tbuckley/cabot-search huggingface dataset:
TIMP-1 production by monocytes may contribute to SSc skin fibrosis
Authors: A. Gessner, C. Huigens, T. Stanly, T. Huegle, J. van Laar
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> Systemic sclerosis is a connective tissue disease characterised by vasculopathy, tissue infiltration of mononuclear cells and fibrosis of skin and inner organs. Mechanisms of fibrogenesis are unknown so far. Under normal circumstances matrix metalloproteinases and their inhibitors (TIMPs) regulate accumulation of extra cellular matrix components in skin. This regulation seems to be disturbed in SSc. Our aims are to investigate the effect of SSc patient serum on healthy circulating monocytes and to identify serum factors that contribute to the TIMP/MMP imbalance. Osteopontin has been identified to be more abundant in patients with SSc and lung fibrosis. As osteopontin has been described to induce TIMP-1 in peripheral blood mononuclear cells (PBMCs) it is of potential interest in TIMP regulation. The results might give us some insight into the role of monocytes in SSc skin fibrosis. As novel gene which may be of interest in SSc we have identified TWIST-1 as potential candidate. TWIST-1 has been described as transcription factor and negative regulator of TIMP-1. <h3>Methods</h3> We collected PBMCs and serum from SSc patients (limited and diffuse). CD14 monocytes were isolated by positive selection and mRNA levels of TIMP-1 were determined with q-RTPCR. Monocytes from healthy donors were cultured with serum from SSc patients and TIMP-1 and TWIST-1 were subsequently investigated by q-RTPCR and ELISA, respectively, or q-RTPCR only (TWIST-1). Furthermore we investigated osteopontin (OPN) as a candidate cytokine for inducing TIMP-1 expression. <h3>Results</h3> mRNA levels of TIMP-1 in SSc CD14 monocytes were significantly upregulated compared to healthy controls. Serum from SSc patients, but not from RA patients or healthy controls, induced TIMP-1 production of healthy monocytes. Osteopontin was more abundant in SSc serum than in healthy controls and we have identified OPN as potential activator for TIMP-1 production. Furthermore we found TWIST-1 expression levels in healthy monocytes treated with SSc serum less expressed than in controls. Interestingly OPN seems to repress TWIST-1 expression which could explain the increasing TIMP-1 expression. <h3>Conclusion</h3> Osteopontin seems to be an important candidate and must be investigated further. As TWIST-1 is a negative regulator of TIMP-1 it is possible that the more abundant OPN levels in SSc serum repress TWIST-1 and thereby promote TIMP-1 expression. This would point OPN out as potential drug target to treat SSc patients.
Genome-Wide “Pleiotropy Scan” Identifies HNF1A Region as a Novel Pancreatic Cancer Susceptibility Locus
Authors: Brandon L. Pierce, Habibul Ahsan
Journal: Cancer Research (2011)

Abstract In genome-wide association (GWA) studies, hundreds of thousands of single-nucleotide polymorphisms (SNP) are tested for association with a disease trait. Typically, GWA studies give equal consideration to all SNPs tested, regardless of existing knowledge of an SNP's functionality or biological plausibility of association. Because many tests are conducted, very low statistical significance thresholds (P &amp;lt; 5 × 10−8) are required to identify true associations with confidence. By restricting GWA analyses to SNPs with enhanced prior probabilities of association, we can reduce the number of tests conducted and relax the required significance threshold, increasing power to detect association. In this analysis of existing GWA data on pancreatic cancer cases (n = 1,736) and controls (n = 1,802) of European descent (the PanScan study), we conduct a GWA scan restricted to SNPs that have been reported to associate with human phenotypes in previous GWA studies (with P &amp;lt; 5 × 10−8). Using this method, we drastically reduce the number of tests conducted (from ∼550,000 to 1,087) and test only SNPs that are known to be (or tag) variants that influence human biological processes. Of the 1,087 SNPs tested, the strongest association observed was for HNF1A SNP rs7310409 (P = 3 × 10−5; PBonferroni = 0.03), an SNP known to associate with circulating C-reactive protein. This association was replicated in an independent sample of 1,094 cases and 1,165 controls (P = 0.02), producing a highly significant association in the combined data sets (P = 2 × 10−6; PBonferroni = 0.002). The HNF1A region also harbors variants that influence several human traits, including maturity-onset diabetes of the young, type 2 diabetes, low-density lipoprotein cholesterol, and N-glycan levels. This novel “pleiotropy scan” method may be useful for identifying susceptibility loci for other cancer phenotypes. Cancer Res; 71(13); 4352–8. ©2011 AACR.
Blockade of ActRIIB Signaling Triggers Muscle Fatigability and Metabolic Myopathy
Authors: Karima Relizani, Etienne Mouisel, Benoit Giannesini, Christophe Hourdé, Ketan Patel, Susanne Morales Gonzalez, Kristina Jülich, Alban Vignaud, France Piétri-Rouxel, Dominique Fortin, Luis Garcia, Stéphane Blot, Olli Ritvos, David Bendahan, Arnaud Ferry, Renée Ventura-Clapier, Markus Schuelke, Helge Amthor
Journal: Molecular Therapy (2014)

Myostatin regulates skeletal muscle size via the activin receptor IIB (ActRIIB). However, its effect on muscle energy metabolism and energy-dependent muscle function remains largely unexplored. This question needs to be solved urgently since various therapies for neuromuscular diseases based on blockade of ActRIIB signaling are being developed. Here, we show in mice, that 4-month pharmacological abrogation of ActRIIB signaling by treatment with soluble ActRIIB-Fc triggers extreme muscle fatigability. This is associated with elevated serum lactate levels and a severe metabolic myopathy in the mdx mouse, an animal model of Duchenne muscular dystrophy. Blockade of ActRIIB signaling downregulates porin, a crucial ADP/ATP shuttle between cytosol and mitochondrial matrix leading to a consecutive deficiency of oxidative phosphorylation as measured by in vivo Phosphorus Magnetic Resonance Spectroscopy ((31)P-MRS). Further, ActRIIB blockade reduces muscle capillarization, which further compounds the metabolic stress. We show that ActRIIB regulates key determinants of muscle metabolism, such as Pparβ, Pgc1α, and Pdk4 thereby optimizing different components of muscle energy metabolism. In conclusion, ActRIIB signaling endows skeletal muscle with high oxidative capacity and low fatigability. The severe metabolic side effects following ActRIIB blockade caution against deploying this strategy, at least in isolation, for treatment of neuromuscular disorders.
Clinical picture of primary HIV infection presenting as a glandular-fever-like illness.
Authors: H. Gaines, M. von Sydow, P. O. Pehrson, P. Lundbegh
Journal: BMJ (1988)

The clinical symptoms and signs were assessed in 20 consecutive patients developing infection with the human immunodeficiency virus (HIV). All were male homosexuals and all presented with a glandular-fever-like illness. Changes in laboratory values were compared with findings in 40 HIV negative male homosexual controls. In the 10 patients for whom date of exposure to the virus could be established the incubation period was 11-28 days (median 14). One or two days after the sudden onset of fever patients developed sore throat, lymphadenopathy, rash, lethargy, coated tongue, tonsillar hypertrophy, dry cough, headache, myalgia, conjunctivitis, vomiting, night sweats, nausea, diarrhoea, and palatal enanthema. Twelve patients had painful, shallow ulcers in the mouth or on the genitals or anus or as manifested by oesophageal symptoms; these ulcers may have been the site of entry of the virus. During the first week after the onset of symptoms mild leucopenia, thrombocytopenia, and increased numbers of banded neutrophils were detected (p less than 0.0005). The mean duration of acute illness was 12.7 days (range 5-44). All patients remained healthy during a mean follow up period of 2.5 years. Heightened awareness of the typical clinical picture in patients developing primary HIV infection will alert the physician at an early stage and so aid prompt diagnosis and help contain the epidemic spread of AIDS.
5-Lipoxygenase plays a pivotal role in endothelial adhesion of monocytes via an increased expression of Mac-1
Authors: Seung Jin Lee, Eun Kyoung Choi, Kyo Won Seo, Jin Ung Bae, Yun Hak Kim, So Youn Park, Sae Ock Oh, Chi Dae Kim
Journal: Cardiovascular Research (2013)

Aims5-Lipoxygenase (5-LO) is known to participate in the pathogenesis of atherosclerosis; however, the underlying mechanisms are unclear. Thus, this study investigated the molecular mechanisms responsible for 5-LO expression in monocytes as well as the role of 5-LO in monocyte adhesion to the vascular endothelium, which is a key early event in macrophage foam cell formation.
Integration of Known Transcription Factor Binding Site Information and Gene Expression Data to Advance from Co-Expression to Co-Regulation
Authors: Maarten Clements, Eugene P. van Someren, Theo A. Knijnenburg, Marcel J.T. Reinders
Journal: Genomics Proteomics & Bioinformatics (2007)

Abstract The common approach to find co-regulated genes is to cluster genes based on gene expression. However, due to the limited information present in any dataset, genes in the same cluster might be co-expressed but not necessarily co-regulated. In this paper, we propose to integrate known transcription factor binding site information and gene expression data into a single clustering scheme. This scheme will find clusters of co-regulated genes that are not only expressed similarly under the measured conditions, but also share a regulatory structure that may explain their common regulation. We demonstrate the utility of this approach on a microarray dataset of yeast grown under different nutrient and oxygen limitations. Our integrated clustering method not only unravels many regulatory modules that are consistent with current biological knowledge, but also provides a more profound understanding of the underlying process. The added value of our approach, compared with the clustering solely based on gene expression, is its ability to uncover clusters of genes that are involved in more specific biological processes and are evidently regulated by a set of transcription factors.
Haptoglobin Enhances Cardiac Transplant Rejection
Authors: Hua Shen, Elizabeth Heuzey, Daniel N. Mori, Christine K. Wong, Christopher M. Colangelo, Lisa M. Chung, Can Bruce, Ilya B. Slizovskiy, Carmen J. Booth, Daniel Kreisel, Daniel R. Goldstein
Journal: Circulation Research (2015)

Rationale: Early graft inflammation enhances both acute and chronic rejection of heart transplants, but it is unclear how this inflammation is initiated. Objective: To identify specific inflammatory modulators and determine their underlying molecular mechanisms after cardiac transplantation. Methods and Results: We used a murine heterotopic cardiac transplant model to identify inflammatory modulators of early graft inflammation. Unbiased mass spectrometric analysis of cardiac tissue before and ≤72 hours after transplantation revealed that 22 proteins including haptoglobin, a known antioxidant, are significantly upregulated in our grafts. Through the use of haptoglobin-deficient mice, we show that 80% of haptoglobin-deficient recipients treated with perioperative administration of the costimulatory blocking agent CTLA4 immunoglobulin exhibited &gt;100-day survival of full major histocompatibility complex mismatched allografts, whereas all similarly treated wild-type recipients rejected their transplants by 21 days after transplantation. We found that haptoglobin modifies the intra-allograft inflammatory milieu by enhancing levels of the inflammatory cytokine interleukin-6 and the chemokine MIP-2 (macrophage inflammatory protein 2) but impair levels of the immunosuppressive cytokine interleukin-10. Haptoglobin also enhances dendritic cell graft recruitment and augments antidonor T-cell responses. Moreover, we confirmed that the protein is present in human cardiac allograft specimens undergoing acute graft rejection. Conclusions: Our findings provide new insights into the mechanisms of inflammation after cardiac transplantation and suggest that, in contrast to its prior reported antioxidant function in vascular inflammation, haptoglobin is an enhancer of inflammation after cardiac transplantation. Haptoglobin may also be a key component in other sterile inflammatory conditions.
Effects of spontaneous and streptokinase-induced recanalization on left ventricular function after myocardial infarction.
Authors: P J De Feyter, M J van Eenige, E E van der Wall, P D Bezemer, C L van Engelen, A J Funke-Kupper, H J Kerkkamp, F C Visser, J P Roos
Journal: Circulation (1983)

The effect of recanalization of the "infarct vessel" on left ventricular (LV) function was assessed 6-8 weeks after acute myocardial infarction (MI) in two groups: patients who had streptokinase-induced recanalization during the acute phase and control patients who had spontaneous recanalization. The ejection fraction and severity of LV wall motion abnormalities in 100 patients with recanalization were compared with those in 78 patients with persistent occlusion of the infarct vessel. Among patients with inferior MI, LV function was significantly better in those with spontaneous (n = 41, p less than 0.05) and streptokinase-induced recanalization (n = 15, p less than 0.02) than in those with persistent occlusion of the infarct vessel (n = 40) in the control group. The LV function was equally good in patients with spontaneous and streptokinase-induced recanalization. Among anterior MI patients, LV function was significantly better in those with streptokinase-induced recanalization (n = 10) than in those with spontaneous recanalization (n = 34, p less than 0.01) or persistent occlusion in the control group (n = 28, p less than 0.001). We conclude that recanalization has a beneficial effect on LV function in patients with MI.
Abstract 2867: Docosahexaenoic acid induces autophagy through p53/AMPK/mTOR signaling in human cancer cells
Authors: Kiapeng Jing, Kyoung-Sub Song, Soyeon Shin, Nayeong Kim Kim, Soyeon Jeong, Jun-Young Heo, Ji-Hoon Park, Kang-Sik Seo, Hyun-Joo Kwon, Hae-Duck Park, Chang Han, Tong Wu, Jong-Il Park, Seung-Kiel Park, Gi-Ryang Kweon, Wan-Hee Yoon, Byung-Doo Hwang, Kyu Lim
Journal: Cancer Research (2011)

Abstract Although Omega 3-polyunsatuarated fatty acids (Omega 3-PUFAs) induce cytotoxicity in several cancer cell lines, the exact mechanisms are not identified yet. In this study, we showed that autophagy is involved in the Omega 3-PUFAs-induced cytotoxicity in cancer cells. Autophagy is characterized by the sequestration of cytoplasmic material within autophagosomes for bulk degradation by lysosomes. We found that docosahexaenoic acid (DHA), an Omega 3-PUFA, induced not only apoptosis but also autophagy in cancer cells. Autophagy was detected after DHA exposure as indicated by induction of LC3 expression, and formation of autophagic vacuolization. We observed that the DHA-induced autophagy was accompanied by loss of p53. Inhibition of p53 by Pifithrin-α or microRNA-p53 significantly increased the DHA-induced autophagy, suggesting that the DHA-induced autophagy is mediated by downregulation of p53. Further experiments showed that the mechanism of the DHA-induced autophagy associated with p53 attenuation, involved an increase in the active form of AMPK which attenuated the mTOR activity as revealed by p27 sequestration. In addition, compelling evidence for the interplay between autophagy and apoptotic cell death induced by DHA is supported by the findings that autophagy inhibition partially decreased the DHA-induced apoptotic cell death and further autophagy induction by p53 inhibitor enhanced apoptosis in response to treatment with DHA in cancer cells. Our results demonstrate that autophagy may be related to the DHA-induced cytotoxicity in cancer cells. [This work was supported by basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (E00026 and R13-2007-020-01000-0]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2867. doi:10.1158/1538-7445.AM2011-2867
Barker &amp; Burstow's care packages for England
Authors: S. Iliffe, J. Manthorpe
Journal: BMJ (2014)

A tale of two markets pointing in the same direction

The market in social care has failed. This is the conclusion of two reports on social care from different perspectives, the Barker report and the Burstow report.1 2 The Barker report is the product of wide discussion following the publication of an interim report3 and explicitly rejects an unplanned and under-resourced social care market. The Burstow report explores the problems of providing acceptable housing based care services, draws on third sector and commercial experiences, and is an implicit cry for help.

The Barker report depicts relations between health and social care as opaque, inefficient, inequitable, and weighted towards individual rather than collective responsibility. Noting that the Poor Law still casts a long shadow, it argues that social care needs to be more generous and to be based on the principle of solidarity. This requires the allocation of an increased proportion of gross domestic product to social care. The option of developing insurance products that people could buy to prepare for their future care …
Evaluation of readability and accuracy of information leaflets in general practice for patients with asthma
Authors: H. Smith, S. Gooding, R. Brown, A. Frew
Journal: BMJ (1998)

Printed education materials are often used to augment healthcare professionals' verbal information to patients. Asthma is one of the commonest chronic diseases managed in general practice, and many leaflets have been produced on its diagnosis, prognosis, management, and treatment, but these have been subjected to little critical review.

We evaluated the readability and accuracy of patient information leaflets available in general practice for asthmatic patients. We invited 70 general practices from the Wessex Research Network to send one copy of each of the leaflets they had on asthma: 168 different leaflets were received from 49 practices. We reviewed the leaflets for readability using the simple measure of gobbledegook (SMOG) formula, which estimates the level of education required to understand the text.1 AF reviewed the leaflets for congruency with current British Thoracic Society guidelines2> and accuracy in other areas.

The reading grade for these publications ranged from …
Characterization of Radiofrequency Ablation Lesions With Gadolinium-Enhanced Cardiovascular Magnetic Resonance Imaging
Authors: Timm Dickfeld, Ritsushi Kato, Menekhem Zviman, Shenghan Lai, Glenn Meininger, Albert C. Lardo, Ariel Roguin, David Blumke, Ronald Berger, Hugh Calkins, Henry Halperin
Journal: Journal of the American College of Cardiology (2006)
Sudden Death: Is There a Human Stress Syndrome?-Reply
Authors: Max Robinowitz
Journal: JAMA (1987)

<h3>In Reply.—</h3> We have investigated further the circumstances of death in the six patients in question and the detailed findings are listed in the Table. Two of the six patients had myocardial contraction bands. Additional myocardial sections from the heart of the patient with rhabdomyolysis and hyperkalemia revealed multiple foci of myocyte necrosis with lymphocytic and plasma cell infiltrates. The differential diagnosis is idiopathic myocarditis, resolving catecholamine necrosis, or shock-induced myocardial necrosis. We favor the last, as the patient survived three days after circulatory collapse.<sup>1</sup>Findings from the toxicology screens were negative in all six; none had prior history of cardiovascular complaints, syncope, or drug- or anesthesia-related problems. Malignant hyperthermia is associated with marked elevations of catecholamine levels, especially norepinephrine, and would be expected to induce myocardial contraction band necrosis.<sup>2,3</sup>It is still possible that malignant hyperthermia may have been present in some of the recruits, as susceptibility
Long-Term Endothelin Receptor Antagonist Administration Improves Alterations in Expression of Various Cardiac Genes in Failing Myocardium of Rats With Heart Failure
Authors: Satoshi Sakai, Takashi Miyauchi, Iwao Yamaguchi
Journal: Circulation (2000)

Background —We reported that long-term (3-month) treatment with the endothelin (ET) type A (ET A ) receptor antagonist BQ-123 markedly improved survival in rats with chronic heart failure (CHF). However, it is not known whether long-term treatment with an ET receptor antagonist improves alterations in the expression of cardiac genes in failing hearts. Methods and Results —CHF rats and control sham-operated rats were treated with BQ-123, SB209670 (ET A/B dual receptor antagonist), or saline (vehicle) for 3 months. The survival of CHF rats was markedly higher in the BQ-123 or SB209670 treatment group than in the saline treatment group. The changes in the gene expression of classic molecular markers for failing hearts (mRNA levels of atrial natriuretic peptide and β-myosin heavy chain) were greatly inhibited by BQ-123 or SB209670 treatment in CHF rats. Long-term BQ-123 treatment also normalized the alterations in the expression of functional molecular markers in failing hearts (eg, mRNA levels of ryanodine receptor, sarcoplasmic reticulum Ca 2+ -ATPase, angiotensin-converting enzyme, angiotensin II type 1 receptor, and prepro-ET-1). Conclusions —We demonstrated for the first time that long-term (3-month) treatment with an ET receptor antagonist improves the alterations in the expression of various cardiac genes of classic molecular markers (eg, mRNA in atrial natriuretic peptide and β-myosin heavy chain) and of functional molecular markers (eg, mRNA levels of ryanodine receptor, sarcoplasmic reticulum Ca 2+ -ATPase, angiotensin-converting enzyme, angiotensin II type 1 receptor, and prepro-ET-1) in the failing hearts of CHF rats, suggesting that the great improvement of survival in CHF rats by an ET blocker is partly attributed to the prevention of molecular changes in failing hearts.
REAPPEARANCE OF REACTION AT SITE OF PREVIOUS DICK TEST COINCIDENT WITH APPEARANCE OF MEASLES RASH IN A CASE OF MEASLES
Authors: N. S. Ferry
Journal: JAMA (1926)

S. F., a man, aged 21, who had not had scarlet fever, had been acting as a test subject for the standardization of scarlet fever toxin and antitoxin, and usually exhibited a typical Dick reaction from 2 to 3 cm. in diameter. April 6, 1926, he was given, on the anterior surface of the right forearm, two intracutaneous injections of scarlet fever toxin, one containing 5 skin test doses of standard toxin as furnished by the Hygienic Laboratory, Washington, and the other, two inches below, containing 1 skin test dose of test toxin. At the same time, two intracutaneous injections of 5 skin test doses of toxin were given on the left forearm, each neutralized with scarlet fever antitoxin, the upper injection containing more antitoxin than was sufficient to neutralize the toxin. As neither of the last two sites showed a reaction at the end of forty-eight hours, while the