tbuckley/cabot-search huggingface dataset:
Increased exhaled nitric oxide in patients with stable chronic obstructive pulmonary disease
Authors: M. Corradi, M. Majori, G. C. Cacciani, G. F. Consigli, E. de'Munari, A. Pesci
Journal: Thorax (1999)

Nitric oxide (NO) plays an important role as an inflammatory mediator in the airways. Since chronic obstructive pulmonary disease (COPD) is characterised by airway inflammation, a study was undertaken to determine NO levels in the exhaled air of patients with COPD.Two groups of patients with clinically stable COPD were studied, 10 current smokers and 10 ex-smokers. Two control groups of healthy subjects consisting of 10 current smokers and 20 non-smokers were also studied. Exhaled NO levels were measured by the collection bag technique and NO chemiluminescence analyser.Mean (SE) levels of exhaled NO in ex-smokers and current smokers with COPD (25.7 (3.0) ppb and 10.2 (1.4) ppb, respectively) were significantly higher than in non-smoker and current smoker control subjects (9.4 (0.8) ppb and 4.6 (0.4) ppb, respectively). In current smokers with COPD exhaled levels of NO were significantly lower than in ex-smokers. In this latter group of patients there was a significant negative correlation between smoking history (pack years) and levels of exhaled NO (r = -0.8, p = 0.002). A positive correlation was seen between forced expiratory volume in one second (FEV1) and levels of exhaled NO (r = 0.65, p = 0.001) in patients with COPD.These data show that exhaled NO is increased in patients with stable COPD, both current and ex-smokers, compared with healthy control subjects.
Genes encoding proteoglycans are associated with the risk of anterior cruciate ligament ruptures
Authors: Sasha Mannion, Asanda Mtintsilana, Michael Posthumus, Willem van der Merwe, Hayden Hobbs, Malcolm Collins, Alison V September
Journal: British Journal of Sports Medicine (2014)

Background Genetic variants within genes involved in fibrillogenesis have previously been implicated in anterior cruciate ligament (ACL) injury susceptibility. Proteoglycans also have important functions in fibrillogenesis and maintaining the structural integrity of ligaments. Genes encoding proteoglycans are plausible candidates to be investigated for associations with ACL injury susceptibility; polymorphisms within genes encoding the proteoglycans aggrecan ( ACAN ), biglycan ( BGN ), decorin ( DCN ), fibromodulin ( FMOD ) and lumican ( LUM ) were examined. Methods A case–control genetic association study was conducted. 227 participants with surgically diagnosed ACL ruptures (ACL group) and 234 controls without any history of ACL injury were genotyped for 10 polymorphisms in 5 proteoglycan genes. Inferred haplotypes were constructed for specific regions. Results The G allele of ACAN rs1516797 was significantly under-represented in the controls (p=0.024; OR=0.72; 95% CI 0.55 to 0.96) compared with the ACL group. For DCN rs516115, the GG genotype was significantly over-represented in female controls (p=0.015; OR=9.231; 95%CI 1.16 to 73.01) compared with the ACL group and the AA genotype was significantly under-represented in controls (p=0.013; OR=0.33; 95% CI 0.14 to 0.78) compared with the female non-contact ACL injury subgroup. Haplotype analyses implicated regions overlapping ACAN (rs2351491 C&gt;T-rs1042631 T&gt;C-rs1516797 T&gt;G), BGN (rs1126499 C&gt;T-rs1042103 G&gt;A) and LUM - DCN (rs2268578 T&gt;C-rs13312816 A&gt;T-rs516115 A&gt;G) in ACL injury susceptibility. Conclusions These independent associations and haplotype analyses suggest that regions within ACAN , BGN , DCN and a region spanning LUM – DCN are associated with ACL injury susceptibility. Taking into account the functions of these genes, it is reasonable to propose that genetic sequence variability within the genes encoding proteoglycans may potentially modulate the ligament fibril properties.
Associations Between Initial Water Pipe Tobacco Smoking and Snus Use and Subsequent Cigarette Smoking
Authors: Samir Soneji, James D. Sargent, Susanne E. Tanski, Brian A. Primack
Journal: JAMA Pediatrics (2014)

Many adolescents and young adults use alternative tobacco products, such as water pipes and snus, instead of cigarettes.To assess whether prior water pipe tobacco smoking and snus use among never smokers are risk factors for subsequent cigarette smoking.We conducted a 2-wave national longitudinal study in the United States among 2541 individuals aged 15 to 23 years old. At baseline (October 25, 2010, through June 11, 2011), we ascertained whether respondents had smoked cigarettes, smoked water pipe tobacco, or used snus. At the 2-year follow-up (October 27, 2012, through March 31, 2013), we determined whether baseline non-cigarette smokers had subsequently tried cigarette smoking, were current (past 30 days) cigarette smokers, or were high-intensity cigarette smokers. We fit multivariable logistic regression models among baseline non-cigarette smokers to assess whether baseline water pipe tobacco smoking and baseline snus use were associated with subsequent cigarette smoking initiation and current cigarette smoking, accounting for established sociodemographic and behavioral risk factors. We fit similarly specified multivariable ordinal logistic regression models to assess whether baseline water pipe tobacco smoking and baseline snus use were associated with high-intensity cigarette smoking at follow-up.Water pipe tobacco smoking and the use of snus at baseline.Among baseline non-cigarette smokers, cigarette smoking initiation, current (past 30 days) cigarette smoking at follow-up, and the intensity of cigarette smoking at follow-up.Among 1596 respondents, 1048 had never smoked cigarettes at baseline, of whom 71 had smoked water pipe tobacco and 20 had used snus at baseline. At follow-up, accounting for behavioral and sociodemographic risk factors, baseline water pipe tobacco smoking and snus use were independently associated with cigarette smoking initiation (adjusted odds ratios: 2.56; 95% CI, 1.46-4.47 and 3.73; 95% CI, 1.43-9.76, respectively), current cigarette smoking (adjusted odds ratios: 2.48; 95% CI, 1.01-6.06 and 6.19; 95% CI, 1.86-20.56, respectively), and higher intensity of cigarette smoking (adjusted proportional odds ratios: 2.55; 95% CI, 1.48-4.38 and 4.45; 95% CI, 1.75-11.27, respectively).Water pipe tobacco smoking and the use of snus independently predicted the onset of cigarette smoking and current cigarette smoking at follow-up. Comprehensive Food and Drug Administration regulation of these tobacco products may limit their appeal to youth and curb the onset of cigarette smoking.
Etanercept: effective in the management of hidradenitis suppurativa
Authors: C. Cusack, C. Buckley
Journal: British Journal of Dermatology (2006)

Hidradenitis suppurativa (HS) is a chronic suppurative condition which is poorly responsive to treatment and is characterized by significant morbidity. Successful treatment of HS in patients treated with infliximab for concomitant Crohn's disease has been reported. More recent reports of positive responses to infliximab [an antitumour necrosis factor (TNF)-alpha agent] in patients who have HS but not Crohn's disease are encouraging.TNF-alpha is implicated in many inflammatory disorders and we wished to determine the efficacy of subcutaneous etanercept, a competitive inhibitor of TNF-alpha in the control of HS symptoms.We commenced six patients with severe, recalcitrant HS on etanercept (25 mg subcutaneously twice weekly in all cases). All patients had a normal chest X-ray and negative purified protein derivative test prior to treatment and were closely monitored throughout the treatment period for signs of infection. Patients self-assessed their disease activity and completed Dermatology Life Quality Index (DLQI) questionnaires immediately before the introduction of therapy and 24 weeks later in the case of four patients, and 12 weeks later in the case of two others. All patients were asked to estimate the time lapse between commencement of treatment and initial response.Treatment was well tolerated by all patients with no reported adverse reactions. A marked reduction in self-reported disease activity (mean reduction of 61% at 24 weeks), in DLQI scores (mean reduction of 64% at 24 weeks) and in relapse rates occurred. All patients rated etanercept as their most effective treatment to date.Our results show the effectiveness of etanercept in this group of patients with particularly challenging disease. Etanercept, unlike infliximab, may be administered subcutaneously, rendering costly day-case admissions unnecessary.
<i>In vivo</i> Induction of Resistance to Gemcitabine Results in Increased Expression of Ribonucleotide Reductase Subunit M1 as the Major Determinant
Authors: Andries M. Bergman, Paul P. Eijk, Veronique W.T. Ruiz van Haperen, Kees Smid, Gijsbert Veerman, Isabelle Hubeek, Paul van den IJssel, Bauke Ylstra, Godefridus J. Peters
Journal: Cancer Research (2005)

Abstract Gemcitabine is a deoxycytidine (dCyd) analogue with activity against several solid cancers. Gemcitabine is activated by dCyd kinase (dCK) and interferes, as its triphosphate dFdCTP, with tumor growth through incorporation into DNA. Alternatively, the metabolite gemcitabine diphosphate (dFdCDP) can interfere with DNA synthesis and thus tumor growth through inhibition of ribonucleotide reductase. Gemcitabine can be inactivated by the enzyme dCyd deaminase (dCDA). In most in vitro models, resistance to gemcitabine was associated with a decreased dCK activity. In all these models, resistance was established using continuous exposure to gemcitabine with increasing concentrations; however, these in vitro models have limited clinical relevance. To develop in vivo resistance to gemcitabine, we treated mice bearing a moderately sensitive tumor Colon 26-A (T/C = 0.25) with a clinically relevant schedule (120 mg/kg every 3 days). By repeated transplant of the most resistant tumor and continuation of gemcitabine treatment for &amp;gt;1 year, the completely resistant tumor Colon 26-G (T/C = 0.96) was created. Initial studies focused on resistance mechanisms known from in vitro studies. In Colon 26-G, dCK activity was 1.7-fold decreased; dCDA and DNA polymerase were not changed; and Colon 26-G accumulated 1.5-fold less dFdCTP, 6 hours after a gemcitabine injection, than the parental tumor. Based on in vitro studies, these relative minor changes were considered insufficient to explain the completely resistant phenotype. Therefore, an expression microarray was done with Colon 26-A versus Colon 26-G. Using independently grown nonresistant and resistant tumors, a striking increase in expression of the RRM1 subunit gene was found in Colon 26-G. The expression of RRM1 mRNA was 25-fold increased in the resistant tumor, as measured by real-time PCR, which was confirmed by Western blotting. In contrast, RRM2 mRNA was 2-fold decreased. However, ribonucleotide reductase enzyme activity was only moderately increased in Colon 26-G. In conclusion, this is the first model with in vivo induced resistance to gemcitabine. In contrast to most in vitro studies, dCK activity was not the most important determinant of gemcitabine resistance. Expression microarray identified RRM1 as the gene with the highest increase in expression in the Colon 26-G, which might clarify its complete gemcitabine-resistant phenotype. This study is the first in vivo evidence for a key role for RRM1 in acquired gemcitabine resistance.
Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors
Authors: Hamza Chettouh, Laetitia Fartoux, Lynda Aoudjehane, Dominique Wendum, Audrey Clapéron, Yves Chrétien, Colette Rey, Olivier Scatton, Olivier Soubrane, Filomena Conti, Françoise Praz, Chantal Housset, Olivier Rosmorduc, Christèle Desbois-Mouthon
Journal: Cancer Research (2013)

Insulin receptor (IR) exists as two isoforms resulting from the alternative splicing of IR pre-mRNA. IR-B promotes the metabolic effects of insulin, whereas IR-A rather signals proliferative effects. IR-B is predominantly expressed in the adult liver. Here, we show that the alternative splicing of IR pre-mRNA is dysregulated in a panel of 85 human hepatocellular carcinoma (HCC) while being normal in adjacent nontumor liver tissue. An IR-B to IR-A switch is frequently observed in HCC tumors regardless of tumor etiology. Using pharmacologic and siRNA approaches, we show that the autocrine or paracrine activation of the EGF receptor (EGFR)/mitogen-activated protein/extracellular signal-regulated kinase pathway increases the IR-A:IR-B ratio in HCC cell lines, but not in normal hepatocytes, by upregulating the expression of the splicing factors CUGBP1, hnRNPH, hnRNPA1, hnRNPA2B1, and SF2/ASF. In HCC tumors, there is a significant correlation between the expression of IR-A and that of splicing factors. Dysregulation of IR pre-mRNA splicing was confirmed in a chemically induced model of HCC in rat but not in regenerating livers after partial hepatectomy. This study identifies a mechanism responsible for the generation of mitogenic IR-A and provides a novel interplay between IR and EGFR pathways in HCC. Increased expression of IR-A during neoplastic transformation of hepatocytes could mediate some of the adverse effects of hyperinsulinemia on HCC.
Variance components analyses of multiple asthma traits in a large sample of Australian families ascertained through a twin proband
Authors: M. A. R. Ferreira, L. O'Gorman, P. Le Souëf, P. R. Burton, B. G. Toelle, C. F. Robertson, N. G. Martin, D. L. Duffy
Journal: Allergy (2005)

Background: Intermediate phenotypes are often measured as a proxy for asthma. It is largely unclear to what extent the same set of environmental or genetic factors regulate these traits. Objective: Estimate the environmental and genetic correlations between self‐reported and clinical asthma traits. Methods: A total of 3073 subjects from 802 families were ascertained through a twin proband. Traits measured included self‐reported asthma, airway histamine responsiveness (AHR), skin prick response to common allergens including house dust mite ( Dermatophagoides pteronyssinus [ D. pter ]), baseline lung function, total serum immunoglobulin E (IgE) and eosinophilia. Bivariate and multivariate analyses of eight traits were performed with adjustment for ascertainment and significant covariates. Results: Overall 2716 participants completed an asthma questionnaire and 2087 were clinically tested, including 1289 self‐reported asthmatics (92% previously diagnosed by a doctor). Asthma, AHR, markers of allergic sensitization and eosinophilia had significant environmental correlations with each other (range: 0.23–0.89). Baseline forced expiratory volume in 1 s (FEV 1 ) showed low environmental correlations with most traits. Fewer genetic correlations were significantly different from zero. Phenotypes with greatest genetic similarity were asthma and atopy (0.46), IgE and eosinophilia (0.44), AHR and D. pter (0.43) and AHR and airway obstruction (−0.43). Traits with greatest genetic dissimilarity were FEV 1 and atopy (0.05), airway obstruction and IgE (0.07) and FEV 1 and D. pter (0.11). Conclusion: These results suggest that the same set of environmental factors regulates the variation of many asthma traits. In addition, although most traits are regulated to great extent by specific genetic factors, there is still some degree of genetic overlap that could be exploited by multivariate linkage approaches.
Differences in local versus systemic TNF production in COPD: inhibitory effect of hyaluronan on LPS induced blood cell TNF release
Authors: M A Dentener
Journal: Thorax (2006)

<b>Background:</b> Chronic obstructive pulmonary disease (COPD) is characterised by both airway inflammation and systemic changes. To elucidate the relationship between local and systemic inflammation, tumour necrosis factor α (TNFα) production by sputum cells and blood cells of patients with COPD and controls was compared and the effect of the extracellular matrix compound hyaluronan (HA) on TNFα release was studied. <b>Methods:</b> Four study groups were included: 10 steroid free COPD patients, 8 steroid treated patients, 10 healthy smokers, and 11 healthy non-smokers. Sputum cells and blood were incubated for 24 hours with or without lipopolysaccharide (LPS) in the absence or presence of HA (122 kDa or HMW fragment). TNFα was measured by ELISA. <b>Results:</b> Sputum cells produced spontaneously high levels of TNFα but were unresponsive to LPS. Sputum cells from COPD patients (both steroid free and steroid treated) produced significantly less TNFα than cells from healthy non-smoking subjects (p = 0.017 and p = 0.001, respectively). In contrast, blood cells produced TNFα only in response to LPS. No differences were observed in TNFα production by blood cells between the patient groups and the control groups. HA (both fragments) partially blocked LPS (1 ng/ml) induced TNFα release by blood cells from all study groups, whereas TNFα production by sputum cells was not influenced by HA. <b>Conclusion:</b> These data indicate a difference between local and systemic TNFα production. Sputum cells of patients with COPD produced less TNFα than controls, which could contribute to impaired local defence. An inhibitory effect of HA on TNFα release in blood cells was observed which was similar in both patients and controls.
Polycystic Kidney Disease and Cancer after Renal Transplantation
Authors: James B. Wetmore, James P. Calvet, Alan S.L. Yu, Charles F. Lynch, Connie J. Wang, Bertram L. Kasiske, Eric A. Engels
Journal: Journal of the American Society of Nephrology (2014)

Autosomal dominant polycystic kidney disease (ADPKD), the most common form of polycystic kidney disease (PKD), is a disorder with characteristics of neoplasia. However, it is not known whether renal transplant recipients with PKD have an increased risk of cancer. Data from the Scientific Registry of Transplant Recipients, which contains information on all solid organ transplant recipients in the United States, were linked to 15 population-based cancer registries in the United States. For PKD recipients, we compared overall cancer risk with that in the general population. We also compared cancer incidence in PKD versus non-PKD renal transplant recipients using Poisson regression, and we determined incidence rate ratios (IRRs) adjusted for age, sex, race/ethnicity, dialysis duration, and time since transplantation. The study included 10,166 kidney recipients with PKD and 107,339 without PKD. Cancer incidence in PKD recipients was 1233.6 per 100,000 person-years, 48% higher than expected in the general population (standardized incidence ratio, 1.48; 95% confidence interval [95% CI], 1.37 to 1.60), whereas cancer incidence in non-PKD recipients was 1119.1 per 100,000 person-years. The unadjusted incidence was higher in PKD than in non-PKD recipients (IRR, 1.10; 95% CI, 1.01 to 1.20). However, PKD recipients were older (median age at transplantation, 51 years versus 45 years for non-PKD recipients), and after multivariable adjustment, cancer incidence was lower in PKD recipients than in others (IRR, 0.84; 95% CI, 0.77 to 0.91). The reason for the lower cancer risk in PKD recipients is not known but may relate to biologic characteristics of ADPKD or to cancer risk behaviors associated with ADPKD.
Circulating triglyceride lipolysis facilitates lipoprotein lipase translocation from cardiomyocyte to myocardial endothelial lining
Authors: T Pulinilkunnil
Journal: Cardiovascular Research (2003)

Objective: Lipoprotein lipase (LPL) mediated hydrolysis of circulating triglyceride (TG)-rich lipoproteins provides the heart with fatty acids. The present study was designed to investigate the influence of circulating TG and their lipolysis in facilitating translocation of LPL from the underlying cardiomyocyte cell surface to the coronary lumen. Methods: The in vivo effects of diazoxide (DZ), an agent that causes rapid hypoinsulinemia, and the in vitro effect of the lipoprotein breakdown product l-α-lysophosphatidylcholine (Lyso-PC) on luminal LPL were examined in Wistar rats. Manipulation of circulating TG in DZ-treated animals and their influence on LPL was also determined. Results: Within 4 h following DZ a major increase in LPL activity and protein occurred at the coronary lumen. Myocyte cell surface LPL was reduced 50% subsequent to DZ. Exposure of isolated control hearts to 1 nM Lyso-PC enhanced luminal LPL to levels observed following DZ. Treatment of DZ animals with either WR 1339 (inhibits circulating TG breakdown) or N6-cyclopentyladenosine (inhibits adipose tissue lipolysis) decreased DZ induced augmentation of cardiac LPL. Conclusions: Using DZ, our studies for the first time demonstrate that LPL at the coronary lumen can be augmented as early as 4 h after hypoinsulinemia and that this increase likely involves posttranslational processing via TG breakdown of circulating lipoproteins and a Lyso-PC dependent mechanism.
A randomised controlled trial comparing stepwise versus immediate withdrawal from non-invasive ventilation in chronic obstructive pulmonary disease patients recovering from acute hypercapnic respiratory failure
Authors: Chung Tat Lun, Chung Ming Chu, Veronica Lee Chan, Wah Shing Leung, Pik Shan Cheung, Suet Lai Cheng, Miranda Tsui
Journal: European Respiratory Journal (2012)

Background 

COPD patients who suffer from exacerbation with acute hypercapnic respiratory failure (AHcRF) benefit from non-invasive ventilation (NIV). The best withdrawal method of NIV is not known.

Aim and objectves 

To compare the success rate of withdrawal in NIV between stepwise withdrawal and immediate withdrawal in COPD patients with AHcRF.

Method 

This was a prospective, single-centre, open-labelled randomised study comparing stepwise and immediate withdrawal of NIV. The primary end-point was the success rate of NIV withdrawal. The secondary end-points were hospital length of stay and duration of NIV use.

Results 

Sixty patients were randomised: 35 patients to the stepwise withdrawal group and 25 patients to the immediate withdrawal group. There was no statistically significant difference in the success rate of withdrawal of NIV and length of stay after randomisation, with the success rate of 74.3% and 56% in stepwise and immediate withdrawal group respectively (p = 0.139). There was statistically significant difference in the duration of NIV with median duration of 5 days and 3 days in stepwise and immediate withdrawal group respectively (p = 0.001). The post-hoc analysis showed the use of LAMA, higher inhaled steroid dosage and higher arterial pH value on randomisation were the factors associated with success in withdrawal in the immediate group.

Conclusion 

Our study showed no significant difference in the success rate and length of stay between stepwise withdrawal and immediate withdrawal of NIV. Duration of NIV was significantly shorter in the immediate withdrawal group.