immune system contribute to fighting pathogens. The innate immune system, which includes phagocytes, dendritic cells (DCs), and natural killer (NK) cells, does not require previous exposure to a pathogen and instead relies on evolutionarily ancient pathways such as Toll-like receptors (TLRs) to recognise molecular patterns associated with harmful pathogens.1 Different TLRs are able to recognise bacterial products or motifs in viral RNA or DNA. TLR activation triggers an immediate response resulting in the activation of phagocytic mechanisms and the production of cytokines and costimulatory signals that activate the cognate immune response.

The cognate or acquired immune system developed in higher vertebrates to provide a more sophisticated response to a wide variety of antigens. It involves lymphocytes that recognise specific antigens from pathogens processed and presented by specialised antigen presenting cells called DCs. A crucial feature of the cognate immune system is immunological memory whereby a subsequent exposure to the same antigen leads to a more potent and sustained immune response. Antigens from pathogens that penetrate the mucosal barrier are taken up by local DCs and carried via lymphatics to draining mesenteric lymph nodes.2 In addition, DCs situated in gut associated lymphoid tissue such as Peyer’s patches sample luminal antigens either directly, by extending finger-like processes into the lumen, or via specialised epithelial cells (M cells) that actively transport luminal antigens to the underlying DCs.3 Antigen containing DCs …