tbuckley/cabot-search huggingface dataset:
Multifaceted allergen avoidance during infancy reduces asthma during childhood with the effect persisting until age 18 years
Authors: Martha Scott, Graham Roberts, Ramesh J Kurukulaaratchy, Sharon Matthews, Andrea Nove, S Hasan Arshad
Journal: Thorax (2012)

<h3>Background</h3> Asthma is a chronic disease that often starts in childhood. The key risk factors are a child9s environment and their genetic characteristics. The aim of this study was to evaluate the efficacy of environmental modification in the first 12 months of life on the prevalence of asthma in high-risk individuals. <h3>Methods</h3> Children (n=120) considered at high risk of allergic disorders (either dual heredity or single heredity and a high cord total IgE), were enrolled in a single-blinded, randomised controlled trial. Infants in the intervention arm were either breast fed with the mother on a low allergen diet or given an extensively hydrolysed formula. Exposure to house dust mite allergen was reduced. The control group followed standard advice. Children were assessed at ages 1, 2, 4, 8 and 18 years for the presence of asthma and atopy. <h3>Results</h3> At 18 years of age, there was a significantly lower prevalence of asthma in the prevention group compared with the control group (OR: 0.23, 95% CI 0.08 to 0.70, p=0.01), primarily due to asthma that developed during childhood but persisted until age 18 years. Repeated-measure analysis showed that there was an overall reduction in asthma prevalence from 1 to 18 years (OR: 0.51, CI 0.32 to 0.81, p=0.04). Prevalence of atopy was not significantly different between the two groups at age 18. <h3>Conclusion</h3> Comprehensive allergen avoidance in the first year of life is effective in preventing asthma onset in individuals considered at high risk due to heredity. The effect occurs in the early years, but persists through to adulthood.
Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis
Authors: Tatiana V Petrova, Terhi Karpanen, Camilla Norrmén, Russell Mellor, Tomoki Tamakoshi, David Finegold, Robert Ferrell, Dontscho Kerjaschki, Peter Mortimer, Seppo Ylä-Herttuala, Naoyuki Miura, Kari Alitalo
Journal: Nature Medicine (2004)
Tumor Necrosis Factor-α Increases Reactive Oxygen Species by Inducing Spermine Oxidase in Human Lung Epithelial Cells: A Potential Mechanism for Inflammation-Induced Carcinogenesis
Authors: Naveen Babbar, Robert A. Casero
Journal: Cancer Research (2006)

Abstract Inflammation has been implicated in the development of many human epithelial cancers, including those of the stomach, lung, colon, and prostate. Tumor necrosis factor-α (TNF-α) is a potent pleiotropic, proinflammatory cytokine produced by many cells in response to injury and inflammation. Here, we show that TNF-α exposure results in increased production of reactive oxygen species (ROS), with a concomitant increase in the production of 8-oxo-deoxyguanosine, a marker for oxidative DNA damage, in human lung bronchial epithelial cells. The source of the ROS in TNF-α–treated cells was determined by both pharmacologic and small interfering RNA (siRNA) strategies to be spermine oxidase (SMO/PAOh1). SMO/PAOh1 oxidizes spermine into spermidine, 3-aminopropanal, and H2O2. Inhibition of TNF-α–induced SMO/PAOh1 activity with MDL 72,527 or with a targeted siRNA prevented ROS production and oxidative DNA damage. Further, similar induction in SMO/PAOh1 is observed with treatment of another inflammatory cytokine, interleukin-6. The data are consistent with a model that directly links inflammation and DNA damage through the production of H2O2 by SMO/PAOh1. Further, these results suggest a common mechanism by which inflammation from multiple sources can lead to the mutagenic changes necessary for the development and progression of epithelial cancers. (Cancer Res 2006; 66(23): 11125-30)
Incomplete Intrapulmonary Lymph Node Retrieval After Routine Pathologic Examination of Resected Lung Cancer
Authors: Robert A. Ramirez, Christopher G. Wang, Laura E. Miller, Courtney A. Adair, Allen Berry, Xinhua Yu, Thomas F. O'Brien, Raymond U. Osarogiagbon
Journal: Journal of Clinical Oncology (2012)

Pathologic nodal stage affects prognosis in patients with surgically resected non-small-cell lung cancer (NSCLC). Unlike examination of mediastinal lymph nodes (LNs), which depends on surgical practice, accurate examination of intrapulmonary (N1) nodes depends primarily on pathology practice. We investigated the completeness of N1 LN examination in NSCLC resection specimens and its potential impact on stage.We performed a case-control study of a special pathologic examination (SPE) protocol using thin gross dissection with retrieval and microscopic examination of all LN-like material on remnant NSCLC resection specimens after routine pathologic examination (RPE). We compared LNs retrieved by the SPE protocol with nodes examined after RPE of the same lung specimens and with those of an external control cohort.We retrieved additional LNs in 66 (90%) of 73 patient cases and discovered metastasis in 56 (11%) of 514 retrieved LNs from 27% of all patients. We found unexpected LN metastasis in six (12%) of 50 node-negative patients. Three other patients had undetected satellite metastatic nodules. Pathologic stage was upgraded in eight (11%) of 73 patients. The time required for the SPE protocol decreased significantly with experience, with no change in the number of LNs found.Standard pathology practice frequently leaves large numbers of N1 LNs unexamined, a clinically significant proportion of which harbor metastasis. By improving N1 LN examination, SPE can have an impact on prognosis and adjuvant management. We suggest adoption of the SPE to improve pathologic staging of resected NSCLC.
Integrative Genomic Analysis of Medulloblastoma Identifies a Molecular Subgroup That Drives Poor Clinical Outcome
Authors: Yoon-Jae Cho, Aviad Tsherniak, Pablo Tamayo, Sandro Santagata, Azra Ligon, Heidi Greulich, Rameen Berhoukim, Vladimir Amani, Liliana Goumnerova, Charles G. Eberhart, Ching C. Lau, James M. Olson, Richard J. Gilbertson, Amar Gajjar, Olivier Delattre, Marcel Kool, Keith Ligon, Matthew Meyerson, Jill P. Mesirov, Scott L. Pomeroy
Journal: Journal of Clinical Oncology (2010)

Medulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large series of primary tumors.We profiled the mRNA transcriptome of 194 medulloblastomas and performed high-density single nucleotide polymorphism array and miRNA analysis on 115 and 98 of these, respectively. Non-negative matrix factorization-based clustering of mRNA expression data was used to identify molecular subgroups of medulloblastoma; DNA copy number, miRNA profiles, and clinical outcomes were analyzed for each. We additionally validated our findings in three previously published independent medulloblastoma data sets.Identified are six molecular subgroups of medulloblastoma, each with a unique combination of numerical and structural chromosomal aberrations that globally influence mRNA and miRNA expression. We reveal the relative contribution of each subgroup to clinical outcome as a whole and show that a previously unidentified molecular subgroup, characterized genetically by c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-183∼96∼182 expression, is associated with significantly lower rates of event-free and overall survivals.Our results detail the complex genomic heterogeneity of medulloblastomas and identify a previously unrecognized molecular subgroup with poor clinical outcome for which more effective therapeutic strategies should be developed.
Abnormalities of the lungs and thoracic cage in the Ehlers-Danlos syndrome.
Authors: J G Ayres, F M Pope, J F Reidy, T J Clark
Journal: Thorax (1985)

Twenty patients with the Ehlers-Danlos syndrome, (10 type I, six type II, and four type IV) were studied to assess the frequency of respiratory abnormalities in this condition. Five patients (25%) had had at least one episode of haemoptysis, but none had any defect of coagulation. There was a high frequency of recurrent sinusitis, notably in those with the type I syndrome. Two patients had bullous lung disease, one of whom (type IV) had had three pneumothoraces and subsequent pleurodesis; he also had tracheomegaly (the Mounier-Kuhn abnormality). Minor skeletal abnormalities such as pectus excavatum were common, particularly in patients with type IV disease. Three patients had the straight back syndrome. There were no consistent spirometric or lung volume abnormalities, but eight patients (40%) had a raised gas transfer coefficient (Kco), possibly due to an increased intrapulmonary vascular volume. Two other patients had very low values of Kco that were unexplained.
Pathology of Genetically Engineered Mouse Models of Pancreatic Exocrine Cancer: Consensus Report and Recommendations
Authors: Ralph H. Hruban, N. Volkan Adsay, Jorge Albores-Saavedra, Miriam R. Anver, Andrew V. Biankin, Gregory P. Boivin, Emma E. Furth, Toru Furukawa, Alison Klein, David S. Klimstra, Gűnter Klőppel, Gregory Y. Lauwers, Daniel S. Longnecker, Jutta Lűttges, Anirban Maitra, G. Johan A. Offerhaus, Lucía Pérez-Gallego, Mark Redston, David A. Tuveson
Journal: Cancer Research (2006)

Abstract Several diverse genetically engineered mouse models of pancreatic exocrine neoplasia have been developed. These mouse models have a spectrum of pathologic changes; however, until now, there has been no uniform nomenclature to characterize these changes. An international workshop, sponsored by The National Cancer Institute and the University of Pennsylvania, was held from December 1 to 3, 2004 with the goal of establishing an internationally accepted uniform nomenclature for the pathology of genetically engineered mouse models of pancreatic exocrine neoplasia. The pancreatic pathology in 12 existing mouse models of pancreatic neoplasia was reviewed at this workshop, and a standardized nomenclature with definitions and associated images was developed. It is our intention that this nomenclature will standardize the reporting of genetically engineered mouse models of pancreatic exocrine neoplasia, that it will facilitate comparisons between genetically engineered mouse models and human pancreatic disease, and that it will be broad enough to accommodate newly emerging mouse models of pancreatic neoplasia. (Cancer Res 2006; 66(1): 95-106)
The distribution of temafloxacin in bronchial epithelial lining fluid, alveolar macrophages and bronchial mucosa
Authors: DR Baldwin, R Wise, JM Andrews, JP Ashby, D Honeybourne
Journal: European Respiratory Journal (1992)

The concentrations of temafloxacin, a new fluoroquinolone antimicrobial, in the potential sites of pulmonary infection were assessed by fibreoptic bronchoscopy with bronchoalveolar lavage. Fourteen patients received a course of temafloxacin, 600 mg twice daily, for three days prior to sampling. The mean serum concentration was 9.6 (SEM 1.2) mg.l-1, compared with 14.9(SEM 1.8) mg.kg-1 for bronchial mucosa, 26.5 (SEM 3.6) mg.l-1 for epithelial lining fluid and 83.0 (SEM 11.5) mg.l-1 for alveolar macrophage. In the ten patients who completed the protocol, site concentrations correlated well with serum concentrations. Temafloxacin was concentrated in each of the potential sites of infection examined and is, therefore, a promising new agent for the treatment of respiratory tract infection.
SDHAF2 (PGL2-SDH5) and Hereditary Head and Neck Paraganglioma
Authors: Henricus P.M. Kunst, Martijn H. Rutten, Jan-Pieter de Mönnink, Lies H. Hoefsloot, Henri J.L.M. Timmers, Henri A.M. Marres, Jeroen C. Jansen, Hannie Kremer, Jean-Pierre Bayley, Cor W.R.J. Cremers
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Hereditary head and neck paraganglioma (HNPGL) syndromes are associated with mutations in the SDHD(PGL1), SDHC(PGL3), and SDHB(PGL4) genes encoding succinate dehydrogenase subunits. We recently described mutations in a previously uncharacterized human gene, now called SDHAF2, and showed that this was the long-sought “imprinted” PGL2 gene. Here, we present a new branch of the Dutch SDHAF2 (PLG2-SDH5) family. Experimental Design: The SDHAF2 family has been collected over a 30-year period. The family described here was linked to PGL2 and at-risk family members were invited to participate in this study. Patients were investigated and treated dependent on tumor size and localization. All family members have now been analyzed for the SDHAF2 mutation status. Results: Among the 57 family members, 23 were linkage positive including 7 risk-free carriers (maternal imprinting). Of the 16 at-risk individuals, 11 had a total of 24 tumors with primarily carotid (71%) and vagal locations (17%). Multifocality of tumors was prominent (91%). Malignancy was not detected. The average age at onset was 33 years, and many patients (42%) were asymptomatic prior to screening. SDHAF2 mutation analysis confirmed the findings of the previously performed linkage analysis without detection of discrepancies. Conclusions: We established the SDHAF2 mutation status of PGL2 family members. Phenotypic characterization of this family confirms the currently exclusive association of SDHAF2 mutations with HNPGL. This SDHAF2 family branch shows a young age at onset and very high levels of multifocality. A high percentage of patients were asymptomatic at time of detection. Clin Cancer Res; 17(2); 247–54. ©2011 AACR.
Modulation of colonic barrier function by the composition of the commensal flora in the rat
Authors: A Garcia-Lafuente
Journal: Gut (2001)

<h3>BACKGROUND AND AIMS</h3> Altered intestinal permeability is a key pathogenetic factor of idiopathic bowel inflammation. We investigated in the rat if changes in the composition of the bowel flora can alter colonic permeability. <h3>METHODS</h3> A colonic segment was surgically excluded from faecal transit and brought out as a loop to the abdominal wall through two colostomies. The loop was used for colonisation with specific bacterial strains after eradication of the native flora with antibiotics. Lumen to blood clearance of dextran (molecular weight 70 000) and mannitol (molecular weight 182) was measured in rats recolonised with a single bacterial strain from rat colonic origin, and in control rats whose colonic loop was kept free of bacteria by antibiotics. Actual colonisation was confirmed by culture of segment effluents. <h3>RESULTS</h3> Colonisation with <i>Escherichia coli</i>,<i>Klebsiella pneumoniae</i>, and<i>Streptococcus viridans</i> significantly increased lumen to blood clearance of mannitol. Colonisation with<i>Lactobacillus brevis</i> had the opposite effect and reduced permeability to mannitol. <i>Bacteroides fragilis </i>did not induce significant changes. Permeability to dextran was not altered by any of the strains tested. <h3>CONCLUSIONS</h3> Certain commensal bacteria can modify colonic wall permeability to luminal substances.
Female Urinary Incontinence in Practice
Authors: C R Chapple
Journal: Journal of the Royal Society of Medicine (2005)

From epidemiological studies we now have a clear picture of the scale of distress resulting from female incontinence. The condition is widespread, and costly to both affected persons and the community. Linda Cardozo (well-known for her work on the subject) and her colleague Matthew Parsons provide an excellent overview in a short space. After an introduction on embryology, anatomy, and physiology they proceed to assessment of the patient with a stepwise approach that gives special emphasis to urodynamics, including imaging of the urinary tract. We are then offered a classification of incontinence, and later chapters are given over to stress incontinence and detrusor overactivity (with useful accounts of therapeutic options). Other topics are voiding difficulty, urinary tract infection and sensory disorders of the lower urinary tract. All these overviews are well balanced, but I confess to slight disappointment with the item on sensory disorders. I would have welcomed more information on pelvic pain syndrome, which is very troublesome in clinical practice; Parsons and Cardozo concentrate on sensory bladder and urethral disorders and say little about management of associated conditions such as endometriosis. Also, when they deal with hormone replacement therapy, I would have appreciated more advice on which preparations to use, in the light of the new findings on adverse effects. They conclude with a review of pads, catheters and containments and a chapter on frequently asked questions. Among the appendices is a useful list of patient-led and professional organizations. The book is well laid out and easy to read.
The HMGB1-RAGE axis is critical in the process of allergic sensitization
Authors: Ashik Ullah, Loh Zhixuan, Gan Wan Jun, J. Margaret Hughes, Carol Armour, Phipps Simon, Sukkar Maria
Journal: European Respiratory Journal (2013)

Allergic sensitization to house dust mite (HDM) is a significant risk factor for asthma onset and progression. Activation of innate pattern-recognition receptors (PRRs) can induce the release of endogenous alarmins that modulate the inflammatory response. RAGE is a PRR with the unique capacity to recognise a diverse repertoire of endogenous alarmins, and can collaborate with toll-like receptor (TLR) 4 (known to ‘sense’ HDM), yet its role in the development of allergic sensitization to HDM and other allergens remains obscure. Here, we report that HDM-induced airway inflammation was diminished in RAGE-deficient mice. Strikingly, early induction of HDM-induced IL-33 and IL-25 was TLR4-dependent; whereas a second ‘wave’ (persistent expression) of these TH2-instructive cytokines was regulated downstream of RAGE activation. HDM sensitization also induced nuclear to cytoplasmic translocation of the alarmin, high mobility group box-1 (HMGB1), and elevated levels in bronchoalveolar lavage fluid. Like innate cytokines, early HMGB1 activation was TLR4-dependent and later on sustained via RAGE signalling. Moreover the magnitude of the TH2 immune response was abolished when HMGB1 was neutralized, implicating its functional role. With evidence that RAGE is engaged secondary to TLR4, we hypothesised that it might function as a common pathway down-stream of various PRRs involved in initial allergen recognition. Of note, we demonstrated that RAGE-deficient mice were also protected against cockroach-extract induced allergic inflammation and had attenuated levels of HMGB1. Together, these studies address HMGB1-RAGE signalling as a critical innate mechanism of allergic sensitization and development of airway inflammation.
Prevention of coronary heart disease
Authors: G Alastair Cooke
Journal: BMJ (2004)

Editor—As Warburton points out in her editorial, we may soon be able to reduce the event rate in patients at risk of coronary heart disease to towards zero.1 The current cocktail of drugs is likely to decrease events by up to 88%.2

We have been fortunate that most of the drugs in this cocktail are cheap (aspirin, thiazides, β blockers). Marshall in his article shows that aspirin (NHS price £0.18 per 28 days) is much more cost effective than clopidogrel (NHS price £35.31 per 28 days) and statins (NHS price £29.68 per 28 days).3 I doubt that anybody would have been surprised by this finding.

If we continue to pursue new treatments that will reduce the risks of ischaemic heart disease further they will inevitably be much less cost effective than aspirin. As the event rate goes down with each successful intervention the number needed to treat for each new drug will increase. If we follow the logic expressed in this article then we should give up trying as nothing will ever be as cost effective as aspirin.

The effective cure of the biggest killer in the Western world would have been a triumph for mankind, medicine, and big pharma. It seems that, like going to the moon, it isn't going to be very cost effective.
Genomic organization of the selectin family of leukocyte adhesion molecules on human and mouse chromosome 1.
Authors: M L Watson, S F Kingsmore, G I Johnston, M H Siegelman, M M Le Beau, R S Lemons, N S Bora, T A Howard, I L Weissman, R P McEver
Journal: The Journal of Experimental Medicine (1990)

A structurally and functionally related group of genes, lymph node homing receptor (LHR), granule membrane protein 140 (GMP-140), and endothelial leukocyte adhesion molecule 1 (ELAM-1) are shown to constitute a gene cluster on mouse and human chromosome 1. In situ hybridization mapped GMP-140 to human chromosome 1 bands 21-24 consistent with chromosomal localization of LHR. Gene linkage analysis in the mouse indicated that these genes and serum coagulation factor V (FV) all map to a region of distal mouse chromosome 1 that is syntenic with human chromosome 1, with no crossovers identified between these four genes in 428 meiotic events. Moreover, long range restriction site mapping demonstrated that these genes map to within 300 kb in both the human and mouse genomes. These data suggest that LHR, ELAM-1, and GMP-140 comprise an adhesion protein family, the selectins, that arose by multiple gene duplication events before divergence of mouse and human. Furthermore, the location of these genes on mouse and human chromosome 1 is consistent with a close evolutionary relationship to the complement receptor-related genes, which also are positioned on the same chromosomes in both species and with which these genes share a region of sequence homology. These data characterize the organization of a genomic region that may be critical for intercellular communication within the immune system.
Clinical and immunologic outcome of patients with cartilage hair hypoplasia after hematopoietic stem cell transplantation
Authors: Victoria Bordon, Andrew R. Gennery, Mary A. Slatter, Els Vandecruys, Genevieve Laureys, Paul Veys, Waseem Qasim, Wilhelm Friedrich, Nico M. Wulfraat, Franziska Scherer, Andrew J. Cant, Alain Fischer, Marina Cavazzana-Calvo, Robbert G. M. Bredius, Luigi D. Notarangelo, Evelina Mazzolari, Benedicte Neven, Tayfun Güngör
Journal: Blood (2010)
Acute impairment of relaxation by low levels of testosterone in porcine coronary arteries
Authors: H Teoh
Journal: Cardiovascular Research (2000)

While there are many suggested reasons for the marked gender bias in cardiovascular events, much of the available data indicate that circulating estrogens are cardioprotective. The possibility that endogenous androgens may be detrimental to the cardiovascular system has received relatively less attention. We investigated the short-term modulatory effects of various concentrations of testosterone on vascular function in isolated porcine coronary artery rings.The higher concentrations (> 1 microM) of testosterone relaxed U46619-contracted coronary artery rings in an endothelium-independent manner. This direct effect was insensitive to the testosterone receptor antagonists, flutamide and cyproterone acetate. Short-term exposure (20 min) to low levels of testosterone (1-100 nM), which were ineffective on their own on vascular function, significantly diminished relaxation to bradykinin and calcium ionophore A23187 but not those produced by levcromakalim and sodium nitroprusside. The inhibitory effect observed with 1 nM testosterone was only partially reversed by flutamide and cyproterone acetate and unaltered in the presence of actinomycin D and cycloheximide.These results demonstrate that acute treatment with testosterone, at concentrations that have no effect on their own, reduces vasorelaxation. Furthermore, they suggest that this modulatory action may be in part independent of the classical testosterone receptor since it was not completely sensitive to the anti-androgens and was not inhibited by the transcriptional and translational inhibitors. These findings support the postulation that testosterone may have unfavorable influences on vascular function.