tbuckley/cabot-search huggingface dataset:
Genetic variability in <i>CRTH2</i> polymorphism increases eotaxin‐2 levels in patients with aspirin exacerbated respiratory disease
Authors: N. S. Palikhe, S.‐H. Kim, B.‐Y. Cho, Y.‐M. Ye, G.‐S. Choi, H.‐S. Park
Journal: Allergy (2009)

To cite this article: Palikhe NS, Kim S‐H, Cho B‐Y, Ye Y‐M, Choi G‐S, Park H‐S. Genetic variability in CRTH2 polymorphism increases eotaxin‐2 levels in patients with aspirin exacerbated respiratory disease. Allergy 2010; 65 : 338–346. Abstract Introduction: CRTH2 is expressed on the surface of eosinophils and has been shown to mediate PGD2‐induced eosinophil migration in vitro . Eosinophilic infiltration in the upper and lower airways is the key feature of asthma. Considering the fact that eosinophil infiltration is prominent in the upper and lower airways of aspirin exacerbated respiratory disease (AERD) compared to aspirin‐tolerant asthma (ATA) patients, we hypothesized that activation of eosinophils via dysregulation of the CRTH2 gene may play an important role and be an important marker for AERD. Methods: The three study groups – 107 with AERD, 115 with ATA and 133 normal healthy controls (NC) – were recruited from Ajou University Hospital, South Korea. Two polymorphisms of the CRTH2 gene at ‐466T&gt;C and ‐129C&gt;A were genotyped using primer extension methods. Results: AERD patients had significantly higher serum eotaxin‐2 levels than did those with ATA ( P = 0.034). A significant difference in the genotype frequencies of CRTH2 ‐466T&gt;C was detected between AERD and ATA patients ( P &lt; 0.05). The serum eotaxin‐2 level was significantly higher in AERD patients carrying the TT genotype of CRTH2 ‐466T&gt;C than those with the CT and CC ( P &lt; 0.05). In vitro functional study demonstrated that the ‐466T allele had lower luciferase activity ( P &lt; 0.001) and lower mRNA expression with higher production of eotaxin‐2 ( P = 0.003) in human lung epithelial cells. EMSA showed that CRTH2 ‐466T produced a specific band with a higher affinity than CRTH2 ‐466C had. Conclusion: The CRTH2 ‐466T&gt;C polymorphism increases serum and cellular eotaxin‐2 production through lowered CRTH2 expression, leading to eosinophilic infiltration in AERD patients.
Loss of 53BP1 Causes PARP Inhibitor Resistance in <i>Brca1</i>-Mutated Mouse Mammary Tumors
Authors: Janneke E. Jaspers, Ariena Kersbergen, Ute Boon, Wendy Sol, Liesbeth van Deemter, Serge A. Zander, Rinske Drost, Ellen Wientjens, Jiuping Ji, Amal Aly, James H. Doroshow, Aaron Cranston, Niall M.B. Martin, Alan Lau, Mark J. O'Connor, Shridar Ganesan, Piet Borst, Jos Jonkers, Sven Rottenberg
Journal: Cancer Discovery (2012)

Inhibition of PARP is a promising therapeutic strategy for homologous recombination-deficient tumors, such as BRCA1-associated cancers. We previously reported that BRCA1-deficient mouse mammary tumors may acquire resistance to the clinical PARP inhibitor (PARPi) olaparib through activation of the P-glycoprotein drug efflux transporter. Here, we show that tumor-specific genetic inactivation of P-glycoprotein increases the long-term response of BRCA1-deficient mouse mammary tumors to olaparib, but these tumors eventually developed PARPi resistance. In a fraction of cases, this resistance is caused by partial restoration of homologous recombination due to somatic loss of 53BP1. Importantly, PARPi resistance was minimized by long-term treatment with the novel PARP inhibitor AZD2461, which is a poor P-glycoprotein substrate. Together, our data suggest that restoration of homologous recombination is an important mechanism for PARPi resistance in BRCA1-deficient mammary tumors and that the risk of relapse of BRCA1-deficient tumors can be effectively minimized by using optimized PARP inhibitors.In this study, we show that loss of 53BP1 causes resistance to PARP inhibition in mouse mammary tumors that are deficient in BRCA1. We hypothesize that low expression or absence of 53BP1 also reduces the response of patients with BRCA1-deficient tumors to PARP inhibitors.
The Face of Evil
Authors: George Young
Journal: Annals of Internal Medicine (2000)

Ad Libitum3 October 2000The Face of EvilGeorge Young, MDGeorge Young, MDBoulder, CO 80304 (Young)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-133-7-200010030-00017 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Perhaps it was the howlsfrom the kennels, or the merciless insomniathat grips men of thought, but that night Louis Pasteur had a frightfuldream that his little patient, Joseph Meister, was dying.He knew the symptoms, having witnessed them himself as a boy in Arbois.The snapping jaws, foam-flecked, the slobbering bite.Then the clumsy attempt at treatment,cauterization at the smithy with a red-hot iron, screams,the smell of burning flesh.And inevitably, later, the faint tingling in the cicatrix,the suffocation at the very sight of water,the paralysis, the coma and death, always the death.He woke to the wind scratching at the window ... Author, Article, and Disclosure InformationAffiliations: Boulder, CO 80304 (Young)Corresponding Author: George Young, MD, Boulder Medical Center, 2750 Broadway, Boulder, CO 80305. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 3 October 2000Volume 133, Issue 7Page: 558KeywordsAsphyxiaComaHand strengthInsomniaParalysisRabbitsSkullSmellSpinal cordSuicide ePublished: 3 October 2000 Issue Published: 3 October 2000 Copyright & PermissionsCopyright © 2000 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Alan Hewett Phillips
Authors: Martin Phillips, Eric Sturdy
Journal: BMJ (2006)

​FormerFormer consultant anaesthetist Royal Gwent Hospital (b 1926; q Guy's Hospital, London 1949; FFARCS), died from a heart attack on 20 May 2005.



Figure 1



After national service in the Royal Army Medical Corps Alan Phillips trained in anaesthetics at Cardiff and was appointed to the staff of the Royal Gwent Hospital in 1959. His early career saw the provision of service throughout Gwent, the last phase of cardiothoracic surgery at the district hospital, and the introduction of the intensive care unit. Later he contributed to the establishment of one of the largest departments in the country. He was president of the Welsh Society of Anaesthetists in 1987. He leaves a wife, Pearl; three children; and seven grandchildren.
Which of you by taking thought can add one cubit unto his stature? Psychosomatic illness in children: a modern synthesis.
Authors: J Apley
Journal: BMJ (1973)

My tlide, taken from the King James Bible, became rather more apt when I tumed to the New Enlish Bible of 1970.Here the word "thought" is more precisely translated as "anxious thought"; and it is the rela¢i between anxious thought and stature, between emotional and bodily processes, that I am discussing.This lecture commemorates Charles West, to whom chil- dren's hospitals and children owe so much.I cannot find that he used the word psychosomatic, though it was Imown in his time.Like Willis and Sydenham before him he did, however, describe patients with what today would be labelled psychosomatic disorders.When he did so, admitted- ly under the broad heading of Malingerng, he logically ruled out organic disease.Since his time psychosomatics has turned from speculations to hard facts in this age of mani- cured medicine.It has a special appeal because it lends itself to the controls of biological science and to measure- ment.In Ryle's memorable phrase, we are learning to "measure the measurable, and make measurable the immeasurable."If you are politely surprised to have listened so far with- out hearing a definition of psychosomatic illness, prepare yourselves for more.I do not propose to define the term.*Chales westLecture delivered at the Royl College ofPhysidiansof London on 7 Februny, 1973.Even though I use it I distrust it.It tends to perpetuate the illusory duality of mind and body associated with Descartes and his intellectual supermarket.There are no separate minds and separate bodies-only human beings.As children themselves might do, let me put this in a simple phrase: "The il child is ill all over."So "psychosomatic" will have to explain itself as we go along.But first I should like to savour with you a few words that describe the psychosomatic approach almost lyrically: "Listening to the child talking with his body."The poet?My friends and I thought it was Anna Freud, distinguished daughter of Sigmund Freud, himself (as Leo Rosten writes) "the Columbus of psychology, which still awaits its Euclid."Anna Freud, however, has charmingly denied the attribu- tion, and I do not know the author's name. StatureBy my definition the paediatrician is "a measuring doctor," and stature or height is undeniably his concern.Knowledge of the process of growth is still far from complete.Discuss- How could emotional factors check growth?In one or more of several ways, as by their effects on metabolism or on the hypothalamus, or by increasing cortisol secretion.It
The Science and Politics of Screening Newborns
Authors: George Cunningham
Journal: New England Journal of Medicine (2002)

A major accomplishment of the public health system has been the development of programs of screening newborns for inherited and congenital metabolic disorders. This effort began in response to the observation that severe mental retardation associated with phenylketonuria could be prevented by the early initiation of a diet low in phenylalanine in affected newborns.1 As a result, universal systems of care were put into place for screening and tracking newborns. When evidence supported benefits from the early detection of and intervention for other disorders, screening tests for these disorders were readily added to the existing systems, resulting in broad access . . .
Assessment of reversibility of airflow obstruction.
Authors: J A Van Noord, J Smeets, J Clément, K P Van de Woestijne, M Demedts
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

The application of the forced oscillation technique to assess reversibility of airflow obstruction was compared with that of indices of forced expiration and plethysmographic airway resistance (Raw). In 125 patients with airflow obstruction, we measured total respiratory resistance (Rrs) and reactance (Xrs), Raw and specific airway conductance (sGaw), maximal flow-volume curves and forced expiratory volume in 1 s (FEV1), before and 30 min after 2 x 20 micrograms salbutamol by MDI. Salbutamol induced significant change in mean value of all measured indices. The changes in impedance data consisted of decrease in mean value and of negative frequency dependence of Rrs, an increase in Xrs with slight decrease of its positive frequency dependence. Multivariate analysis of differences between pre- and postbronchodilator values showed that the single indices with the greatest sensitivity to detect the effect of salbutamol were, in decreasing order, (1) in relative change (% baseline value): Raw, Rrs at 6 Hz (Rrs6), forced vital capacity (FVC), FEV1, and (2) in absolute change: FVC, sGaw or Raw, Rrs6, FEV1, maximal expiratory flow (MEF50). The effect of salbutamol was described best in (1) by a combination of Raw and FVC and in (2) by sGaw and FVC. For individual detection of bronchodilator effect, threshold values were calculated from mean reproducibility of the three baseline values of the various indices, attempting to estimate whether response to a bronchodilator is statistically significant. The greatest number of significant responses were observed for Raw, sGaw, FEV1, and FVC in that succession, Rrs6 being markedly less sensitive. This discrepancy is due to the lack of Rrs6 response to bronchodilators in patients with severe airway obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparative distribution of the alpha 1(IV), alpha 5(IV), and alpha 6(IV) collagen chains in normal human adult and fetal tissues and in kidneys from X-linked Alport syndrome patients.
Authors: B Peissel, L Geng, R Kalluri, C Kashtan, H G Rennke, G R Gallo, K Yoshioka, M J Sun, B G Hudson, E G Neilson
Journal: Journal of Clinical Investigation (1995)

We have shown previously that the 5' ends of the genes for the alpha 5(IV) and alpha 6(IV) collagen chains lie head-to-head on Xq22 and are deleted in patients with Alport syndrome (AS)-associated diffuse leiomyomatosis. In this study, we raised a rabbit anti-human alpha 6(IV)chain antibody, demonstrated its specificity by the analysis of recombinant NC1 domains af all six type IV chains, and studied the distribution of the alpha 6(IV) chain in relation to the alpha 1(IV) and alpha 5(IV) chains in human adult and fetal tissues involved in AS and diffuse leiomyomatosis. The alpha 6(IV) chain colocalizes with the alpha 5(IV) chain in basement membranes (BMs) of many tissues, but not in glomerular BM. These data exclude the alpha 6(IV) chain as a site for AS mutations. The head-to-head genomic pairing of the alpha 5(IV) and alpha 6 (IV) genes implies coordinate transcription of the two genes. Differential localization of the alpha 5(IV) and alpha 6(IV) chains shows that the two chains are not always coordinately regulated. The alpha 6(IV) chain, together with the alpha 3(IV)-alpha 5(IV) chains, was absent from all renal BMs in eight patients with X-linked AS while the alpha 1(IV) and alpha 2(IV) chains were increased. The data support the existence of two independent collagen networks, one for the alpha 3(IV)-alpha 6(IV) chains and one for the alpha 1(IV) and alpha 2(IV) chains.
The effects of oral liarozole on epidermal proliferation and differentiation in severe plaque psoriasis are comparable with those of acitretin
Authors: None Kuijpers, None Van Pelt, None Bergers, None Boegheim, None Den Bakker, None Siegenthaler, None Van DE Kerkhof, None Schalkwijk
Journal: British Journal of Dermatology (1998)

The imidazole derivative liarozole is a potent inhibitor of cytochrome P450-dependent 4-hydroxyla-tion of endogenous all-trans retinoic acid, thereby increasing the levels of all-trans retinoic acid in both plasma and skin. As part of a large, double-blind, randomized clinical study, we investigated the cell biological alterations in uninvolved and lesional skin of 20 patients with severe plaque psoriasis, who were treated with either liarozole or acitretin. The extent and severity of the skin lesions, as recorded by the Psoriasis Area and Severity Index score, was significantly reduced (P≤ 0·05) after 12 weeks of treatment in both the acitretin- and the liarozole-treated group. A significant decrease in the markers for inflammation (neutrophils), epidermal proliferation (Ki-67-positive cells), normal differentiation (transglutaminase) and abnormal differentiation [cytokeratin 16 and skin-derived antileucoproteinase (SKALP), also known as elafin] was seen in both groups. No significant differences were noted in clinical scores or cell biological scores between the liarozole- and acitretin-treated group. None of the markers returned to the levels seen in uninvolved skin or in normal human skin. The expression of epidermal fatty acid binding protein (E-FABP) was only minimally decreased after 12 weeks of treatment, a substantial part of the stratum spinosum remaining positive. SKALP levels in serum fell in both groups with similar kinetics and showed a statistically significant correlation with clinical scores. A remarkable finding in the uninvolved skin of patients treated with liarozole or acitretin was the distinct focal expression of SKALP in the granular layer and the expression of E-FABP in the spinous layers, which is not found in normal human skin. Although the mechanism of action differs fundamentally, liarozole and acitretin show similar effects with respect to clinical effects and cell biological changes in the lesional and non-lesional skin.
Magnesium inhibits nickel-induced genotoxicity and formation of reactive oxygen.
Authors: Y C Hong, S R Paik, H J Lee, K H Lee, S M Jang
Journal: Environmental Health Perspectives (1997)

Nickel compounds are recognized to cause nasal and lung cancers. Magnesium is an effective protector against nickel-induced carcinogenesis in vivo, although its mechanisms of protection remain elusive. The effects of magnesium carbonate on the cytotoxicity and genotoxicity induced by nickel subsulfide were examined with respect to the inhibition of cell proliferation, micronuclei formation, DNA-protein cross-link formation, and intranuclear nickel concentration. The generation of reactive oxygen by nickel chloride was also analyzed by observing 8-hydroxy-deoxyguanosine formation from deoxyguanosine in the presence and absence of magnesium chloride. The suppression of up to 64% of the proliferation of BALB/3T3 fibroblasts by nickel subsulfide (1 microgram/ml) was reversed by magnesium. The nickel compound increased not only the number of micronuclei but also the amount of DNA-protein cross-links examined with CHO and BALB/3T3 cells, respectively. These genotoxic effects of nickel were again lessened by magnesium carbonate. In addition, the cellular accumulation of nickel increased 80-fold with nickel subsulfide treatment and decreased with magnesium carbonate treatment. Nickel also enhanced 8-hydroxy-deoxyguanosine formation in the presence of H2O2 and ascorbic acid, where magnesium played another suppressive role. In fact, inhibition by magnesium was still observed even in the absence of nickel treatment. These results suggest that the protective role of magnesium in nickel-induced cytotoxicity and genotoxicity can be attributed to its ability to reduce either the intracellular nickel concentration or reactive oxygen formation.
Management of medical research. Open up the evaluation process.
Authors: T H Pennington
Journal: BMJ (1993)

research team leaders) are widely appreciated.Any self respecting piece of writing on social science would have begun by repeating that distinction.Instead, the ambiguity is concealed to suggest conffict.There are genuine and challenging problems in the management of research units, but the authors do not mention these at all.In both of the senses of management, both in units and in the section that serves the four review boards at the MRC's head office, the question is being continually asked: How can we do it even better?A representative, authoritative, and analytical study of research management functions would have been helpful.Instead we are given a "blackwash" job-a waste of an opportunity and of ink.Even if the interview data summarised in the article were unquestionable it is not clear that the opinions reported, or the schemes of various management styles depicted, relate at all closely to the findings or to the realities of the management style in the MRC.I certainly do not recognise the descriptions offered.At my unit we have found no difficulty in engaging people's differing styles in our liaison with the head office, and I do not think that the MRC has a single pervasive management style in the sense claimed in the article.It is ironic that Gillett and Harrow advocate more of a purchaser-provider split in research funding.As funding agencies, and hence purchasers, the research councils have always kept their research providers at arm's length via boards and grants committees, on which government departments and experts outside the organisation are predominantly represented-a longstanding instance of a purchaser-provider split.In the MRC
Volume Regulation in Lymphoid Leukemia Cells and Assignment of Cell Lineage
Authors: Erwin W. Gelfand, Roy K. K. Cheung, Kyungsae Ha, Sergio Grinstein
Journal: New England Journal of Medicine (1984)

Normal T lymphocytes readjust their volume after swelling in hypotonic medium, whereas B lymphocytes remain swollen. The difference between the two cell types appears to lie in the inability of B cells to increase their permeability to potassium in response to swelling. We have studied mononuclear cells from the bone marrow of 65 patients with lymphocytic leukemia, to determine whether the response to a hypotonic environment could be used to assign cell lineage. In contrast to leukemic cells of B-cell lineage (as in B-cell acute or chronic lymphocytic leukemia and non-T-cell,non-B-cell acute lymphocytic leukemia), T-cell–leukemia cells responded within five minutes to hypotonic swelling with an increase in potassium permeability and restoration toward isotonic volume. We conclude that the response to hypotonic shock may distinguish leukemic cells of T-cell origin from those derived from B-cell precursors and provides a simple, rapid, and reliable means for assigning cell lineage to lymphoid leukemia cells. (N Engl J Med 1984; 311:939–44.)
A NEW APPARATUS FOR FILLING PIPETS
Authors: Robert D. Maddox
Journal: JAMA (1913)

There is a demand for a more simple and efficient method of filling pipets, especially those used in blood work, where accuracy of dilution is essential. Several recent instruments have not been satisfactory, chiefly because the production of the vacuum necessary to raise the fluid in the capillary tube depends on some form of piston or other sliding mechanism, which either complicates the apparatus or does not permit of sufficiently delicate use. To overcome these objections I have made an apparatus that is simple, inexpensive and Lighly efficient, as with ordinarily careful manipulation it will give accurate results. In this apparatus a well-established principle is used: a vacuum is produced by the compression of a rubber tube or hose, one end of which is attached to the pipet, between two movable rollers, so that the tubing may be moved in either direction between the rollers as they are revolved, just
The Government and the Review Body
Authors: F. Lennon
Journal: BMJ (1970)

<h3>Summary</h3> Cell lineage in the adult hippocampus comprises multipotent and neuron-committed progenitors. In the present work, we fate-mapped neuronal progenitors using Dcx-CreERT2 and CAG-CAT-EGFP double-transgenic mice (cDCX/EGFP). We show that three days after tamoxifen-mediated recombination in cDCX/EGFP adult mice, GFP+ cells in the dentate gyrus co-expresses DCX and about 6% of these cells are proliferative neuronal progenitors. After 30 days, 20% of GFP+ generated from these progenitors differentiate into GFAP+ astrocytes. Administration of the chemoconvulsants kainic acid (KA) or pilocarpine (PL) led to a significant increase in the number of GFP+ cells in both ipsi and contralateral dentate gyrus. However, while PL favored the differentiation of neurons in both ipsi- and contralateral sides, KA stimulated neurogenesis only in the contralateral side. In the ipsilateral side, KA injection led to an unexpected increase of astrogliogenesis in the Dcx-lineage. These different effects of KA and PL in the Dcx-lineage are associated with distinct alterations of the parvalbuminergic plexus and inflammatory responses in the hippocampi. Finally, we also observed a small number of GFP+/GFAP+ cells displaying radial-glia morphology ipsilaterally 3 days after KA administration, indicating that Dcx-progenitors could regress to a multipotent stage. Altogether, our data suggest that cell lineage in the adult hippocampus is not unidirectional and can be modulated by environmental signals.