tbuckley/cabot-search huggingface dataset:
Small Amounts of α-Myosin Heavy Chain Isoform Expression Significantly Increase Power Output of Rat Cardiac Myocyte Fragments
Authors: Todd J. Herron, Kerry S. McDonald
Journal: Circulation Research (2002)

Myocardial performance is likely affected by the relative expression of the two myosin heavy chain (MyHC) isoforms, namely α-MyHC and β-MyHC. The relative expression of each isoform is regulated developmentally and in pathophysiological states. Many pathophysiological states are associated with small shifts in the relative expression of each MyHC isoform, yet the functional consequence of these shifts remains unclear. The purpose of this study was to determine the functional effect of a small shift in the relative expression of α-MyHC. To this end, power output was measured in rat cardiac myocyte fragments that expressed ≈12% α-MyHC and in myocyte fragments that expressed ≈0% α-MyHC, as determined in the same cells by SDS-PAGE analysis after mechanical experiments. Myocyte fragments expressing ≈12% α-MyHC developed ≈52% greater peak normalized power output than myocyte fragments expressing ≈0% α-MyHC. These results indicate that small amounts of α-MyHC expression significantly augment myocyte power output.
Quinapril, an ACE Inhibitor, Reduces Markers of Oxidative Stress in the Metabolic Syndrome
Authors: Bobby V. Khan, Srikanth Sola, Wright B. Lauten, Rama Natarajan, W. Craig Hooper, Rekha G. Menon, Stamatios Lerakis, Tarek Helmy
Journal: Diabetes Care (2004)

Patients with the metabolic syndrome often have abnormal levels of proinflammatory and pro-oxidative mechanisms within their vasculature. We sought to determine whether the ACE inhibitor quinapril regulates markers of oxidative stress in the metabolic syndrome.Forty patients with the metabolic syndrome were randomized in a double-blind manner to either the ACE inhibitor quinapril (20 mg/day) or matching placebo for 4 weeks. Serum markers of vascular oxidative stress were measured.After 4 weeks of therapy, serum 8-isoprostane was reduced by 12% in the quinapril group when compared with placebo (quinapril, 46.7 +/- 1.0; placebo, 52.7 +/- 0.9 pg/ml; P = 0.001). Erythrocyte superoxide dismutase activity increased 35% in the quinapril group when compared with placebo (quinapril, 826.3 +/- 17.1; placebo, 612.3 +/- 6.9 units/g Hb; P < 0.001). In addition, lag time to oxidation of LDL, a marker of oxidative stress, was increased by 48% in the quinapril group when compared with placebo (quinapril 89.2 +/- 9.2 vs. placebo 60.1 +/- 12.3 min; P < 0.001). Therapy with quinapril was well tolerated.The addition of the ACE inhibitor quinapril reduces markers of vascular oxidative stress and may attenuate the progression of the pathophysiology seen in the metabolic syndrome.
Reasons for medical help-seeking behaviour of patients with recent-onset arthralgia
Authors: Jessica A B van Nies, Elisabeth Brouwer, Diederik P C de Rooy, Floris A van Gaalen, Tom W J Huizinga, Marcel D Posthumus, Annette H M van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2012)

Patient delay in seeking medical help may cause suboptimal use of the therapeutic window in rheumatoid arthritis. We aimed to assess the motivations and the urgency with which patients with arthralgia seek medical help.612 patients with arthralgia-visiting two Dutch Early Arthritis Recognition Clinics-were studied. Patients filled out a questionnaire with questions on their symptoms and their reasons for seeking medical help. Comparisons were made for patients with short or prolonged patient delay, patients with and without arthritis, age and gender.The median symptom duration was 4 weeks. A prolonged delay in seeking help was associated with a gradual onset of symptoms (78%) and the perception that symptoms would not be serious or would go away (16% and 48%, respectively). Arthralgia patients who promptly sought medical help more often had an acute onset of symptoms and more frequently reported impairments at work or in daily functioning than patients who postponed seeking help (all p<0.005). Patients with and without arthritis generally had similar reasons for seeking help. The proportion of patients who had a prolonged patient delay was comparable between male and female subjects and between age categories. Particularly younger patients postponed seeking help because they thought their symptoms would disappear spontaneously.This large-scale study observed several reasons and symptom characteristics influencing the help-seeking behaviour of persons with arthralgia. These data can be helpful to define strategies aiming at early identification of arthritis.
Beyond the IFN- horizon: biomarkers for immunodiagnosis of infection with Mycobacterium tuberculosis
Authors: Novel N. Chegou, Jan Heyckendorf, Gerhard Walzl, Christoph Lange, Morten Ruhwald
Journal: European Respiratory Journal (2013)

Latent infection with Mycobacterium tuberculosis (LTBI) is defined by the presence of M. tuberculosis-specific immunity in the absence of active tuberculosis. LTBI is detected using interferon-γ release assays (IGRAs) or the tuberculin-skin-test (TST). In clinical practice, IGRAs and the TSTs have failed to distinguish between active tuberculosis and LTBI and their predictive value to identify individuals at risk for the future development of tuberculosis is limited. There is an urgent need to identify biomarkers that improve the clinical performance of current immunodiagnostic methods for tuberculosis prevention, diagnosis and treatment monitoring. Here, we review the landscape of potential alternative biomarkers useful for detection of infection with M. tuberculosis. We describe what individual markers add in terms of specificity for active/latent infection, prediction of progression to active tuberculosis and immunodiagnostic potential in high-risk groups' such as HIV-infected individuals and children.
Effect of topical treatment with skin barrier-enhancing emollients on nosocomial infections in preterm infants in Bangladesh: a randomised controlled trial
Authors: Gary L Darmstadt, Samir K Saha, ASM Nawshad Uddin Ahmed, MAK Azad Chowdhury, Paul A Law, Saifuddin Ahmed, Muhammad Asif Alam, Robert E Black, Mathuram Santosham
Journal: The Lancet (2005)
An overview of interventions designed to reduce risk factors for sport injury
Authors: K McBain, I Shrier, R Shultz, W H Meeuwisse, M Klugl, D Garza, G O Matheson
Journal: British Journal of Sports Medicine (2011)

Background While physical activity is associated with an overall reduction in mortality, morbidity and an improved quality of life, it also increases the risk of injury and illness. Objective To identify gaps in the literature with respect to interventions designed to reduce risk factors for sport injury. Design Review. Databases PubMed, Cinahl, Web of Science, Embase, and Sports Discus were searched. Setting All ages, sex, levels of competition and Olympic sports were included. Main outcome measurement Pattern of publications over time stratified by study design, intervention type, sport and anatomic site. Results Only 144 of 2525 articles retrieved by the search strategy met the inclusion criteria. Cross-over study designs increased by 175% since the late 1980's until 2005 but have declined 32% since. Randomised controlled trial (RCT) study designs increased by 650% since the early 1990's. Protective equipment was the focus of 61.8% of the studies and training the remaining 35.4%. Equipment research studied stability devices (83.1%) and attenuating devices (13.5%) while training research studied balance and coordination (54.9%), strength and power (43.1%) and stretching (15.7%). Almost 92.1% of the studies were of the lower extremity and 78.1% were of the joint (non-bone)-ligament type. 57.5% of the reports studied contact sports, 24.2% collision, and 25.75% non-contact sports. Conclusion We were surprised to find only 144 publications examining interventions designed to reduce risk factors for sport injury. The decrease in cross-over study design and increase in RCTs indicate a shift in research focus. Most notable was the finding that studies using equipment interventions have been decreasing since 2000 (35% decline) while those using training interventions have been increasing (213% increase).
A cluster of acute flaccid paralysis and cranial nerve dysfunction temporally associated with an outbreak of enterovirus D68 in children in Colorado, USA
Authors: Kevin Messacar, Teri L Schreiner, John A Maloney, Adam Wallace, Jan Ludke, M Stephen Oberste, W Allan Nix, Christine C Robinson, Mary P Glodé, Mark J Abzug, Samuel R Dominguez
Journal: The Lancet (2015)
Pentoxifylline improves nonalcoholic steatohepatitis: A randomized placebo-controlled trial
Authors: Claudia O. Zein, Lisa M. Yerian, Prema Gogate, Rocio Lopez, John P. Kirwan, Ariel E. Feldstein, Arthur J. McCullough
Journal: Hepatology (2011)

The primary aim of this study was to compare the effects of pentoxifylline (PTX) versus placebo on the histological features of nonalcoholic steatohepatitis (NASH). In all, 55 adults with biopsy-confirmed NASH were randomized to receive PTX at a dose of 400 mg three times a day (n = 26) or placebo (n = 29) over 1 year. The primary efficacy endpoint was defined as improvement in histological features of NASH through reduction in steatosis, lobular inflammation, and/or hepatocellular ballooning as reflected by a decrease of ≥2 points in the nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 1 year, intention-to-treat analysis showed a decrease of ≥2 points in the NAS in 38.5% of patients on PTX versus 13.8% of those on placebo ( P = 0.036). Per protocol analysis, a decrease of ≥2 points in the NAS from baseline was observed in 50% of the patients on PTX versus 15.4% of those on placebo ( P = 0.01). The mean change in NAS score from baseline was −1.6 in the PTX group, versus −0.1 in the placebo group ( P &lt; 0.001). PTX significantly improved steatosis (mean change in score −0.9 versus −0.04 with placebo, P &lt; 0.001) and lobular inflammation (median change −1 versus 0 with placebo, P = 0.02). No significant effects in hepatocellular ballooning were observed. PTX also improved liver fibrosis (mean change in fibrosis score was −0.2 among those on PTX versus +0.4 among those on placebo, P = 0.038). Although not statistically significant ( P = 0.17), improvement in fibrosis was observed in a greater proportion (35%) of patients in the PTX group compared to placebo (15%). Adverse effects were similar in both groups. Conclusion: PTX improved histological features of NASH compared to placebo. PTX was well tolerated in patients with NASH (ClinicalTrials.gov number NCT00590161). (Hepatology 2011)
The Role of Somatic Mutation in the Pathogenic Anti-DNA Response
Authors: B Diamond, J B Katz, E Paul, C Aranow, D Lustgarten, M D Scharff
Journal: Annual Review of Immunology (1992)

Anti-DNA antibodies represent a significant autospecificity in systemic lupus erythematosus because they are essentially diagnostic of the disease and they contribute to renal pathology. The molecular genetic characterization of these antibodies from both lupus-prone mice and humans with lupus has shown them to be somatically mutated. In many cases the nature of the mutations suggests that DNA or some structurally homologous molecule is driving the response. In other cases the high replacement-to-silent mutation ratio in framework regions of the antibody suggests selection by idiotype or by some mechanism other than antigen itself. Current studies of immunoglobulin variable region genes encoding anti-DNA antibodies reveal no disease associated polymorphisms. There are also no data suggesting that the nature of the recombination process that forms intact variable region genes or of the process of somatic mutation differs in autoimmune and nonautoimmune strains or kindred. Current data suggest, rather, that a defect in regulation is responsible for auto-antibody production in SLE. The finding that most if not all anti-double stranded DNA antibodies are somatically mutated suggests the defect is in maintenance of peripheral rather than central tolerance.
The Role of Interleukin (IL)-10 in the Persistence of <i>Leishmania major</i> in the Skin after Healing and the Therapeutic Potential of Anti–IL-10 Receptor Antibody for Sterile Cure
Authors: Yasmine Belkaid, Karl F. Hoffmann, Susana Mendez, Shaden Kamhawi, Mark C. Udey, Tom A. Wynn, David L. Sacks
Journal: The Journal of Experimental Medicine (2001)

Some pathogens (e.g., Mycobacterium tuberculosis, Toxoplasma gondii, Leishmania spp) have been shown to persist in their host after clinical cure, establishing the risk of disease reactivation. We analyzed the conditions necessary for the long term maintenance of Leishmania major in genetically resistant C57BL/6 mice after spontaneous healing of their dermal lesions. Interleukin (IL)-10 was found to play an essential role in parasite persistence as sterile cure was achieved in IL-10-deficient and IL-4/IL-10 double-deficient mice. The requirement for IL-10 in establishing latency associated with natural infection was confirmed in IL-10-deficient mice challenged by bite of infected sand flies. The host-parasite equilibrium was maintained by CD4+ and CD8+ T cells which were each able to release IL-10 or interferon (IFN)-gamma, and were found to accumulate in chronic sites of infection, including the skin and draining lymph node. A high frequency of the dermal CD4+ T cells released both IL-10 and IFN-gamma. Wild-type mice treated transiently during the chronic phase with anti-IL-10 receptor antibodies achieved sterile cure, suggesting a novel therapeutic approach to eliminate latency, infection reservoirs, and the risk of reactivation disease.
Factors Associated With Increased Survival After Photodynamic Therapy for Cholangiocarcinoma
Authors: Ganapathy A. Prasad, Kenneth K. Wang, Todd H. Baron, Navtej S. Buttar, Louis–Michel Wongkeesong, Lewis R. Roberts, Andrew J. LeRoy, Lori S. Lutzke, Lynn S. Borkenhagen
Journal: Clinical Gastroenterology and Hepatology (2007)
Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain
Authors: M.J. During, D.D. Spencer
Journal: The Lancet (1993)

An alteration in excitatory and inhibitory influences may underlie epilepsy. We used bilateral intrahippocampal microdialysis to test the hypothesis that an increase in extracellular glutamate may trigger spontaneous seizures. The concentrations of glutamate and γ-aminobutyric acid (GABA), the brain's major inhibitory neutrotransmitter, were measured in microdialysates before and during seizures in 6 patients with complex partial epilepsy investigated before surgery. Before seizures, concentrations of glutamate were higher in the epileptogenic hippocampus, whereas GABA concentrations were lower. During seizures, there was a sustained increase in extracellular glutamate to potentially neurotoxic concentrations in the epileptogenic hippocampus. Moreover, the increase preceded seizure. GABA concentrations were unchanged before seizures, but increased during them, with a greater rise in the non-epileptogenic hippocampus, suggesting that a rise in extracellular glutamate may precipitate seizures and that the concentrations reached may cause cell death.
Synergistic Activity of Sorafenib and Sulforaphane Abolishes Pancreatic Cancer Stem Cell Characteristics
Authors: Vanessa Rausch, Li Liu, Georgios Kallifatidis, Bernd Baumann, Jürgen Mattern, Jury Gladkich, Thomas Wirth, Peter Schemmer, Markus W. Büchler, Margot Zöller, Alexei V. Salnikov, Ingrid Herr
Journal: Cancer Research (2010)

Recent evidence suggests that pancreatic cancer and other solid tumors contain a subset of tumorigenic cells capable of extensive self-renewal that contribute to metastasis and treatment resistance. Sorafenib (SO) is a promising new multikinase inhibitor for treatment of advanced kidney and liver cancers. We report here targeting of pancreatic cancer stem cells (CSC) by SO and the development of a strategy to enhance this effect. Although SO administration diminished clonogenicity, spheroid formation, aldehyde dehydrogenase 1 (ALDH1) activity, growth on immunodeficient mice, proliferation, and angiogenesis and induced apoptosis, we observed SO-induced activation of NF-kappaB associated with survival and regrowth of spheroids. For enhanced elimination of CSC characteristics by SO, we cotreated cells with sulforaphane (SF). This broccoli isothiocyanate was recently described to eliminate pancreatic CSCs by downregulation of NF-kappaB activity without inducing toxic side effects. On combination treatment, SF completely eradicated SO-induced NF-kappaB binding, which was associated with abrogated clonogenicity, spheroid formation, ALDH1 activity, migratory capacity, and induction of apoptosis. In vivo, combination therapy reduced the tumor size in a synergistic manner. This was due to induction of apoptosis, inhibition of proliferation and angiogenesis, and downregulation of SO-induced expression of proteins involved in epithelial-mesenchymal transition. Our data suggest that SF may be suited to increase targeting of CSCs by SO.
FrzA/sFRP-1, a secreted antagonist of the Wnt-Frizzled pathway, controls vascular cell proliferation in vitro and in vivo
Authors: Jérome Ezan, Lionel Leroux, Laurent Barandon, Pascale Dufourcq, Béatrice Jaspard, Catherine Moreau, Cécile Allières, Danièle Daret, Thierry Couffinhal, Cécile Duplàa
Journal: Cardiovascular Research (2004)

Objective: FrzA, a member of the group of secreted frizzled related proteins (sFRP) that is expressed in the cardiovascular system, has been shown to antagonize the Wnt/frizzled signaling pathway. We have recently demonstrated its role in vascular cell growth control in vitro. In this study, we aimed to examine the mechanisms by which FrzA exerts its antiproliferative effect on vascular cells in vitro and its potential effect in vivo. Methods and results: On synchronized, growth-arrested endothelial cells (EC) and smooth muscle cells (SMC) treated with the recombinant purified FrzA protein, flow cytometry analysis showed that the recombinant FrzA protein delayed G1 phase and entry into S-phase. Western blot experiments demonstrated that the treatment of EC or SMC with FrzA was associated with a decrease in the level of the cyclins and cyclin-dependent kinases and an increase in cytosolic phospho-β-catenin levels. The FrzA-induced cell cycle delay was resolved by 24 h. C57BL/6J mice underwent surgery to produce unilateral hindlimb ischemia and empty adenoviruses (AdE) or adenoviruses coding for FrzA (AdFrzA) were injected at the time of the surgery. In AdFrzA-treated mice in the 7 days following surgery, we showed a decrease in cell proliferation, capillary density, and blood flow recovery and a reduced expression of cyclin and cdk activity in the ischemic muscle compared to that in the AdE-treated ischemic muscle. To gain insight into the pathway activated by FrzA overexpression, we showed an increase in the level of cytosolic phospho-β-catenin, a marker of β-catenin degradation, in AdFrzA-treated ischemic muscle compared to that in control AdE-treated ischemic muscle. Conclusion: We provided the first evidence that an impairment of the Wnt-Frizzled pathway, via FrzA overexpression, controlled proliferation and neovascularization after muscle ischemia.
Effect of sertraline on symptoms and survival in patients with advanced cancer, but without major depression: a placebo-controlled double-blind randomised trial
Authors: Martin R Stockler, Rachel O'Connell, Anna K Nowak, David Goldstein, Jane Turner, Nicholas RC Wilcken, David Wyld, Ehtesham A Abdi, Amanda Glasgow, Philip J Beale, Michael Jefford, Haryana Dhillon, Stephane Heritier, Candace Carter, Ian B Hickie, R John Simes
Journal: The Lancet Oncology (2007)
Intravesical Delivery of Small Activating RNA Formulated into Lipid Nanoparticles Inhibits Orthotopic Bladder Tumor Growth
Authors: Moo Rim Kang, Glen Yang, Robert F. Place, Klaus Charisse, Hila Epstein-Barash, Muthiah Manoharan, Long-Cheng Li
Journal: Cancer Research (2012)

Practical methods for enhancing protein production in vivo remain a challenge. RNA activation (RNAa) is emerging as one potential solution by using double-stranded RNA (dsRNA) to increase endogenous gene expression. This approach, although related to RNA interference (RNAi), facilitates a response opposite to gene silencing. Duplex dsP21-322 and its chemically modified variants are examples of RNAa-based drugs that inhibit cancer cell growth by inducing expression of tumor suppressor p21(WAF1/CIP1) (p21). In this study, we investigate the therapeutic potential of dsP21-322 in an orthotopic model of bladder cancer by formulating a 2'-fluoro-modified derivative (dsP21-322-2'F) into lipid nanoparticles (LNP) for intravesical delivery. LNP composition is based upon clinically relevant formulations used in RNAi-based therapies consisting of PEG-stabilized unilamellar liposomes built with lipid DLin-KC2-DMA. We confirm p21 induction, cell-cycle arrest, and apoptosis in vitro following treatment with LNP-formulated dsP21-322-2'F (LNP-dsP21-322-2'F) or one of its nonformulated variants. Both 2'-fluoro modification and LNP formulation also improve duplex stability in urine. Intravesical delivery of LNP-dsP21-322-2'F into mouse bladder results in urothelium uptake and extends survival of mice with established orthotopic human bladder cancer. LNP-dsP21-322-2'F treatment also facilitates p21 activation in vivo leading to regression/disappearance of tumors in 40% of the treated mice. Our results provide preclinical proof-of-concept for a novel method to treat bladder cancer by intravesical administration of LNP-formulated RNA duplexes.
Expression of Epidermal Growth Factor Receptors on Normal Human Gastric Epithelia and Gastric Carcinomas
Authors: K Sakai, S Mori, T Kawamoto, S Taniguchi, O Kobori, Y Morioka, T Kuroki, K Kano
Journal: JNCI Journal of the National Cancer Institute (1986)

Tissues of normal human gastric mucosae and 15 advanced gastric carcinomas were studied immunohistologically for the presence of receptors for epidermal growth factor (EGF) by use of a murine monoclonal antibody (528IgG), which reacts with the binding domain of human EGF receptor. On normal gastric mucosae, only parietal cells showed positive staining. On cancer tissues, definite staining was observed in 9 of 15 cases. Their staining intensities were variable and weaker in general compared to those of either gastric parietal cells or normal tonsilar squamous epithelium. No apparent correlation of EGF receptor staining with the grade of histologic differentiation or lymph node metastases of these gastric carcinomas was noted.
Tumour related inhibition of macrophage chemotaxis in patients with colon cancer.
Authors: A Hermanowicz, P R Gibson, D P Jewell
Journal: Gut (1987)

The chemotactic migration in vitro of peripheral blood, intestinal mucosal, and mesenteric lymph node mononuclear cells has been assessed in patients with colorectal carcinoma. Peripheral blood mononuclear cells of patients exhibited normal chemotaxis. For control patients with non-malignant, non-inflammatory intestinal disease, the chemotaxis of mucosal mononuclear cells was similar to that of autologous peripheral blood mononuclear cells. The chemotactic migration of mucosal mononuclear cells, however, isolated distant from a colon cancer was less than that of autologous peripheral blood mononuclear cells. Chemotactic migration was progressively impaired with increasing closeness to the tumour itself. Chemotaxis of mucosal mononuclear cell was independent of the site of tumour and the Dukes9 grading. Mononuclear cells from mesenteric lymph nodes, however, exhibited impaired migration only in patients with Dukes9 C tumours. Supernatants of the collagenase digestion of either tumour or adjacent mucosa contained macrophage directed inhibitors of chemotaxis and these inhibitors were not produced by tumour mononuclear cells. The presence of such inhibitors in the digestion supernatants and the demonstration that proximity to the tumour was associated with impaired mononuclear cell motility suggest that the production of macrophage directed chemotactic inhibitors is by colon cancer cells and that this may be occurring in vivo.