tbuckley/cabot-search huggingface dataset:
Regulation of Thrombomodulin Expression in Human Vascular Smooth Muscle Cells by COX-2–Derived Prostaglandins
Authors: Kerstin Rabausch, Ellen Bretschneider, Mario Sarbia, Jutta Meyer-Kirchrath, Petra Censarek, Robert Pape, Jens W. Fischer, Karsten Schrör, Artur-Aron Weber
Journal: Circulation Research (2005)

There is concern that cyclooxygenase (COX)-2 inhibitors may promote atherothrombosis by inhibiting vascular formation of prostacyclin (PGI2) and an increased thrombotic risk of COX-2 inhibitors has been reported. It is widely accepted that the prothrombotic effects of COX-2 inhibitors can be explained by the removal of platelet-inhibitory PGI2. Using microarray chip technology, we have previously demonstrated that thrombomodulin (TM) mRNA is upregulated in cultured human coronary artery smooth muscle cells by the stable prostacyclin mimetic iloprost. This study is the first to demonstrate a stimulation of the expression of functionally active thrombomodulin in human smooth muscle cells by prostaglandins, endogenously formed via the COX-2 pathway. Because TM is an important inhibitor of blood coagulation, these findings provide a novel platelet-independent mechanism to explain the prothrombotic effects of COX-2 inhibitors. The full text of this article is available online at http://circres.ahajournals.org.
Non-A, non-B hepatitis specific antibodies directed at host-derived epitope: implication for an autoimmune process
Authors: S. Mishiro, Y. Hoshi, A. Yoshikawa, T. Gotanda, F. Tsuda, K. Takeda, Y. Akahane, K. Takahashi, H. Yoshizawa, H. Okamoto, D.A. Peterson, E. Muchmore
Journal: The Lancet (1990)
Adaptive Designs for Randomized Trials in Public Health
Authors: C. Hendricks Brown, Thomas R. Ten Have, Booil Jo, Getachew Dagne, Peter A. Wyman, Bengt Muthén, Robert D. Gibbons
Journal: Annual Review of Public Health (2009)

In this article, we present a discussion of two general ways in which the traditional randomized trial can be modified or adapted in response to the data being collected. We use the term adaptive design to refer to a trial in which characteristics of the study itself, such as the proportion assigned to active intervention versus control, change during the trial in response to data being collected. The term adaptive sequence of trials refers to a decision-making process that fundamentally informs the conceptualization and conduct of each new trial with the results of previous trials. Our discussion below investigates the utility of these two types of adaptations for public health evaluations. Examples are provided to illustrate how adaptation can be used in practice. From these case studies, we discuss whether such evaluations can or should be analyzed as if they were formal randomized trials, and we discuss practical as well as ethical issues arising in the conduct of these new-generation trials.
Individual IL-3 priming is crucial for consistent in vitro activation of donor basophils in patients with chronic urticaria
Authors: Thomas Gentinetta, Tatjana Pecaric-Petkovic, Daniel Wan, Franco H. Falcone, Clemens A. Dahinden, Werner J. Pichler, Oliver V. Hausmann
Journal: Journal of Allergy and Clinical Immunology (2011)
Vascular Dysfunction Detected by a Simplified Venous Occlusion Test in NIDDM Patients
Authors: Akira Mizuno, Junichi Isobe, Kenji Shima
Journal: Diabetes Care (1993)

To elucidate the relationship between angiopathies and vascular function evaluated by a simplified venous occlusion test in patients with NIDDM.The serum concentration of FDP was measured before and 5 min after venous occlusion in 23 NIDDM patients, 11 patients with cerebrovascular accident, and 10 age-matched healthy control subjects.The increment of serum FDP level after venous occlusion was significantly less in patients with NIDDM (60.6 +/- 33.5 to 81.5 +/- 49.6 ng/ml) and in those with cerebrovascular accident (101.4 +/- 51.5 to 116.2 +/- 47.2 ng/ml) than in control subjects (79.9 +/- 41.0 to 148.8 +/- 65.4 ng/ml). The increment of serum FDP after venous occlusion in NIDDM patients with macroangiopathy was significantly lower than that in those without macroangiopathy.The responsiveness of fibrinolytic activity to venous occlusion was significantly less in NIDDM patients with macroangiopathy, as in patients with cerebrovascular accident, compared with that in healthy control subjects.
Neuropathic pain: mechanisms and their clinical implications
Authors: S. P. Cohen, J. Mao
Journal: BMJ (2014)

Neuropathic pain can develop after nerve injury, when deleterious changes occur in injured neurons and along nociceptive and descending modulatory pathways in the central nervous system. The myriad neurotransmitters and other substances involved in the development and maintenance of neuropathic pain also play a part in other neurobiological disorders. This might partly explain the high comorbidity rates for chronic pain, sleep disorders, and psychological conditions such as depression, and why drugs that are effective for one condition may benefit others. Neuropathic pain can be distinguished from non-neuropathic pain by two factors. Firstly, in neuropathic pain there is no transduction (conversion of a nociceptive stimulus into an electrical impulse). Secondly, the prognosis is worse: injury to major nerves is more likely than injury to non-nervous tissue to result in chronic pain. In addition, neuropathic pain tends to be more refractory than non-neuropathic pain to conventional analgesics, such as non-steroidal anti-inflammatory drugs and opioids. However, because of the considerable overlap between neuropathic and nociceptive pain in terms of mechanisms and treatment modalities, it might be more constructive to view these entities as different points on the same continuum. This review focuses on the mechanisms of neuropathic pain, with special emphasis on clinical implications.
GP consortium agrees partnership with private firm to run referral service
Authors: A. O'Dowd
Journal: BMJ (2011)

Concerns have been raised over an early deal signed between one of the new pathfinder GP commissioning consortiums and the private firm UnitedHealth UK.

The referral management deal with UnitedHealth UK has been jointly agreed by the NHS Hounslow primary care trust and the London based Great West Commissioning Consortium.

The trust said that this was an innovative new service to support GPs in their new role as commissioners and to improve the quality of referrals. But the BMA said that it was disappointed at this early partnership between a consortium and the private sector.

NHS Hounslow said that the “referral facilitation service” had been developed with local GPs—with the blessing of all the area’s 57 general practices­—and would handle all referrals, including consultant to consultant referrals, from February 2011. It will act as a first port …
P108 Phenotypic changes in Pseudomonas aeruginosa (Psa) populations during exacerbations in adult Cystic Fibrosis patients infected with non-epidemic strains
Authors: A. Ashish, J. Fothergill, E. Mowat, M. Gautam, C. Winstanley, M. Walshaw
Journal: Thorax (2010)

<h3>Background</h3> Chronic infection with Psa in most CF patients is due to single unique strains, which over time accumulate mutations resulting in mucoid conversion, loss of motility, auxotrophy and increased antibiotic resistance, in turn leading to multiple phenotypes. However, changes in Psa population morphology related to short term pressures (eg, during IV antibiotic-treated exacerbations), have not previously been studied. We therefore looked at Psa population structure during exacerbations. <h3>Methods</h3> Sputum samples from four CF patients chronically infected (for at least 4 years) with unique single Psa strains were analysed at the beginning and end of an intravenous antibiotic-treated exacerbation, where every patient had subjective and spirometric improvement. From each sample, 40 single Psa colonies were selected (with every morphological type proportionately represented), and colony morphology, susceptibility to six antibiotics (ciprofloxacin, ceftazidime, colomycin, meropenem, tobramycin, tazocin), hypermutability (rate of spontaneous mutation to rifampicin resistance) and auxotrophy (ability to grow on glucose M9 media) determined. Additionally, the density of Psa (colony forming units (CFU) per ml) in sputum samples was measured. <h3>Results</h3> Although the predominant colony morphology changed from green, non-mucoid and smooth (mean 67%, range 43–98) to straw-coloured, non-mucoid and smooth (57%, 5–95) (p=0.001), there was no change in mean antibiotic resistance to all antibiotics (21.5% vs 20.3%, p=0.9), prevalence of hypermutable isolates (38% vs 25%, p=0.48) and auxotrophic mutants (66% vs 98%, p=0.17). However, there was an increase in Psa sputum density (mean CFU/ml 1.3 x10<sup>5</sup> vs 2.0x10<sup>6</sup>, p&lt;0.001), despite the use of relevant antimicrobial therapy. <h3>Conclusion</h3> The changes in prevalent population composition following antibiotic pressure, associated with clinical improvement, might suggest that some morphotypes alone are responsible for the adverse clinical features. Conversely, the increase in sputum density of Psa despite objective clinical improvement implies that the exacerbation has occurred independently of the presence of the organism, supporting the observation that clinical improvement is often seen in CF patients even where the Psa seems resistant to the administered antibiotics. Further work need to be done to tease out the role of Psa in clinical exacerbations of CF patients with chronic infection.
Cardiovascular risk factors (CVRF) and late cardiovascular disease (LCD) in orthotopic liver transplantation (OLT)
Authors: M. Romero, A. Parera, M. Salcedo, F.G. Durán, J. Casariego, JA Carneros, M. Abeytua, E. Cos, G. Clemente
Journal: Journal of Hepatology (1998)
Combining corticosteroids and NK1R antagonists: A new drugs combination to treat allergic diseases
Authors: Karim Maghni, Lucero Castellanos, Sandra Favret, Mélanie Welman
Journal: European Respiratory Journal (2012)

Introduction.  Recently, using the rat mast cell/basophil cell line RBL-2H3, a major model system for the study of FceRI intracellular signaling pathways, we found that optimal pharmacological blocking of autocrine activation of the neurokinin-1 receptor (NK1R) in response to FceRI clustering suppresses antigen-induced 50 % of maximal cell degranulation, and decreases by nearly 50 % antigen-induced maximal cell activation.   Aim.  To determine whether combining corticosteroids and NK1R antagonist may be a powerful therapeutic combination to control IgE-FceRI complex responses in allergic diseases.   Methodology.  IgE-sensitized RBL-2H3 cells were incubated with various concentrations of corticosteroids in combination or not with NK1R antagonist prior to FceRI clustering. Cells degranulation and cysteinyl-leukotrienes (Cys-LTs) production were examined.   Results : Maximal concentrations of respective corticosteroids decreased by nearly 50 % allergen-induced maximal degranulation and Cys-LTs production in basophils. Pharmacological blocking of NK1R alone has also produced similar inhibitory effects in basophils. Interestingly, the combination of corticosteroids and NK1R antagonist improved both time response and concentration efficacy of corticosteroids with nearly total inhibition of basophil allergic responses.   Conclusion : Combining corticosteroids and NK1R antagonist (patent WO2007/096782) is a promising therapeutic combination to increase corticosteroids efficacy while decreasing effective doses, and may give a second “breath” to corticosteroids patents that are no longer protected.   Supported by the Canadian Institutes of Health Research .
Psychoanalysis, Psychotherapy and the New England Medical Scene,1894-1944
Authors: ERIC T. CARLSON
Journal: American Journal of Psychiatry (1979)

Book Reviews price has also been a deterrent.This summary of volumes 1 and 2 is, therefore, most welcome, and Mr. Ronan has produced a readable condensation amounting to about one-third of the original.It is, however, dealing with somewhat dated material, opinions and facts having changed in the last two decades, but there is some attempt to bring the text up to date.This abridgement will be widely popular, for its deals with the general features of the history of Chinese science and its earliest periods.The further volumes promised will be most welcome and useful.
Effects of a leukotriene B4 receptor antagonist on bleomycin-induced pulmonary fibrosis
Authors: T. Izumo, M. Kondo, A. Nagai
Journal: European Respiratory Journal (2009)

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with poor prognosis. Leukotrienes play an important role in IPF, and leukotriene (LT)B 4 is one of the key eicosanoids in IPF. In this study, we investigated whether ONO-4057, a LTB 4 receptor (BLTR) antagonist is capable of preventing bleomycin-induced pulmonary fibrosis. On day 1, C57BL/6 male mice were given a single intratracheal injection of bleomycin (2.5 mg·kg −1 ), and ONO-4057 (1.0 mg·kg −1 ) or vehicle alone, administered by intraperitoneal injection on days 1–5 each week for 3 weeks after the bleomycin injection. ONO-4057 reduced the total cell count in bronchoalveolar lavage fluid (BALF) on days 7, 14 and 21 and the Ashcroft score and the lung hydroxyproline content on days 14 and 21. The LTB 4 , interleukin (IL)-6, IL-13, transforming growth factor (TGF)-β levels in BALF and the TGF-β expression in lung tissue, assessed by immunohistochemistry were decreased on day 7, whereas interferon (IFN)-γ level in BALF was increased on day 14. The results of this study indicated that the BLTR antagonist inhibited the development of bleomycin-induced pulmonary fibrosis in mice by decreasing inflammation and altering TGF-β, IL-6, IL-13 and IFN-γ.
Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b
Authors: Jeong Kyu Kim, Ji Heon Noh, Kwang Hwa Jung, Jung Woo Eun, Hyun Jin Bae, Min Gyu Kim, Young Gyoon Chang, Qingyu Shen, Won Sang Park, Jung Young Lee, Jürgen Borlak, Suk Woo Nam
Journal: Hepatology (2012)

Sirtuins are nicotinamide adenine dinucleotide oxidized form (NAD+)-dependent deacetylases and function in cellular metabolism, stress resistance, and aging. For sirtuin7 (SIRT7), a role in ribosomal gene transcription is proposed, but its function in cancer has been unclear. In this study we show that SIRT7 expression was up-regulated in a large cohort of human hepatocellular carcinoma (HCC) patients. SIRT7 knockdown influenced the cell cycle and caused a significant increase of liver cancer cells to remain in the G1/S phase and to suppress growth. This treatment restored p21WAF1/Cip1, induced Beclin-1, and repressed cyclin D1. In addition, sustained suppression of SIRT7 reduced the in vivo tumor growth rate in a mouse xenograft model. To explore mechanisms in SIRT7 regulation, microRNA (miRNA) profiling was carried out. This identified five significantly down-regulated miRNAs in HCC. Bioinformatics analysis of target sites and ectopic expression in HCC cells showed that miR-125a-5p and miR-125b suppressed SIRT7 and cyclin D1 expression and induced p21WAF1/Cip1-dependent G1 cell cycle arrest. Furthermore, treatment of HCC cells with 5-aza-2′-deoxycytidine or ectopic expression of wildtype but not mutated p53 restored miR-125a-5p and miR-125b expression and inhibited tumor cell growth, suggesting their regulation by promoter methylation and p53 activity. To show the clinical significance of these findings, mutations in the DNA binding domain of p53 and promoter methylation of miR-125b were investigated. Four out of nine patients with induced SIRT7 carried mutations in the p53 gene and one patient showed hypermethylation of the miR-125b promoter region. Conclusion : Our findings suggest the oncogenic potential of SIRT7 in hepatocarcinogenesis. A regulatory loop is proposed whereby SIRT7 inhibits transcriptional activation of p21WAF1/Cip1 by way of repression of miR-125a-5p and miR-125b. This makes SIRT7 a promising target in cancer therapy. (Hepatology 2013)
Decoding Hereditary Colorectal Cancer
Authors: C. Richard Boland
Journal: New England Journal of Medicine (2006)

This year, colorectal cancer will strike about 150,000 people in the United States and 500,000 worldwide. Much of the morbidity and mortality of the disease could be prevented if we knew more about the risk of colorectal cancer developing and were able to take effective preemptive action.About 3 to 4 percent of cases of colorectal cancer occur in the familial cancer syndromes. The commonest of these is the Lynch syndrome (also called hereditary nonpolyposis colorectal cancer), which is caused by a germ-line mutation in one of four DNA mismatch-repair genes.1 The identification of patients with the Lynch syndrome is . . .
Resistance of cytotoxic T lymphocytes to the lytic effects of their toxic granules.
Authors: C R Verret, A A Firmenich, D M Kranz, H N Eisen
Journal: The Journal of Experimental Medicine (1987)

A cytotoxic T lymphocyte (CTL) characteristically kills target cells one after the other by releasing toxic granules that contain one or more cytolytic components. To determine how CTLs avoid destroying themselves when they release granules and lyse target cells, 7 murine CD8+ CTL cell lines were compared with 19 other cell lines for susceptibility to lysis by the isolated toxic granules. Murine CD8+ CTLs were clearly the most resistant cells: granules did not lyse them even after they were exposed to azide, cyanide, and 2-deoxyglucose, conditions that were found to enhance the susceptibility of all the other cells tested, including other T cells. Thus, resistance of CD8+ CTLs to cytotoxic granules appears to be independent of cellular ATP. To reconcile these findings with other observations that, under some circumstances, CTLs can be lysed by other CTLs, we suggest a model in which a CTL releases only a limited proportion of its toxic granules at each antigen-specific encounter with a target cell; the amount released is sufficient to kill most target cells but to leave the CTL undamaged and with enough granules to attack other target cells.
Descending Inhibitory Pain Modulation Is Impaired in Patients With Chronic Pancreatitis
Authors: Søren Schou Olesen, Christina Brock, Anne Lund Krarup, Peter Funch–Jensen, Lars Arendt–Nielsen, Oliver H. Wilder–Smith, Asbjørn Mohr Drewes
Journal: Clinical Gastroenterology and Hepatology (2010)
Fanconi's Anemia in Adulthood: Chemoradiation-Induced Bone Marrow Failure and a Novel FANCA Mutation Identified by Targeted Deep Sequencing
Authors: Iain Beehuat Tan, Ioana Cutcutache, Zhi Jiang Zang, Jabed Iqbal, Seow Fong Yap, William Hwang, Wan-Teck Lim, Bin Tean Teh, Steve Rozen, Eng-Huat Tan, Patrick Tan
Journal: Journal of Clinical Oncology (2011)
Autoantibodies in infectious mononucleosis have specificity for the glycine-alanine repeating region of the Epstein-Barr virus nuclear antigen.
Authors: G Rhodes, H Rumpold, P Kurki, K M Patrick, D A Carson, J H Vaughan
Journal: The Journal of Experimental Medicine (1987)

Viruses have been postulated to be involved in the induction of autoantibodies by: autoimmunization with tissue proteins released by virally induced tissue damage; immunization with virally encoded antigens bearing molecular similarities to normal tissue proteins; or nonspecific (polyclonal) B cell stimulation by the infection. Infectious mononucleosis (IM) is an experiment of nature that provides the opportunity for examining these possibilities. We show here that IgM antibodies produced in this disease react with at least nine normal tissue proteins, in addition to the virally encoded Epstein-Barr nuclear antigen (EBNA-1). The antibodies are generated to configurations in the glycine-alanine repeat region of EBNA-1 and are crossreactive with the normal tissue proteins through similar configurations, as demonstrated by the effectiveness of a synthetic glycine-alanine peptide in inhibiting the reactions. The antibodies are absent in preillness sera and gradually disappear over a period of months after illness, being replaced by IgG anti-EBNA-1 antibodies that do not crossreact with the normal tissue proteins but that are still inhibited by the glycine-alanine peptide. These findings are most easily explained by either a molecular mimicry model of IgM autoantibody production or by the polyclonal activation of a germline gene for a crossreactive antibody. It also indicates a selection of highly specific, non-crossreactive anti-EBNA-1 antibodies during IgM to IgG isotype switching.
Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations
Authors: L. Jayaram, M. M. Pizzichini, R. J. Cook, L-P. Boulet, C. Lemière, E. Pizzichini, A. Cartier, P. Hussack, C. H. Goldsmith, M. Laviolette, K. Parameswaran, F. E. Hargreave
Journal: European Respiratory Journal (2006)

One important goal of asthma treatment is to reduce exacerbations. The current authors investigated if the use of sputum cell counts to guide treatment would achieve this goal. A total of 117 adults with asthma were entered into a multicentre, randomised, parallel group-effectiveness study for two treatment strategies over a 2-yr period. In one strategy (the clinical strategy: CS) treatment was based on symptoms and spirometry. In the other (the sputum strategy: SS) sputum cell counts were used to guide corticosteroid therapy to keep eosinophils ≤2%; symptoms and spirometry were used to identify clinical control, exacerbations and other treatments. Patients were blind to sputum cell counts in both strategies and physicians were blind in the CS, thus removing bias. First, the minimum treatment to maintain control was identified in 107 patients (Phase 1) and then this treatment was continued (Phase 2) for the remaining of the 2 yrs. The primary outcomes were the relative risk reduction for the occurrence of the first exacerbation in Phase 2 and the length of time without exacerbation. The current authors also examined the type and severity of exacerbations and the cumulative dose of inhaled steroid needed. The duration and number of exacerbations in Phase 1 were similar in both groups. In Phase 2 there were a 126 exacerbations of which 79 occurred in the CS (62.7%) and 47 (37.3%) in the SS groups. The majority of the 126 exacerbations (101; 80.1%) were mild. The majority of the 102 exacerbations, where sputum examination was performed before any treatment (n = 70), were noneosinophilic. In the SS patients, the time to the first exacerbation was longer (by 213 days) especially in those considered to need treatment with a long acting β 2 -agonist (by 490 days), the relative risk ratio was lower (by 49%), and the number of exacerbations needing prednisone was reduced (5 versus 15). This benefit was seen mainly in patients needing treatment with inhaled steroid in a daily dose equivalent to fluticasone &gt;250 μg, and was due to fewer eosinophilic exacerbations. The cumulative dose of corticosteroid during the trial was similar in both groups. Monitoring sputum cell counts was found to benefit patients with moderate-to-severe asthma by reducing the number of eosinophilic exacerbations and by reducing the severity of both eosinophilic and noneosinophilic exacerbations without increasing the total corticosteroid dose. It had no influence on the frequency of noneosinophilic exacerbations, which were the most common exacerbations.