tbuckley/cabot-search huggingface dataset:
Idiopathic pulmonary fibrosis and pirfenidone
Authors: H. R. Collard
Journal: European Respiratory Journal (2010)

The last decade has seen important progress in the clinical investigation of idiopathic pulmonary fibrosis (IPF). Basic insights into mechanisms of fibroproliferation have been translated into novel investigational agents, networks of clinical centres capable of enrolling hundreds of patients in research studies have been developed, and multiple high-quality treatment trials have been successfully completed and published 1–5. These are all major accomplishments that unarguably move the field forward. But to patients and providers faced with this devastating diagnosis, there remain distressingly few management options, and no definitive therapy has yet been identified.

It is into this environment of hope and frustration that the latest clinical trial of pirfenidone arrives 6. It has been 11 years since a small trial of pirfenidone therapy in patients with IPF suggested a possible benefit 7, and substantial excitement surrounds the publication of these data. Do the results of Taniguchi et al. 6 justify the use of pirfenidone in patients with IPF? Ultimately, this is for the academic and regulatory communities to decide. This editorial aims to inform the discussion by summarising the results and limitations of this important trial.

275 subjects were blindly randomised to high-dose pirfenidone, low-dose pirfenidone or …
Adult patients may outgrow their asthma: a 25-year follow-up study.
Authors: C I Panhuysen, J M Vonk, G H Koëter, J P Schouten, R van Altena, E R Bleecker, D S Postma
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

The present study investigated the outcome of asthma in a population of 181 adult patients 13 to 44 yr of age (median, 24 yr) who were extensively tested between 1962 and 1970 and in whom asthma was diagnosed. When retested 25 yr later, 38 subjects (21%) did not show bronchial hyperresponsiveness (BHR)(PC20 > 16 mg/ml), 45 subjects (25%) showed a FEV1 > 90% predicted, and 72 subjects (40%) did not report pulmonary symptoms. When absence of asthma was defined as no BHR, FEV1 > 90% predicted, and the absence of pulmonary symptoms reported by the patient, 20 subjects (11%) were no longer considered asthmatic when retested. Absence of asthma after 25 yr was associated with a younger age and less severe airway obstruction at first testing, odds ratios (OR) being 0.36 for age/10 yr, and 1.42 for FEV1/height2 (dl/m2). Absence of BHR was associated with a younger age, a higher FEV1, and a shorter untreated period (years between onset of asthma symptoms and specialized treatment of the disease) at first testing, and a lower total serum IgE level (IU/L) at second testing (OR, 0.48 for age/10 yr; OR, 1.37 for FEV1/height2; OR, 0.93 for untreated period; OR, 0.33 for log [IgE]). Neither sex nor atopy (one or more positive skin tests) were significant determinants of the outcome of both asthma and BHR. Our results suggest that in a substantial proportion of symptomatic asthmatics the disease improved, and that subsets may outgrow their asthma, even in adulthood. The data lend indirect support to the hypothesis that milder disease and earlier intervention are important for a beneficial outcome of asthma.
Inactivation of the von Hippel-Lindau tumour suppressor gene induces Neuromedin U expression in renal cancer cells
Authors: Sarah K Harten, Miguel A Esteban, Deepa Shukla, Margaret Ashcroft, Patrick H Maxwell
Journal: Molecular Cancer (2011)

209 000 new cases of renal carcinoma are diagnosed each year worldwide and new therapeutic targets are urgently required. The great majority of clear cell renal cancer involves inactivation of VHL, which acts as a gatekeeper tumour suppressor gene in renal epithelial cells. However how VHL exerts its tumour suppressor function remains unclear. A gene expression microarray comparing RCC10 renal cancer cells expressing either VHL or an empty vector was used to identify novel VHL regulated genes.NMU (Neuromedin U) is a neuropeptide that has been implicated in energy homeostasis and tumour progression. Here we show for the first time that VHL loss-of-function results in dramatic upregulation of NMU expression in renal cancer cells. The effect of VHL inactivation was found to be mediated via activation of Hypoxia Inducible Factor (HIF). Exposure of VHL expressing RCC cells to either hypoxia or dimethyloxalylglycine resulted in HIF activation and increased NMU expression. Conversely, suppression of HIF in VHL defective RCC cells via siRNA of HIF-α subunits or expression of Type 2C mutant VHLs reduced NMU expression levels. We also show that renal cancer cells express a functional NMU receptor (NMUR1), and that NMU stimulates migration of renal cancer cells.These findings suggest that NMU may act in an autocrine fashion, promoting progression of kidney cancer. Hypoxia and HIF expression are frequently observed in many non-renal cancers and are associated with a poor prognosis. Our study raises the possibility that HIF may also drive NMU expression in non-renal tumours.
Studies on the familial incidence and clinical history of patients with chronic unconjugated hyperbilirubinaemia.
Authors: P M Smith, J E Middleton, R Williams
Journal: Gut (1967)

EDITORIAL COMMENT Congenital unconjugated hyperbilirubinaemia represents in all probability a collection of conditions possibly of differing inheritance.Some forms may even be acquired.Certainly this paper suggests that these differences may exist and indicates that the degree ofjaundice is very variable.
UV erythema and the skin oxygen tension of the lower leg—observations with relevance to leg ulcer treatment
Authors: P.M. Gaylarde, F.M. Tatnall, H.J. Dodd, I. Sarkany
Journal: British Journal of Dermatology (1985)

Direct measurements of skin oxygen tension on the lower leg have shown low values in the standing position (Dodd, Gaylarde & Sarkany, 1984). This is the result of reflex vasoconstriction stimulated by high venous pressure. Exercise reduces venous pressure in normal limbs and produces a rise in skin oxygen tension, whereas limbs affected by venous ulceration fail to show this response. Recumbency reduces venous pressure and produces a consequent rise in skin oxygen tension, a finding which accords well with the beneficial effect of bed rest on the healing of venous leg ulcers. Since reflex vasoconstriction appears to be the mechanism by which persistent venous hypertension leads to skin hypoxia and ulceration, an agent capable of reducing this vasoconstriction might be expected to produce a favourable effect on the healing of venous leg ulcers in ambulant patients. Preliminary observations with a number of drugs including glyceryl trinitrate, amyl nitrite, naftidofuryl oxalate, ethyl alcohol and aspirin have shown that they do not block the normal vasoconstrictor response to increased venous pressure and therefore have no beneficial effect on the skin oxygen tension of the lower limb. We have found that the effect of ultraviolet erythema (3 MED of UV‐B) is to reduce or abolish the fall in skin oxygen tension normally seen on changing from the recumbent to the standing position and the erythema is accompanied by an increase in oxygen tension in the recumbent position. This phenomenon lasts for approximately 48 h and judiciously repeated UV treatment may be of therapeutic value. Our findings suggest that there is a need to re‐examine the role of UV irradiation in the management of skin disorders resulting from venous insufficiency.
Stretching before or after exercise does not reduce delayed-onset muscle soreness: Figure 1
Authors: Nicholas Henschke, C Christine Lin
Journal: British Journal of Sports Medicine (2011)

<h3>Objective</h3> The influence of eosinophilic oesophagitis (EoE)-associated inflammation upon oesophageal epithelial biology remains poorly understood. We investigated the functional role of autophagy in oesophageal epithelial cells (keratinocytes) exposed to the inflammatory EoE milieu. <h3>Design</h3> Functional consequences of genetic or pharmacological autophagy inhibition were assessed in endoscopic oesophageal biopsies, human oesophageal keratinocytes, single cell-derived ex vivo murine oesophageal organoids as well as a murine model recapitulating EoE-like inflammation and basal cell hyperplasia. Gene expression, morphological and functional characterisation of autophagy and oxidative stress were performed by transmission electron microscopy, immunostaining, immunoblotting, live cell imaging and flow cytometry. <h3>Results</h3> EoE-relevant inflammatory conditions promoted autophagy and basal cell hyperplasia in three independent murine EoE models and oesophageal organoids. Inhibition of autophagic flux via chloroquine treatment augmented basal cell hyperplasia in these model systems. Oesophageal keratinocytes stimulated with EoE-relevant cytokines, including tumour necrosis factor-α and interleukin-13 exhibited activation of autophagic flux in a reactive oxygen species-dependent manner. Autophagy inhibition via chloroquine treatment or depletion of Beclin-1 or ATG-7, augmented oxidative stress induced by EoE-relevant stimuli in murine EoE, oesophageal organoids and human oesophageal keratinocytes. Oesophageal epithelia of paediatric EoE patients with active inflammation displayed increased autophagic vesicle content compared with normal and EoE remission subjects. Functional flow cytometric analysis revealed autophagic flux in human oesophageal biopsies. <h3>Conclusions</h3> Our findings reveal for the first time that autophagy may function as a cytoprotective mechanism to maintain epithelial redox balance and homeostasis under EoE inflammation-associated stress, providing mechanistic insights into the role of autophagy in EoE pathogenesis.
Intraclass Differences Among Antihypertensive Drugs
Authors: R.D. Feldman, Y. Hussain, L.M. Kuyper, F.A. McAlister, R.S. Padwal, S.W. Tobe
Journal: The Annual Review of Pharmacology and Toxicology (2014)

The four major classes of antihypertensive drugs—diuretics, β-blockers, calcium channel blockers, and renin-angiotensin system inhibitors (including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers)—have significant qualitative and quantitative differences in the adverse effects they cause. Structural and chemical differences have been identified within these classes, especially among the calcium channel blockers and, to a lesser extent, among the thiazide/thiazide-like diuretics. However, it has been more difficult to demonstrate that these differences translate into differential effects with respect to either the surrogate endpoint of blood pressure reduction or, more importantly, hypertension-related cardiovascular complications. Based on a hierarchy-of-evidence approach, differences are apparent between hydrochlorothiazide and chlorthalidone based on evidence of moderate quality. Low-quality evidence suggests atenolol is less effective than other β-blockers. However, no significant intraclass differences have been established among the other classes of antihypertensive drugs.
Minimum clinically important difference for the COPD Assessment Test: a prospective analysis
Authors: Samantha S C Kon, Jane L Canavan, Sarah E Jones, Claire M Nolan, Amy L Clark, Mandy J Dickson, Brigitte M Haselden, Michael I Polkey, William D-C Man
Journal: The Lancet Respiratory Medicine (2014)

BackgroundThe COPD Assessment Test (CAT) is responsive to change in patients with chronic obstructive pulmonary disease (COPD). However, the minimum clinically important difference (MCID) has not been established. We aimed to identify the MCID for the CAT using anchor-based and distribution-based methods.MethodsWe did three studies at two centres in London (UK) between April 1, 2010, and Dec 31, 2012. Study 1 assessed CAT score before and after 8 weeks of outpatient pulmonary rehabilitation in patients with COPD who were able to walk 5 m, and had no contraindication to exercise. Study 2 assessed change in CAT score at discharge and after 3 months in patients admitted to hospital for more than 24 h for acute exacerbation of COPD. Study 3 assessed change in CAT score at baseline and at 12 months in stable outpatients with COPD. We focused on identifying the minimum clinically important improvement in CAT score. The St George's Respiratory Questionnaire (SGRQ) and Chronic Respiratory Questionnaire (CRQ) were measured concurrently as anchors. We used receiver operating characteristic curves, linear regression, and distribution-based methods (half SD, SE of measurement) to estimate the MCID for the CAT; we included only patients with paired CAT scores in the analysis.FindingsIn Study 1, 565 of 675 (84%) patients had paired CAT scores. The mean change in CAT score with pulmonary rehabilitation was −2·5 (95% CI −3·0 to −1·9), which correlated significantly with change in SGRQ score (r=0·32; p<0·0001) and CRQ score (r=–0·46; p<0·0001). In Study 2, of 200 patients recruited, 147 (74%) had paired CAT scores. Mean change in CAT score from hospital discharge to 3 months after discharge was −3·0 (95% CI −4·4 to −1·6), which correlated with change in SGRQ score (r=0·47; p<0·0001). In Study 3, of 200 patients recruited, 164 (82%) had paired CAT scores. Although no significant change in CAT score was identified after 12 months (mean 0·6, 95% CI −0·4 to 1·5), change in CAT score correlated significantly with change in SGRQ score (r=0·36; p<0·0001). Linear regression estimated the minimum clinically important improvement for the CAT to range between −1·2 and −2·8 with receiver operating characteristic curves consistently identifying −2 as the MCID. Distribution-based estimates for the MCID ranged from −3·3 to −3·8.InterpretationThe most reliable estimate of the minimum important difference of the CAT is 2 points. This estimate could be useful in the clinical interpretation of CAT data, particularly in response to intervention studies.FundingMedical Research Council and UK National Institute of Health Research.
Insulin-like growth factor-1 stimulation of lymphopoiesis.
Authors: R Clark, J Strasser, S McCabe, K Robbins, P Jardieu
Journal: Journal of Clinical Investigation (1993)

We show that treatment of adult mice with recombinant human insulin-like growth factor 1 (rhIGF-1) induces striking modifications in lymphocyte number and function. 9-mo-old male mice received rhIGF-1 (4 mg/kg per d) or its excipient by subcutaneous infusion from osmotic minipumps for 7 or 14 d. Mice were weighed daily and bled at sacrifice; the spleen and thymus were harvested and single cell suspensions were made for analysis of cell phenotype and cell number. The responses of splenocytes to mitogens (concanavalin A, lipopolysaccharide, and pokeweed mitogen), alloantigens and dinitrophenyl ovalbumin were measured. After either 7 or 14 d of treatment, rhIGF-1 had an overall whole-body anabolic effect, resulting in increased body and organ weights with prominent increases in the weight of the spleen and thymus. Furthermore, the rhIGF-1 treated mice were normoglycemic but had reduced blood urea nitrogens, again reflecting the anabolic activity of rhIGF-1. The increased spleen and thymus weights were associated with a large increase in the number of lymphocytes in both organs. In addition to an increase in T cells, specifically CD4+ T cells, a dramatic increase in splenic B cells was also observed. This increase was accompanied by an enhanced responsiveness to dinitrophenyl ovalbumin resulting in increased immunoglobulin production. However, despite the increases in cellularity, there was a decrease in the in vitro responses of spleen cells to mitogens after 7 d of rhIGF-1 treatment. In contrast, treatment with rhIGF-1 for 14 d increased both the cell number and mitogenic responses of splenocytes suggesting that some time is required for the cells populating the peripheral organs to gain mitogenic responsiveness. It is clear from these data that rhIGF-1, at doses that have whole-body anabolic activity, can expand cell number in lymphoid tissue in a normal adult mouse. These dual effects of rhIGF-1, of increasing lymphocyte number and activity, indicate that, in a normal adult animal, rhIGF-1 can cause major changes in lymphoid tissues that are of potential benefit to the functioning of the immune system.
Contributions by MutL Homologues <i>Mlh3</i> and <i>Pms2</i> to DNA Mismatch Repair and Tumor Suppression in the Mouse
Authors: Peng-Chieh Chen, Sandra Dudley, Wayne Hagen, Diana Dizon, Leslie Paxton, Denise Reichow, Song-Ro Yoon, Kan Yang, Norman Arnheim, R. Michael Liskay, Steven M. Lipkin
Journal: Cancer Research (2005)

Abstract Germ line DNA mismatch repair mutations in MLH1 and MSH2 underlie the vast majority of hereditary non-polyposis colon cancer. Four mammalian homologues of Escherichia coli MutL heterodimerize to form three distinct complexes: MLH1/PMS2, MLH1/MLH3, and MLH1/PMS1. Although MLH1/PMS2 is generally thought to have the major MutL activity, the precise contributions of each MutL heterodimer to mismatch repair functions are poorly understood. Here, we show that Mlh3 contributes to mechanisms of tumor suppression in the mouse. Mlh3 deficiency alone causes microsatellite instability, impaired DNA-damage response, and increased gastrointestinal tumor susceptibility. Furthermore, Mlh3;Pms2 double-deficient mice have tumor susceptibility, shorter life span, microsatellite instability, and DNA-damage response phenotypes that are indistinguishable from Mlh1-deficient mice. Our data support previous results from budding yeast that show partial functional redundancy between MLH3 and PMS2 orthologues for mutation avoidance and show a role for Mlh3 in gastrointestinal and extragastrointestinal tumor suppression. The data also suggest a mechanistic basis for the more severe mismatch repair–related phenotypes and cancer susceptibility in Mlh1- versus Mlh3- or Pms2-deficient mice. Contributions by both MLH1/MLH3 and MLH1/PMS2 complexes to mechanisms of mismatch repair–mediated tumor suppression, therefore, provide an explanation why, among MutL homologues, only germ line mutations in MLH1 are common in hereditary non-polyposis colon cancer.
An investigation of biomarkers derived from legacy microarray data for their utility in the RNA-seq era
Authors: Zhenqiang Su, Hong Fang, Huixiao Hong, Leming Shi, Wenqian Zhang, Wenwei Zhang, Yanyan Zhang, Zirui Dong, Lee J Lancashire, Marina Bessarabova, Xi Yang, Baitang Ning, Binsheng Gong, Joe Meehan, Joshua Xu, Weigong Ge, Roger Perkins, Matthias Fischer, Weida Tong
Journal: Genome biology (2014)

Abstract Background Gene expression microarray has been the primary biomarker platform ubiquitously applied in biomedical research, resulting in enormous data, predictive models, and biomarkers accrued. Recently, RNA-seq has looked likely to replace microarrays, but there will be a period where both technologies co-exist. This raises two important questions: Can microarray-based models and biomarkers be directly applied to RNA-seq data? Can future RNA-seq-based predictive models and biomarkers be applied to microarray data to leverage past investment? Results We systematically evaluated the transferability of predictive models and signature genes between microarray and RNA-seq using two large clinical data sets. The complexity of cross-platform sequence correspondence was considered in the analysis and examined using three human and two rat data sets, and three levels of mapping complexity were revealed. Three algorithms representing different modeling complexity were applied to the three levels of mappings for each of the eight binary endpoints and Cox regression was used to model survival times with expression data. In total, 240,096 predictive models were examined. Conclusions Signature genes of predictive models are reciprocally transferable between microarray and RNA-seq data for model development, and microarray-based models can accurately predict RNA-seq-profiled samples; while RNA-seq-based models are less accurate in predicting microarray-profiled samples and are affected both by the choice of modeling algorithm and the gene mapping complexity. The results suggest continued usefulness of legacy microarray data and established microarray biomarkers and predictive models in the forthcoming RNA-seq era.
Thrombolysis for submassive pulmonary embolism
Authors: T A R Seemungal
Journal: Thorax (2003)

▴ Konstantinides S, Geibel A, Heusel G, et al . Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl Med J2002;347:1143–50 [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] This was a randomised placebo controlled trial of alteplase (100 mg over 2 hours) with heparin v placebo with heparin in 256 patients with submassive pulmonary embolism (PE) defined as … [1]: {openurl}?query=rft.jtitle%253DNew%2BEngland%2BJournal%2Bof%2BMedicine%26rft.stitle%253DNEJM%26rft.issn%253D0028-4793%26rft.aulast%253DKonstantinides%26rft.auinit1%253DS.%26rft.volume%253D347%26rft.issue%253D15%26rft.spage%253D1143%26rft.epage%253D1150%26rft.atitle%253DHeparin%2Bplus%2BAlteplase%2BCompared%2Bwith%2BHeparin%2BAlone%2Bin%2BPatients%2Bwith%2BSubmassive%2BPulmonary%2BEmbolism%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJMoa021274%26rft_id%253Dinfo%253Apmid%252F12374874%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1056/NEJMoa021274&link_type=DOI [3]: /lookup/external-ref?access_num=12374874&link_type=MED&atom=%2Fthoraxjnl%2F58%2F1%2F72.atom [4]: /lookup/external-ref?access_num=000178465100004&link_type=ISI
Treatment of advanced chronic heart failure with normal left ventricular ejection fraction. Response to the letter by Dr. Martinez‐Selles
Authors: Marco Metra, Dirk Brutsaert, Kenneth Dickstein, Alan G. Fraser, Claes‐Hakan Bergh, Michael Böhm, Antonello Gavazzi, Tiny Jaarsma, Piotr Ponikowski, Michel Komajda
Journal: European Journal of Heart Failure (2007)
CEREBRO-SPINAL MENINGITIS: Preliminary Note on Certain Pathological Findings and their Bearing on Treatment
Authors: W. E. C. Dickson
Journal: BMJ (1917)

before evacuatioi,.Ilis condition whlen evacuated was quite satisfactory.He was still jaundiced, wasted, and anaemic.He stated that he felt quite well, andcl was apparently con- valescing rapidly.When last
Long-term nasal ventilation in neuromuscular disorders: report of a consensus conference
Authors: D Robert, TN Willig, P Leger, J Paulus
Journal: European Respiratory Journal (1993)

Following the colloquium entitled "Nasal Ventilation and Neuromuscular Disease", which took place in Lyon, France, October 24, 1991, a group of authorities on neuromuscular disorders met to establish a consensus concerning the application of this technique, in the clinical setting, for patients with Duchenne's muscular dystrophy, non-Duchenne myopathies and the spinal muscular atrophies. This report summarizes recommendations issuing from this conference. The conclusions drawn from this work should not be applied to patients with other diagnoses.