tbuckley/cabot-search huggingface dataset:
Hypoxia potentiates nitric oxide synthesis and transiently increases cytosolic calcium levels in pulmonary artery endothelial cells
Authors: V Hampl, DN Cornfield, NJ Cowan, SL Archer
Journal: European Respiratory Journal (1995)

There is indirect, contradictory evidence both for increased and reduced synthesis of the endothelium-derived vasodilator, nitric oxide, in the pulmonary circulation during acute hypoxia. Therefore, we decided to directly measure the effect of acute hypoxia on nitric oxide production by cultured pulmonary endothelium. Because increases in the intracellular free calcium concentration are known to initiate nitric oxide synthesis, we also studied cytosolic calcium levels. We measured the accumulation of the stable nitric oxide metabolite, nitrite, in the fluid used to superfuse the cultured bovine pulmonary artery endothelial cells at an oxygen tension (PO2) of either 20.3 (normoxia) or 4.9 kPa (hypoxia) (152 or 37 mmHg). Intracellular calcium levels were measured with dual-excitation microfluorimetry after loading the cells with the fluorescent calcium indicator, fura 2. Basal NO synthesis, measured as nitrite accumulation over 10 min, was significantly higher under hypoxic than normoxic conditions (8.3 +/- 2.2 versus 4.6 +/- 0.8 nM). Hypoxia transiently increased cytosolic calcium concentration (from 113 +/- 10 to 231 +/- 45 nM). Ryanodine and thapsigargin (which deplete intracellular calcium stores), but not the removal of extracellular calcium, inhibited the hypoxic increase in cytosolic calcium, indicating that it resulted primarily from release of intracellular calcium. Bradykinin-elicited NO synthesis was potentiated by hypoxia. Bradykinin-induced increase in cytosolic calcium was not inhibited by hypoxia. We conclude that hypoxia acutely increases cytosolic calcium levels and basal and bradykinin-stimulated nitric oxide synthesis in pulmonary artery endothelium.
The Acidic Tumor Microenvironment Promotes the Reconversion of Nitrite into Nitric Oxide: Towards a New and Safe Radiosensitizing Strategy
Authors: Françoise Frérart, Pierre Sonveaux, Géraldine Rath, Alexandra Smoos, Ahlam Meqor, Nicolas Charlier, Bénédicte F. Jordan, Julie Saliez, Agnès Noël, Chantal Dessy, Bernard Gallez, Olivier Feron
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The biological status of nitrite recently evolved from an inactive end product of nitric oxide catabolism to the largest intravascular and tissue storage of nitric oxide (NO). Although low partial O2 pressure favors enzymatic reconversion of nitrite into NO, low pH supports a nonenzymatic pathway. Because hypoxia and acidity are characteristics of the tumor microenvironment, we examined whether nitrite injection could preferentially lead to NO production in tumors and influence response to treatments. Experimental Design: The effects of nitrite were evaluated on arteriole vasorelaxation, tumor cell respiration and tumor blood flow, oxygenation, and response to radiotherapy. Results: We first showed that a small drop in pH (−0.6 pH unit) favored the production of bioactive NO from nitrite by documenting a higher cyclic guanosine 3′,5′-monophosphate–dependent arteriole vasorelaxation. We then documented that an i.v. bolus injection of nitrite to tumor-bearing mice led to a transient increase in partial O2 pressure in tumor but not in healthy tissues. Blood flow measurements failed to reveal an effect of nitrite on tumor perfusion, but we found that O2 consumption by nitrite-exposed tumor cells was decreased at acidic pH. Finally, we showed that low dose of nitrite could sensitize tumors to radiotherapy, leading to a significant growth delay and an increase in mouse survival (versus irradiation alone). Conclusions: This study identified low pH condition (encountered in many tumors) as an exquisite environment that favors tumor-selective production of NO in response to nitrite systemic injection. This work opens new perspectives for the use of nitrite as a safe and clinically applicable radiosensitizing modality.
Preference Toward a T-Helper Type 1 Response in Patients With Coronary Spastic Angina
Authors: Hirofumi Soejima, Atsushi Irie, Shinzo Miyamoto, Ichiro Kajiwara, Sunao Kojima, Jun Hokamaki, Tomohiro Sakamoto, Tomoko Tanaka, Michihiro Yoshimura, Yasuharu Nishimura, Hisao Ogawa
Journal: Circulation (2003)

Coronary artery spasm plays an important role in the pathogenesis of ischemic heart diseases such as unstable angina (UA) and acute myocardial infarction. Nitric oxide (NO) plays an important role in coronary artery spasm. We previously reported a deficiency in NO activity in the spasm arteries of patients with coronary spastic angina (CSA). Others have reported that NO influences the immune response. Therefore, we investigated the balance between T-helper type 1 (Th1) and 2 (Th2) responses in patients with CSA by evaluating the frequencies of interferon (IFN)-gamma-producing T cells and interleukin (IL)-4-producing T cells in the peripheral blood of such patients.Peripheral blood mononuclear cells were collected from 50 consecutive patients with CSA, 23 consecutive patients with UA, 36 patients with stable angina (SA), and 21 patients with chest pain syndrome (CPS). Cytokine-producing CD4+ T cells were quantified by 3-color flow cytometry after stimulation with phorbol myristate acetate and ionomycin. UA and CSA were associated with a significant increase in the frequency of CD4+ T cells that produced IFN-gamma, whereas these conditions caused no significant difference in the frequency of CD4+ T cells that produced IL-4. Culturing with an NO donor compound for 24 hours before stimulation inhibited the increase in the frequency of CD4+ T cells that produced IFN-gamma.We demonstrated that there was a preference toward the Th1-type response in patients with CSA and that T cells showed a reduced Th1-type response after being treated with NO.
L1 (LINE-1) retrotransposable elements provide a "fossil" record of the phylogenetic history of murid rodents.
Authors: K. Usdin, P. Chevret, F. M. Catzeflis, R. Verona, A. V. Furano
Journal: Molecular Biology and Evolution (1995)

The single most difficult problem in phylogenetic analysis is deciding whether a shared taxonomic character is due to common ancestry or one that appeared independently due to convergence, parallelism, or reversion to an ancestral state. Mammalian L1 retrotransposons undergo periodic amplifications in which multiple copies of the elements are interspersed in the genome. Because these elements apparently are transmitted only by inheritance and are retained in the genome, a shared L1 amplification event can only be an inherited ancestral character. We propose that L1 amplification events can be an excellent tool for analyzing mammalian evolution and demonstrate here how we addressed several refractory problems in rodent systematics using L1 DNA as a taxonomic character.
Sunitinib: From Rational Design to Clinical Efficacy
Authors: Laura Q.M. Chow, S. Gail Eckhardt
Journal: Journal of Clinical Oncology (2007)

Sunitinib (SU011248) is an oral small molecular tyrosine kinase inhibitor that exhibits potent antiangiogenic and antitumor activity. Tyrosine kinase inhibitors such as SU6668 and SU5416 (semaxanib) demonstrated poor pharmacologic properties and limited efficacy; therefore, sunitinib was rationally designed and chosen for its high bioavailability and its nanomolar-range potency against the antiangiogenic receptor tyrosine kinases (RTKs)—vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). Sunitinib inhibits other tyrosine kinases including, KIT, FLT3, colony-stimulating factor 1 (CSF-1), and RET, which are involved in a number of malignancies including small-cell lung cancer, GI stromal tumors (GISTs), breast cancer, acute myelogenous leukemia, multiple endocrine neoplasia types 2A and 2B, and familial medullary thyroid carcinoma. Sunitinib demonstrated robust antitumor activity in preclinical studies resulting not only in tumor growth inhibition, but tumor regression in models of colon cancer, non–small-cell lung cancer, melanoma, renal carcinoma, and squamous cell carcinoma, which were associated with inhibition of VEGFR and PDGFR phosphorylation. Clinical activity was demonstrated in neuroendocrine, colon, and breast cancers in phase II studies, whereas definitive efficacy has been demonstrated in advanced renal cell carcinoma and in imatinib-refractory GISTs, leading to US Food and Drug Administration approval of sunitinib for treatment of these two diseases. Studies investigating sunitinib alone in various tumor types and in combination with chemotherapy are ongoing. The clinical benchmarking of this small-molecule inhibitor of members of the split-kinase domain family of RTKs will lead to additional insights regarding the biology, potential biomarkers, and clinical utility of agents that target multiple signaling pathways in tumor, stromal, and endothelial compartments.
Diagnosis of tuberculosis in patients with psoriasis: the need for a modified approach
Authors: I. D. Bassukas, G. Gaitanis, S. H. Constantopoulos
Journal: European Respiratory Journal (2011)

To the Editors:

We read with interest the TBNET consensus statement on the diagnosis and treatment of tuberculosis (TB) in patients screened for tumour necrosis factor (TNF)-α antagonist therapy [1]. Admittedly, accumulated evidence during the last decade demonstrates that adherence to such guidelines has minimised the risk of TB reactivation in patients receiving immunosuppressive regimens, including anti-TNF-α therapy. For TNF-α antagonists specifically, targeted preventive chemotherapy prior to the onset of therapy has significantly reduced the risk of progression of latent TB infection (LTBI) to overt disease, yet at the cost of increased risk for significant treatment-associated toxicity. Thus, in an effort to avoid possible over-treatment prior to treatment with TNF-α antagonists and to accurately identify patients who would benefit from anti-TB treatment, patient cohorts inherently predisposed to overdiagnosis of LTBI should be identified. In the TBNET consensus statement, the author panel concludes: “Screening for latent infection and preventive chemotherapy against TB should not be different for patients with different underlying disease […] who are candidates for …
Phase III, Placebo-Controlled Trial of Three Doses of Citalopram for the Treatment of Hot Flashes: NCCTG Trial N05C9
Authors: Debra L. Barton, Beth I. LaVasseur, Jeff A. Sloan, Allen N. Stawis, Kathleen A. Flynn, Missy Dyar, David B. Johnson, Pamela J. Atherton, Brent Diekmann, Charles L. Loprinzi
Journal: Journal of Clinical Oncology (2010)

Purpose Up to 75% of women experience hot flashes, which can negatively impact quality of life. As hot flash physiology is not definitively understood, it cannot be assumed that effective agents represent class effects. Therefore, there is a continued need for rigorous evaluation to identify effective nonhormonal options for hot flash relief. Methods A randomized, double-blind trial evaluated citalopram at target doses of 10, 20, or 30 mg/d versus placebo for 6 weeks. Postmenopausal women with at least 14 bothersome hot flashes per week recorded hot flashes for 7 days before starting treatment and were then titrated to their target doses. The primary end point was the change from baseline to 6 weeks in hot flash score. Results Two hundred fifty-four women were randomly assigned onto this study. Data for hot flash scores and frequencies showed significant improvement in hot flashes with citalopram over placebo, with no significant differences among doses. Reductions in mean hot flash scores were 2.0 (23%), 7.0 (49%), 7.7 (50%), and 10.7 (55%) for placebo and 10, 20, and 30 mg of citalopram, respectively (P ≤ .002). Improvement in secondary outcomes, such as the Hot Flash Related Daily Interference Scale, was statistically superior in the 20-mg arm. Citalopram was well-tolerated, with no significant negative adverse effects. Conclusion Citalopram is an effective, well-tolerated agent in managing hot flashes. There does not appear to be a significant dose response above 10 mg/d, but broader helpful effects of the agent appear to be more evident at 20 mg/d.
Allelic polymorphism in the T cell receptor and its impact on immune responses
Authors: Stephanie Gras, Zhenjun Chen, John J. Miles, Yu Chih Liu, Melissa J. Bell, Lucy C. Sullivan, Lars Kjer-Nielsen, Rebekah M. Brennan, Jacqueline M. Burrows, Michelle A. Neller, Rajiv Khanna, Anthony W. Purcell, Andrew G. Brooks, James McCluskey, Jamie Rossjohn, Scott R. Burrows
Journal: The Journal of Experimental Medicine (2010)

In comparison to human leukocyte antigen (HLA) polymorphism, the impact of allelic sequence variation within T cell receptor (TCR) loci is much less understood. Particular TCR loci have been associated with autoimmunity, but the molecular basis for this phenomenon is undefined. We examined the T cell response to an HLA-B*3501–restricted epitope (HPVGEADYFEY) from Epstein-Barr virus (EBV), which is frequently dominated by a TRBV9*01+ public TCR (TK3). However, the common allelic variant TRBV9*02, which differs by a single amino acid near the CDR2β loop (Gln55→His55), was never used in this response. The structure of the TK3 TCR, its allelic variant, and a nonnaturally occurring mutant (Gln55→Ala55) in complex with HLA-B*3501HPVGEADYFEY revealed that the Gln55→His55 polymorphism affected the charge complementarity at the TCR–peptide-MHC interface, resulting in reduced functional recognition of the cognate and naturally occurring variants of this EBV peptide. Thus, polymorphism in the TCR loci may contribute toward variability in immune responses and the outcome of infection.
Commentary on "Feasibility of a walking workstation to increase daily walking"
Authors: P Cejudo
Journal: British Journal of Sports Medicine (2008)

workstations with systems to remind participants to walk after they have been sitting for a while may increase use.In summary, we have demonstrated that it is feasible to place the walking workstation in the workplace and that participants will use them.Future research is needed to evaluate the workstation's effect on employee productivity, well-being, health and weight loss.
Sarcoma of the Stomach: A Correction
Authors: A. C. Wilson
Journal: BMJ (1901)

IL-12 family cytokines are implicated in the pathogenesis of various autoimmune diseases, but their role in the regulation of extracellular matrix expression and its contribution to the phenotype of systemic sclerosis (SSc) remain to be elucidated. Among the IL-12 family members, IL-35 decreases type I collagen expression in cultured dermal fibroblasts. IL-35 consists of p35 and EBI3 subunits, and EBI3 alone could downregulate the protein and mRNA expression of type I or type III collagen in the presence or absence of TGF-β costimulation. We found that collagen mRNA stability was reduced by EBI3 via the induction of miR-4500. The IL-35 levels in the sera or on the surface of T cells were not altered in SSc patients, while EBI3 expression was decreased in the keratinocytes of the epidermis and regulatory T cells of the dermis in SSc skin compared with normal skin, which may induce collagen synthesis in SSc dermal fibroblasts. We also found that gp130, the EBI3 receptor, was expressed in both normal and SSc fibroblasts. Moreover, we revealed that EBI3 supplementation by injection into the skin improves mice skin fibrosis. Decreased EBI3 in SSc skin may contribute to an increase in collagen accumulation and skin fibrosis. Clarifying the mechanism regulating the extracellular matrix expression by EBI3 in SSc skin may lead to better understanding of this disease and new therapeutic strategies using ointment or microinjection of the subunit.
Use of Emergency Medical Services in Acute Myocardial Infarction and Subsequent Quality of Care
Authors: John G. Canto, Robert J. Zalenski, Joseph P. Ornato, William J. Rogers, Catarina I. Kiefe, David Magid, Michael G. Shlipak, Paul D. Frederick, Costas G. Lambrew, Katherine A. Littrell, Hal V. Barron
Journal: Circulation (2002)

Background— National practice guidelines strongly recommend activation of the 9-1-1 Emergency Medical Systems (EMS) by patients with symptoms consistent with an acute myocardial infarction (MI). We examined use of the EMS in the United States and ascertained the factors that may influence its use by patients with acute MI. Methods and Results— From June 1994 to March 1998, the National Registry of Myocardial Infarction 2 enrolled 772 586 patients hospitalized with MI. We excluded those who transferred in, arrived at the hospital &gt;6 hours from symptom onset, or who were in cardiogenic shock. We compared baseline characteristics and initial management for patients who arrived by ambulance versus self-transport. EMS was used in 53.4% of patients with MI, a proportion that did not vary significantly over the 4-year study period. Nonusers of the EMS were on average younger, male, and at relatively lower risk on presentation. In addition, payer status was significantly associated with EMS use. Use of EMS was independently associated with slightly wider use of acute reperfusion therapies and faster time intervals from door to fibrinolytic therapy (12.1 minutes faster, P &lt;0.001) or to urgent PTCA (31.2 minutes faster, P &lt;0.001). Conclusions— Only half of patients with MI were transported to the hospital by ambulance, and these patients had greater and significantly faster receipt of initial reperfusion therapies. Wider use of EMS by patients with suspected MI may offer considerable opportunity for improvement in public health.
Venezuelan haemorrhagic fever
Authors: R. Salas, M.E. Pacheco, B. Ramos, M.E. Taibo, E. Jaimes, C. Vasquez, J. Querales, N. de Manzione, O. Godoy, A. Betancourt, F. Araoz, R. Bruzual, J. Garcia, R.B. Tesh, R. Rico-Hesse, R.E. Shops
Journal: The Lancet (1991)

An outbreak of severe haemorrhagic illness began in the municipality of Guanarito, Portuguesa State, Venezuela, in September, 1989. Subsequent detailed study of 15 cases confirmed the presence of a new viral disease, designated Venezuelan haemorrhagic fever. Characteristic features are fever, toxicity, headache, arthralgia, diarrhoea, conjunctivitis, pharyngitis, leucopenia, thrombocytopenia, and haemorrhagic manifestations. Other features include facial oedema, cervical lymphadenopathy, nausea/vomiting, cough, chest or abdominal pain, and convulsions. The patients ranged in age from 6 to 54 years; all were residents of rural areas in central Venezuela, and 9 died. Infection with Guanarito virus, a newly recognised arenavirus, was shown by direct culture or by serological confirmation in all cases. Epidemiological studies suggest that the disease is endemic in some rural areas of central Venezuela and that it is rodent-borne. Venezuelan haemorrhagic fever has many similarities to Lassa fever and to the arenavirus haemorrhagic fevers that occur in Argentina and Bolivia.
Prostaglandin EP2 receptor signalling inhibits the expression of matrix metalloproteinase 13 in human osteoarthritic chondrocytes
Authors: T. Sato, K. Konomi, R. Fujii, H. Aono, S. Aratani, N. Yagishita, N. Araya, K. Yudoh, M. Beppu, Y. Yamano, K. Nishioka, T. Nakajima
Journal: Annals of the Rheumatic Diseases (2010)

Matrix metalloproteinase (MMP) 13 is a pathogenic collagenase that causes cartilage destruction and plays a leading role in causing osteoarthritis. This study focused on 114 genes that are differentially expressed between intact and damaged osteoarthritis cartilage, in order to determine which molecules are involved in suppressing MMP-13 expression.MMP-13 concentrations were measured in the supernatant of human osteoarthritis chondrocyte cultures transfected with small interfering RNA (siRNA) against the 114 genes. MMP-13 levels changed most dramatically in response to siRNA against prostaglandin EP2 receptor. The authors performed further measurements of MMP-13 production in osteoarthritis chondrocytes stimulated by the EP2 agonist butaprost in the presence or absence of interleukin-1β (IL-1β) and/or cyclooxygenase-2 (COX-2) inhibitor. They also assessed the effect of butaprost on chondrocyte viability, and investigated the involvement of the cAMP-protein kinase A (PKA) pathway on EP2 signalling using inhibitors. Cartilage-related gene expression was examined in chondrocytes treated with butaprost. The authors also investigated which E series of prostaglandin (EP) receptors are expressed in osteoarthritis cartilage.MMP-13 messenger RNA expression was significantly affected by two molecules, EP2 receptor and SLC14A1, a urea transporter. In IL-1β-treated osteoarthritis chondrocytes, butaprost suppressed MMP-13 production, which was further decreased by COX-2 inhibitor. EP2 signalling downregulated MMP-13 mRNA expression via the cAMP-PKA pathway without affecting cell viability. Although EP2 signalling enhanced IL-6 expression, the expressions of several catabolic factors (MMP-1, MMP-3, MMP-13, ADAMTS5, IL-1β and tumour necrosis factor alpha) were inhibited. EP2 receptor was the major EP receptor in osteoarthritis cartilage.The results suggest that EP2 signalling has 'anti-catabolic' effects in osteoarthritis chondrocytes.
Functional Ephrin-B2 Expression for Promotive Interaction Between Arterial and Venous Vessels in Postnatal Neovascularization
Authors: Shin-ichiro Hayashi, Takayuki Asahara, Haruchika Masuda, Jeffrey M. Isner, Douglas W. Losordo
Journal: Circulation (2005)

Ephrin-B2, one of the transmembrane ligands, is a genetic marker of arterial endothelial cells (ECs) at embryonic stages and is essential for cardiovascular development, but its roles in ischemic cardiovascular disease are not well understood. In this study, we focused on the function of ephrin-B2 in postnatal neovascularization.We found that ephrin-B2 is exclusively expressed and significantly upregulated in the arterial vasculature after the initial angiogenic responses in tissue ischemia. Upregulation of ephrin-B2 is also observed in EC cordlike formation in vitro. Interestingly, ephrin-B2 expression on ECs was enhanced by promotive angiogenic growth factors, such as vascular endothelial growth factor, basic fibroblast growth factor, and hepatocyte growth factor, whereas it was attenuated by angiopoietin-1, a factor for blood vessel maturation. Moreover, an ephrin-B2-rich environment was shown to induce neovascularization mainly through venous angiogenesis in an in vivo cornea micropocket assay.Our study indicates that the ephrin-B2 ligand is likely to have functional expression on angiogenic arterial ECs and induce a subsequent promotive effect on venous vessels during postnatal neovascularization.
Acute Stress Disorder and Posttraumatic Stress Disorder in Children and Adolescents Involved in Assaults or Motor Vehicle Accidents
Authors: Richard Meiser-Stedman, William Yule, Patrick Smith, Ed Glucksman, Tim Dalgleish
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: The authors investigated acute stress disorder and later posttraumatic stress disorder (PTSD) in children and adolescents who had been involved in assaults or motor vehicle accidents. METHOD: They interviewed 93 patients 10–16 years old who were seen in an emergency department for having been assaulted or involved in a motor vehicle accident within 4 weeks after the assault or accident to assess acute stress disorder. At 6 months, they reinterviewed 64 (68.8%) of the patients to assess PTSD. RESULTS: At initial interview, 18 (19.4%) of the 93 patients had acute stress disorder and 23 (24.7%) met all acute stress disorder criteria except dissociation. At 6 months, eight of the 64 patients (12.5%) had PTSD. Acute stress disorder and PTSD did not differ in prevalence between patients who had been assaulted and those who had been in accidents. Sensitivity and specificity statistics and regression modeling revealed that the diagnosis of acute stress disorder was a good predictor of later PTSD but that dissociation did not play a significant role. CONCLUSIONS: Acute stress disorder has merit as a predictor of later PTSD in children and adolescents, but dissociation has questionable utility.