tbuckley/cabot-search huggingface dataset:
Intestinal steroidogenesis controls PPARγ expression in the colon and is impaired during ulcerative colitis
Authors: Guillaume Bouguen, Audrey Langlois, Madjid Djouina, Julien Branche, Dine Koriche, Edmone Dewaeles, Alice Mongy, Johan Auwerx, Jean-Frederic Colombel, Pierre Desreumaux, Laurent Dubuquoy, Benjamin Bertin
Journal: Gut (2014)

<h3>Background and aims</h3> Immune tolerance breakdown during UC involves the peroxisome proliferator-activated receptor-γ (PPARγ), a key factor in mucosal homoeostasis and the therapeutic target of 5-aminosalycilates, which expression is impaired during UC. Here we assess the impact of glucocorticoids (GCs) on PPARγ expression, focusing especially on extra-adrenal cortisol production by colonic epithelial cells (CECs). <h3>Methods</h3> Activation of PPARγ in the colon was evaluated using transgenic mice for the luciferase gene under PPAR control (peroxisome proliferator response element-luciferase mice). Protein and mRNA expression of PPARγ were evaluated with colon fragments and purified CEC from mice. Cortisol production and steroidogenic factor expression were quantified in human CEC of patients with UC and those of controls. Gene expression knockdown by short hairpin RNA in Caco-2 cells was used for functional studies. <h3>Results</h3> GCs were able to raise luciferase activity in peroxisome proliferator response element-luciferase mice. In the mice colons and Caco-2 cells, PPARγ expression was increased either with GCs or with an inducer of steroidogenesis and then decreased after treatment with a steroidogenesis inhibitor. Cortisol production and steroidogenic factor expression, such as liver receptor homologue-1 (LRH-1), were decreased in CEC isolated from patients with UC, directly correlating with PPARγ impairment. Experiments on Caco-2 cells lacking LRH-1 expression confirmed that LRH-1 controls PPARγ expression by regulating GC synthesis in CEC. <h3>Conclusions</h3> These results demonstrate cortisol control of PPARγ expression in CEC, highlighting cortisol production deficiency in colonocytes as a key molecular event in the pathophysiology of UC.
Insulin-like growth factor induces phosphorylation of immunoreactive insulin receptor substrate and its association with phosphatidylinositol-3 kinase in human thymocytes.
Authors: R Kooijman, J J Lauf, A C Kappers, G T Rijkers
Journal: The Journal of Experimental Medicine (1995)

Insulin receptor substrate 1 (IRS-1) is the principle cellular substrate for insulin and insulin-like growth factor I (IGF-I) receptor signaling. After phosphorylation of tyrosine residues within the YMXM or YXXM motifs, IRS-1 associates with phosphatidylinositol-3 kinase (PI3K). This signaling pathway and the presence of an IRS-1-like molecule have been demonstrated in IRS-1-transfected and in nontransfected hematopoietic cell lines, respectively. IGF-I has been implicated in lymphocyte development and function, and recently, we showed that functional type-I IGF receptors are present on human thymocytes and peripheral T cells. In this study, we addressed IGF-I signal transduction in nontransformed, freshly isolated, human thymocytes, as well as in blood T cells. Using Western blot analysis, we found that IGF-I induced phosphorylation of a 160-180-kD protein (pp170) in human thymocytes and that phosphorylated pp170 becomes associated with PI3K and is recognized by anti-IRS-1. In blood T cells, this immunoreactive IRS-1 (irIRS-1) is less abundantly expressed than in thymocytes, as assessed with immunoblotting. As a consequence, phosphorylated pp170 was not or hardly detectable after stimulation with IGF-I, and irIRS-1 was not detected in PI3K immunoprecipitates from lysates of IGF-I-stimulated T cells. However, IGF-I induced the tyrosine phosphorylation of other cellular proteins, indicating that differential expression of irIRS-1 contributes to a distinct signaling pathway in T cells.
Seroconversion in Patients With Rheumatic Diseases Treated With Immunomodulators or Immunosuppressants, Who Were Inadvertently Revaccinated Against Yellow Fever
Authors: Ana C. V. Oliveira, Licia M. H. Mota, Leopoldo L. Santos‐Neto, Marisol Simões, Olindo A. Martins‐Filho, Pedro L. Tauil
Journal: Arthritis & Rheumatology (2014)
High-Resolution SNPs and Microsatellite Haplotypes Point to a Single, Recent Entry of Native American Y Chromosomes into the Americas
Authors: S. L. Zegura
Journal: Molecular Biology and Evolution (2003)

A total of 63 binary polymorphisms and 10 short tandem repeats (STRs) were genotyped on a sample of 2,344 Y chromosomes from 18 Native American, 28 Asian, and 5 European populations to investigate the origin(s) of Native American paternal lineages. All three of Greenberg's major linguistic divisions (including 342 Amerind speakers, 186 Na-Dene speakers, and 60 Aleut-Eskimo speakers) were represented in our sample of 588 Native Americans. Single-nucleotide polymorphism (SNP) analysis indicated that three major haplogroups, denoted as C, Q, and R, accounted for nearly 96% of Native American Y chromosomes. Haplogroups C and Q were deemed to represent early Native American founding Y chromosome lineages; however, most haplogroup R lineages present in Native Americans most likely came from recent admixture with Europeans. Although different phylogeographic and STR diversity patterns for the two major founding haplogroups previously led to the inference that they were carried from Asia to the Americas separately, the hypothesis of a single migration of a polymorphic founding population better fits our expanded database. Phylogenetic analyses of STR variation within haplogroups C and Q traced both lineages to a probable ancestral homeland in the vicinity of the Altai Mountains in Southwest Siberia. Divergence dates between the Altai plus North Asians versus the Native American population system ranged from 10,100 to 17,200 years for all lineages, precluding a very early entry into the Americas.
Agonists of Toll-like Receptors 2 and 4 Activate Airway Smooth Muscle via Mononuclear Leukocytes
Authors: Gavin E. Morris, Moira K. B. Whyte, Gillian F. Martin, Peter J. Jose, Steven K. Dower, Ian Sabroe
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Rationale: Toll-like receptors 2 and 4 (TLR2, TLR4) enable cellular responses to bacterial lipoproteins, LPS, and endogenous mediators of cell damage. They have an established role in the activation of leukocytes, endothelial cells, and some smooth muscle cell types, but their roles in airway smooth muscle are uncertain. Objectives: To determine the roles of TLRs in activation of airway smooth muscle. Methods: Airway smooth muscle cells were cultured with TLR agonists, in the presence or absence of mononuclear leukocytes. Measurements and Main Results: We observed expression of TLR2 and TLR4 mRNAs, which could be upregulated by treatment with proinflammatory cytokines in primary human airway smooth muscle, but no important functional responses to agonists of these TLRs were seen. Coincubation of airway smooth muscle with peripheral blood mononuclear cells, at concentrations as low as 250 mononuclear cells/ml, resulted in a marked cooperative response to TLR stimuli, and synergistic production of cytokines, including chemokines (interleukin [IL-]-8) and IL-6. This cooperative response was greater when monocytes were enriched and was transferable using supernatants from LPS-stimulated peripheral blood mononuclear cells. Activation of cocultures required IL-1 generation from mononuclear cells, and was blocked by IL-1 receptor antagonist, though IL-1 generation alone was not sufficient to account for the magnitude of mononuclear cell–dependent coculture activation. Conclusions: These data indicate that potent amplification of inflammation induced by TLR agonists, such as LPS, may be achieved by cooperativity between airway smooth muscle and leukocytes involved in immune surveillance or inflammation.
Ability of prolonged interferon treatment to suppress relapse after cessation of therapy in patients with chronic hepatitis C: A multicenter randomized controlled trial
Authors: Akinori Kasahara, Norio Hayashi, Naoki Hiramatsu, Masahide Oshita, Hideki Hagiwara, Kazuhiro Katayama, Michio Kato, Manabu Masuzawa, Harumasa Yoshihara, Yutaka Kishida, Yoji Shimizu, Atsuo Inoue, Hideyuki Fusamoto, Takenobu Kamada
Journal: Hepatology (1995)

The aim of this study was to determine whether 12 months course of interferon alfa (IFN-alpha) therapy could improve the beneficial effect of IFN in chronic hepatitis C. Eighty-eight patients were treated with natural IFN-alpha for either 28 weeks (45 cases) or 52 weeks (43 cases). Sustained response was achieved in 15 (33.3%) of 45 cases treated for 28 weeks and in 23 (53.5%) of 43 cases treated for 52 weeks. Transient response with relapse of alanine transaminase (ALT) after completion of therapy was observed in 13 cases (28.9%) treated for 28 weeks and in 4 cases (9.3%) treated for 52 weeks. Thus, ALT relapse was suppressed by prolonged IFN treatment. No response was found in 17 cases (37.8%) treated for 28 weeks and in 16 cases (37.2%) treated for 52 weeks, indicating that approximately 38% of the patients with chronic hepatitis C were resistant to IFN therapy even with prolonged treatment. The rate of sustained response was significantly higher in patients with type 2a or 2b than in those with type 1b. Even in type 1b cases, it was higher in the 52-week treatment group than in the 28-week treatment group, and the rate of transient response was lower in the 52-week treatment group, indicating that relapse in type 1b cases was suppressed by prolonged IFN therapy. IFN therapy was not effective for patients with advanced liver fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)
The third vasculature gets attention
Authors: R. Hirschberg
Journal: Cardiovascular Research (2008)

Traditionally, researchers studying the vasculature examine either the biology of the large, arterial, high-pressure vessels or the resistance-regulating (arteriolar) or microvessels (capillaries), or less commonly, the venous, low-pressure vasculature. The lymphatic vasculature gets far less attention by the cardiovascular research community. This is despite the fact that the lymphatics play very important roles in the tissue clearance of macromolecules, in the removal of immigrated cells from tissues such as after inflammation, and in the interstitial fluid homeostasis. Nevertheless, comparably little is known about the growth and maintenance of lymphatics during adult life.

In a laudable paper in this issue of Cardiovascular Research , Jin et al. describe experimental studies examining the post-developmental regulation of lymphangiogenesis by a novel regulator and validate in vitro findings in a lymphedema disease model in mice.1 These investigators developed the hypothesis that adrenomedullin promotes lymphangiogenesis after injury. This is suggested by a series of previous observations indicating that this peptide with known vasodilator functions (and diuresis induction due to … 

*Corresponding author. Tel: +1 310 222 3891; fax: +1 310 782 1837. E-mail address : rhirschberg{at}labiomed.org
Working Hours of Junior Doctors
Authors: J. P. Turney
Journal: BMJ (1970)

MEDIBCATOISNALin the Bristol centre" conceals some important facts.Rates marginally better than those described in the document were in- troduced here in September, and proved unacceptable to the deputies.This was mainly because these represented (as far as 90% of the sessions were concerned) only a 5 % increase on previous rates, even though
Congenital hypothyroid goiter with deficient thyroglobulin. Identification of an endoplasmic reticulum storage disease with induction of molecular chaperones.
Authors: G Medeiros-Neto, P S Kim, S E Yoo, J Vono, H M Targovnik, R Camargo, S A Hossain, P Arvan
Journal: Journal of Clinical Investigation (1996)

Recent advances in understanding the molecular pathogenesis of congenital hypothyroid goiter in cog/cog mice, have raised important questions concerning the maturation of thyroglobulin (the thyroid prohormone) in certain human kindreds with congenital goiter. We have now examined affected siblings from two unrelated families that synthesize an apparently normally glycosylated, > 300 kD immunoreactive thyroglobulin, yet have a reduced quantity of intraglandular thyroglobulin and that secreted into the circulation. From thyroid tissues of the four patients, light microscopic approaches demonstrated presence of intracellular thyroglobulin despite its absence in thyroid follicle lumina, while electron microscopy indicated abnormal distention of the endoplasmic reticulum (ER). We have confirmed biochemically that most intrathyroidal thyroglobulin fails to reach the (Golgi) compartment where complex carbohydrate modification takes place. Moreover, the disease in the affected patients is associated with massive induction of specific ER molecular chaperones including the hsp90 homolog, GRP94, and the hsp70 homolog, BiP. The data suggest that these patients synthesize a mutant thyroglobulin which is defective for folding/assembly, leading to a markedly reduced ability to export the protein from the ER. Thus, these kindreds suffer from a thyroid ER storage disease, a cell biological defect phenotypically indistinguishable from that found in cog/cog mice.
Retinoid concentrations in skin, serum and adipose tissue of patients treated with etretinate*
Authors: O. ROLLMAN, A. VAHLQUIST
Journal: British Journal of Dermatology (1983)

Synthetic and natural retinoids were analysed in epidermis, dermis, subcutis and serum of twenty-seven patients treated with etretinate (0.6-1.0 mg/kg/day) for 1-36 months. The concentrations of etretinate (including its major metabolite) in serum and normal-appearing epidermis were 150-600 ng/ml and 50-350 ng/g, respectively. The serum and epidermal values were significantly correlated (P less than 0.05). The drug progressively accumulated in the subcutis attaining a maximum value of 15,500 ng/g. After the treatment, etretinate disappeared from the epidermis within 1 week. By contrast, the drug remained in the subcutis for several months after cessation of treatment. The epidermal composition of endogenous retinoids changed during etretinate therapy as reflected in an increased ratio of 3-dehydroretinol to all-trans retinol.
Rituximab dissociates the tight link between disease activity and joint damage in rheumatoid arthritis patients
Authors: Daniel Aletaha, Farideh Alasti, Josef S Smolen
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background/objective</h3> Progression of joint damage is linked to disease activity. This link is dissociated upon treatment with tumour necrosis factor (TNF)- or IL-6-inhibitors plus methotrexate (MTX). It is hitherto unknown if this may also be true for therapies targeting B-cells. We thus evaluated if rituximab (RTX) therapy inhibits joint damage irrespective of its effects on disease activity. <h3>Methods</h3> We used a random 90% sample of data from two arms of the IMAGE trial comprising patients with active early rheumatoid arthritis (RA) receiving MTX (n=188) or MTX+RTX 1000 mg (n=204). Patients were divided into low, moderate and high disease activity at one year of treatment by simplified disease activity index (low disease activity (LDA), moderate disease activity (MDA), high disease activity (HDA)), or by swollen joint count (SJC) or C reactive protein (CRP) tertiles. Progression of damage by the Genant modified total Sharp score (TGSS) was compared between therapies (Kruskal-Wallis, Wilcoxon tests) for each of these subgroups. <h3>Results</h3> In patients treated with MTX, 1-year progression of TGSS In LDA, MDA and HDA was 0.40±0.88, 1.04±1.73, and 1.31±3.02, respectively. In contrast, on RTX+MTX, TGSS progression was 0.38±1.07, 0.39±1.28, and −0.05±0.44, respectively (for MDA and HDA the progression of TGSS was significantly lower in the combined group than in the MTX group: p=0.003 and p=0.05, respectively). Additional analyses (tertiles of SJC, CRP, and matching for disease activity) confirmed the primary analysis. <h3>Conclusions</h3> In early RA, progression of joint damage increases with increasing disease activity on MTX. RTX plus MTX retards damage independently of its effects on disease activity, since even in HDA destruction is halted, contrasting MTX monotherapy. This indicates that beyond cytokine blockade (TNF- and IL-6 inhibitors), also cell-directed therapy (anti-CD20 antibody) conveys profound anti-destructive effects and dissociates the link between disease activity and joint damage.
Points from Letters: Review Body Report
Authors: R. M. Mitchell
Journal: BMJ (1974)

some extent those retiring between 1969 and 1972 will be given less than their olleagues who retired after 24 March 1972.This means that there has to be for them a different formula from that for general practitioners retiring after 24 March 1972 and it is on this that there have been some-what protracted negotiations with the De- partment.We have certainly put every pressure on the Department to expedite matters and we hope that with the help of our professional expert advisers we -may be able to reach an early settlement."-ED.,
Pulmonary hypertension in patients with sickle cell disease: not so frequent but so different
Authors: G. Simonneau, F. Parent
Journal: European Respiratory Journal (2011)

Until recently, the prevalence and characteristics of pulmonary hypertension (PH) in adults with sickle cell disease remained uncertain. In previous studies, the prevalence of PH, as defined by a tricuspid valve regurgitant jet velocity (TRJV) of ≥2.5 m·s−1, has been reported as high as 30% [1, 2]. However, in these studies, the diagnosis of PH was not systematically confirmed on right heart catheterisation (RHC), a procedure that is recommended in international guidelines as the standard of care [3]. Moreover, recent screening programmes for PH in high-risk populations have shown that using a TRJV of ≥2.5 m·s−1 to define PH results in a substantial number of false-positive cases not confirmed on RHC [4–6]. The use of RHC also makes it possible to accurately distinguish between pre-capillary and post-capillary PH, which is especially important in this setting, since the presence of post-capillary PH due to associated left heart disease has been frequently reported in adult patients with sickle cell disease [7, 8].

Two simultaneous studies, one recently published in the New England Journal of Medicine [9] and the other in this issue of European Respiratory Journal [10], have addressed this issue using the same methodology. All patients with sickle cell disease underwent Doppler echocardiography, with measurement of TRJV. RHC was performed in all patients in whom PH was …
Gene expression profiles in circulating tumor cells to predict prognosis in metastatic breast cancer patients
Authors: B. Mostert, A.M. Sieuwerts, J. Kraan, J. Bolt-de Vries, P. van der Spoel, A. van Galen, D.J. Peeters, L.Y. Dirix, C.M. Seynaeve, A. Jager, F.E. de Jongh, P. Hamberg, J.M.L. Stouthard, D.F.S. Kehrer, M.P. Look, M. Smid, J.W. Gratama, J.A. Foekens, J.W.M. Martens, S. Sleijfer
Journal: Annals of Oncology (2014)
Dehydroretronecine-Induced Skin Tumors in Mice23
Authors: William D. Johnson, Kent A. Robertson, Joel G. Pounds, James R. Allen
Journal: JNCI Journal of the National Cancer Institute (1978)

Journal Article Dehydroretronecine-Induced Skin Tumors in Mice Get access William D. Johnson, William D. Johnson 4Department of Pathology, University of Wisconsin Medical School and Regional Primate Research Center, University of Wisconsin, Madison, Wis. 53706. Search for other works by this author on: Oxford Academic PubMed Google Scholar Kent A. Robertson, Kent A. Robertson 4Department of Pathology, University of Wisconsin Medical School and Regional Primate Research Center, University of Wisconsin, Madison, Wis. 53706. Search for other works by this author on: Oxford Academic PubMed Google Scholar Joel G. Pounds, Joel G. Pounds 4Department of Pathology, University of Wisconsin Medical School and Regional Primate Research Center, University of Wisconsin, Madison, Wis. 53706. 5Present address: National Center for Toxicological Research, Jefferson, Ark. 72079. Search for other works by this author on: Oxford Academic PubMed Google Scholar James R. Allen James R. Allen 4Department of Pathology, University of Wisconsin Medical School and Regional Primate Research Center, University of Wisconsin, Madison, Wis. 53706. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 61, Issue 1, July 1978, Pages 85–89, https://doi.org/10.1093/jnci/61.1.85 Published: 01 July 1978 Article history Received: 26 April 1977 Accepted: 07 February 1978 Published: 01 July 1978
The Clinical Results in the First Five Hundred Patients with Mitral Stenosis Undergoing Valvuloplasty
Authors: LAURENCE B. ELLIS, DWIGHT E. HARKEN
Journal: Circulation (1955)

A report is made of the clinical results in the first 500 patients operated on by mitral valvuloplasty in whom a preoperative diagnosis of predominant mitral stenosis had been made. The operation appears to offer some protection against late peripheral embolization. Four hundred forty of 442 surviving patients have been followed for periods of from six months to five years. Seventy seven per cent of the entire group are significantly improved. Thirty one per cent have had one or more attacks of a postoperative syndrome, but in only 7 per cent has there been clear-cut evidence of active rheumatic fever. Improvement in objective clinical findings, in particular in cardiac murmurs, heart size and the electrocardiogram, have been less striking than the subjective improvement.
Comparison of alcohol dehydrogenase expression in Drosophila melanogaster and D. simulans.
Authors: M S Thomson, J W Jacobson, C C Laurie
Journal: Molecular Biology and Evolution (1991)

Alcohol dehydrogenase (ADH) gene expression was analyzed in Drosophila melanogaster and its sibling species D. simulans. The levels of ADH activity, ADH-cross-reacting material (CRM), and ADH-mRNA were analyzed for several strains of each species, which derive from diverse geographic locations around the world. There is considerable quantitative variation in ADH activity, CRM level, and RNA level among strains within species at all developmental stages. However, the only consistent differences between the two species are in pupal RNA level and in late-adult activity and CRM level. Late-adult melanogaster flies that are homozygous for the Slow allozyme have approximately twice the level of ADH activity and CRM as do simulans flies. The regression of activity on CRM over strains is highly significant and essentially the same for each species, which means that most, if not all, of the activity difference between the species is due to a difference in concentration of the ADH protein. In contrast, there is no significant regression of CRM level on mRNA level in adults of either species; nor is there a significant difference in RNA level between species. Therefore, the difference in ADH protein concentration is not due to RNA template availability. Thus, the interspecific difference in ADH level in adults must be due either to a difference in the rate of translation of the two RNAs or to a difference in protein stability.