tbuckley/cabot-search huggingface dataset:
Investigational Analysis Reveals a Potential Role for Neutrophils in Giant-Cell Arteritis Disease Progression
Authors: Suchita Nadkarni, Jesmond Dalli, Jane Hollywood, Justin C. Mason, Bhaskar Dasgupta, Mauro Perretti
Journal: Circulation Research (2013)

Giant-cell arteritis (GCA) is a large-vessel vasculitis characterized by immune cell infiltration, yet the potential involvement of neutrophils has rarely been studied.We investigated whether alterations in neutrophil reactivity occurred in the pathogenesis of GCA or during its clinical management with a canonical glucocorticoid dose regimen during a 6-month period.Blood samples were taken within 48 hours of therapy commencement and at weeks 1, 4, and 24 after glucocorticoid dose. Flow cytometric analysis revealed 3 distinct neutrophil populations and phenotypes. Within 48 hours of steroid treatment, neutrophils displayed an AnxA1(hi)CD62L(lo)CD11b(hi) phenotype, whereas week 1 neutrophils were AnxA1(hi)CD62L(lo)CD11b(lo) and displayed minimal adhesion to endothelial monolayers under flow, and week 24 (i.e., lowest glucocorticoid dose) neutrophils were AnxA1(hi)CD62L(hi)CD11b(hi) with increased endothelial adhesion under flow. Week 24 plasma analyses showed high levels of C-X-C motif chemokine ligand 5, interleukin (IL) 8, IL-17, and IL-6. Importantly, comparison of week 1 and week 24 samples revealed a suppressive neutrophil effect on T-cell proliferation at the former time point only. Finally, in vitro incubation of naive neutrophils with concentrations of IL-6 and IL-17 quantified in GCA plasma at weeks 1 and 24 replicated this differential modulation of lymphocyte proliferation.This translational study highlights a novel clinical manifestation of GCA, with evidence for a neutrophil component and an escaped proinflammatory phenotype when glucocorticoid therapy is tapered. These results indicate potential involvement of neutrophils in GCA pathogenesis.
Nitric oxide in breast cancer: induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis.
Authors: Yasushi Nakamura, Hironao Yasuoka, Masahiko Tsujimoto, Katsuhide Yoshidome, Masaaki Nakahara, Kazuyasu Nakao, Misa Nakamura, Kennichi Kakudo
Journal: Clinical Cancer Research (2006)

Metastasis to regional lymph nodes through the lymphatic vessels is a common step in the progression of cancer. Recent evidence suggests that tumor production of vascular endothelial growth factor-C (VEGF-C) promotes lymphagiogenesis, which in turn promotes lymphatic metastasis. Nitric oxide (NO) may also increase metastatic ability in human cancers.Nitrite/nitrate levels and VEGF-C production were assessed in MDA-MB-231 breast cancer cells after induction and/or inhibition of NO synthesis. Formation of nitrotyrosine, a biomarker for peroxynitrate formation from NO in vivo, was analyzed in primary human breast carcinoma with long-term follow-up. The relationship between nitrotyrosine levels and lymph node status, VEGF-C immunoreactivity, and other established clinicopathologic variables, as well as prognosis, was analyzed.Production of nitrite/nitrate and VEGF-C in MDA-MB-231 cells was increased by treatment with the NO donor DETA NONOate. The NO synthase inhibitor N(G)-nitro-l-arginine methyl ester eliminated this increase. High-grade nitrotyrosine staining was observed in 57.5% (65 of 113) of the invasive breast carcinomas. Nitrotyrosine levels were significantly correlated with VEGF-C immunoreactivity and lymph node metastasis. Survival curves determined by the Kaplan-Meier method showed that high nitrotyrosine levels were associated with reduced disease-free and overall survival. In multivariate analysis, high nitrotyrosine levels emerged as a significant independent predictor for overall survival.Our data showed a role for NO in stimulating VEGF-C expression in vitro. Formation of its biomarker nitrotyrosine was also correlated with VEGF-C expression and lymph node metastasis. Furthermore, high nitrotyrosine levels may serve as a significant prognostic factor for long-term survival in breast cancer.
Erythrocytes in sickle cell anemia are heterogeneous in their rheological and hemodynamic characteristics.
Authors: D K Kaul, M E Fabry, P Windisch, S Baez, R L Nagel
Journal: Journal of Clinical Investigation (1983)

To understand the contribution to the pathophysiology of sickle cell anemia of the different erythrocyte density types present in the blood of these patients, we have studied the viscosimetric and hemodynamic characteristics of four major classes of hemoglobin SS erythrocytes. We have isolated reticulocytes, discocytes, dense discocytes, and irreversibly sickled cells (fractions I-IV) on Percoll-Renografin density gradients. Bulk viscosity was studied in a coneplate viscosimeter and the hemodynamic studies were performed on the isolated, artificially perfused mesoappendix vasculature of the rat (Baez preparation). Bulk viscosity measurements at shear rates of 230 S-1 demonstrate that when the cells are oxygenated, fraction I (reticulocyte rich) has a higher viscosity than expected from its low intracellular hemoglobin concentration. The rest of the fractions exhibit moderate increases in bulk viscosity pari-passu with the corresponding increases in density (mean corpuscular hemoglobin concentration). When deoxygenated, all cell fractions nearly doubled their bulk viscosity and the deoxy-oxy differences remained constant. The Baez preparation renders a different picture: oxygenated fractions behave as predicted by the viscosimetric data, but, when deoxygenated, cell fractions exhibit dramatically increased peripheral resistance and the deoxy-oxy difference are directly proportional to cell density, thus, the largest increases were observed for fractions III and IV. The differences between the rheological and the hemodynamic measurements are most probably due to the different sensitivity of the two methods to the extent of intracellular polymerization. These results also demonstrate that the hitherto unrecognized fraction III cells (very dense discocytes that change shape very little on deoxygenation) are as detrimental to the microcirculation as the irreversibly sickled cell-rich fraction IV. They may, however, induce obstruction by a different mechanism. As the extent to which these fractions are populated by erythrocytes varies considerably from patient to patient, the distribution function of cell densities in each sickle cell anemia patient might have consequences for the type of pathophysiological events occurring in their microcirculation.
Myocardial infarction in sickle cell anemia
Authors: O'Neill Barrett, Donald E. Saunders, Dee E. McFarland, J. O'Neal Humphries
Journal: American Journal of Hematology (1984)

Abstract A review of the electrocardiograms (ECG) of 108 patients with sickle cell anemia found only 3 with patterns consistent with myocardial infarction. Two of the 3 patients with ECG infarct patterns had postmortem examination confirmation of the infarction. These two patients had no significant coronary atherosclerosis nor did the other six autopsied patients in the present series. Literature reports of postmortem examinations on patients with sickle cell anemia confirm the scarcity of coronary atherosclerosis and myocardial infarction in these patients. Forty of the 108 ECGs showed signs of left ventricular hypertrophy and 20 others had nondiagnostic ST and T wave abnormalities. Nine showed first degree AV block and four right bundle branch block.
Real-Time Video Imaging of Protease Expression In Vivo
Authors: Lei Zhu, Jin Xie, Magdalena Swierczewska, Fan Zhang, Qimeng Quan, Ying Ma, Xuexun Fang, Kwangmeyung Kim, Seulki Lee, Xiaoyuan Chen
Journal: Theranostics (2011)

We demonstrate the first true real-time in vivo video imaging of extracellular protease expression using an ultrafast-acting and extended-use activatable probe.This simple, one-step technique is capable of boosting fluorescent signals upon target protease cleavage as early as 30 minutes from injection in a small animal model and is able to sustain the strong fluorescent signal up to 24 hours.Using this method, we video imaged the expression and inhibition of matrix metalloproteinases (MMPs) in a tumor-bearing mouse model.The current platform can be universally applied to any target protease of interest with a known peptide substrate and is adaptable to a wide range of real-time imaging applications with high throughputs such as for in vivo drug screening, examinations of the therapeutic efficacy of drugs, and monitoring of disease onset and development in animal models.
Effect of smoking on duodenal ulcer healing with cimetidine and oxmetidine.
Authors: R Gugler, H G Rohner, P Kratochvil, G Brandstatter, H Schmitz
Journal: Gut (1982)

The effect of oxmetidine 800 mg/day, a new histamine H2-receptor antagonist, on duodenal ulcer healing was compared with cimetidine 1000 mg/day in a two-centre double-blind trial. Ninety-nine patients completed the study. After four weeks, ulcers were healed in 74% of the cimetidine-treated patients and in 78% of the oxmetidine-treated patients (p greater than 0.05). Healing rates after eight weeks increased to 90% in the cimetidine group and to 94% in the oxmetidine group. Healing rates after four weeks were, however, different in the two centres (p less than 0.01): in centre 1 88% of the cimetidine-treated, but 63% of the oxmetidine-treated patients healed, in centre 2 rates were 60% (cimetidine) and 92% (oxmetidine). Analysis of patient data revealed that in the two centres treatment success was inversely correlated (p less than 0.01) with the percentage of smokers in each treatment group. Smoking significantly influences duodenal ulcer healing with histamine H2-receptor antagonists.
Let's not forget: the GOLD criteria for COPD are based on post-bronchodilator FEV1
Authors: P.J. Sterk
Journal: European Respiratory Journal (2004)

One of the major steps forward in the field of chronic obstructive pulmonary disease (COPD) has been the recent global consensus on the definition, classification and management of the disease. This so-called “GOLD” guideline is based on international consensus meetings held since 1998, which have resulted in detailed recommendations, as published in 2001 1 and updated in 2003 2. The impact of such consensus cannot easily be overestimated. Not only is it a landmark with regard to providing reliable and up-to-date knowledge about this disease, but it also enables worldwide harmonisation of epidemiological, clinical and experimental research studies in patients with COPD. The latter is essential for the smooth comparison of results and, therefore, for further advances in the field.

COPD is a heterogeneous disease with various clinical presentations. The basic abnormality in all patients with COPD is airflow limitation that is not fully reversible. Therefore, the GOLD experts have defined the disease based on spirometric criteria by using the forced expiratory volume in one second (FEV1) and its ratio to the forced vital capacity (FVC). The main criterion for COPD is a FEV1/FVC ratio <70%. Subclassification into mild, moderate, severe and very severe disease is achieved by including various levels of FEV1 as percentage of …
Involvement of Urokinase‐Type Plasminogen Activator System in Cancer: An Overview
Authors: Ahmed H. Mekkawy, Mohammad H. Pourgholami, David L. Morris
Journal: Medicinal Research Reviews (2014)

Abstract Currently, there are several studies supporting the role of urokinase‐type plasminogen activator (uPA) system in cancer. The association of uPA to its receptor triggers the conversion of plasminogen into plasmin. This process is regulated by the uPA inhibitors (PAI‐1 and PAI‐2). Plasmin promotes degradation of basement membrane and extracellular matrix (ECM) components as well as activation of ECM latent matrix metalloproteases. Degradation and remodeling of the surrounding tissues is crucial in the early steps of tumor progression by facilitating expansion of the tumor mass, release of tumor growth factors, activation of cytokines as well as induction of tumor cell proliferation, migration, and invasion. Hence, many tumors showed a correlation between uPA system component levels and tumor aggressiveness and survival. Therefore, this review summarizes the structure of the uPA system, its contribution to cancer progression, and the clinical relevance of uPA family members in cancer diagnosis. In addition, the review evaluates the significance of uPA system in the development of cancer‐targeted therapies.
Formylpeptide receptor-2 contributes to colonic epithelial homeostasis, inflammation, and tumorigenesis
Authors: Keqiang Chen, Mingyong Liu, Ying Liu, Teizo Yoshimura, Wei Shen, Yingying Le, Scott Durum, Wanghua Gong, Chunyan Wang, Ji-Liang Gao, Philip M. Murphy, Ji Ming Wang
Journal: Journal of Clinical Investigation (2013)

Commensal bacteria and their products provide beneficial effects to the mammalian gut by stimulating epithelial cell turnover and enhancing wound healing, without activating overt inflammation. We hypothesized that N-formylpeptide receptors, which bind bacterial N-formylpeptides and are expressed by intestinal epithelial cells, may contribute to these processes. Here we report that formylpeptide receptor-2 (FPR2), which we show is expressed on the apical and lateral membranes of colonic crypt epithelial cells, mediates N-formylpeptide–dependent epithelial cell proliferation and renewal. Colonic epithelial cells in FPR2-deficient mice displayed defects in commensal bacterium–dependent homeostasis as shown by the absence of responses to N-formylpeptide stimulation, shortened colonic crypts, reduced acute inflammatory responses to dextran sulfate sodium (DSS) challenge, delayed mucosal restoration after injury, and increased azoxymethane-induced tumorigenesis. These results indicate that FPR2 is critical in mediating homeostasis, inflammation, and epithelial repair processes in the colon.
Increased lung neutrophil apoptosis and inflammation resolution in nonresponding pneumonia
Authors: I. Moret, M.J. Lorenzo, B. Sarria, E. Cases, E. Morcillo, M. Perpiñá, J.M. Molina, R. Menéndez
Journal: European Respiratory Journal (2011)

Neutrophil activation state and its relationship with an inflammatory environment in community-acquired pneumonia (CAP) remain insufficiently elucidated. We aimed to evaluate the neutrophil apoptosis and cytokine pattern in CAP patients after 72 h of treatment, and their impact on infection resolution. Apoptosis of blood and bronchoalveolar lavage (BAL) neutrophils was measured in nonresponding CAP (NCAP), in responding CAP (blood only) and in patients without infection (control). Pro-inflammatory (interleukin (IL)-6, IL-8) and anti-inflammatory (IL-10) cytokines were measured. Main outcomes were clinical stability and days of hospitalisation. Basal neutrophil apoptosis was higher in the BAL and blood of NCAP, whereas spontaneous apoptosis (after 24 h culture) was lower. Cytokines in NCAP were higher than in responding CAP and control: IL-6 was increased in BAL and blood, IL-8 in BAL and IL-10 in blood. An increased basal apoptosis (≥20%) in BAL of NCAP was associated with lower systemic IL-10 (p&lt;0.01), earlier clinical stability (p=0.05) and shorter hospital stay (p=0.02). A significant correlation was found for systemic IL-6 and IL-10 with days to reach stability and length of stay. After 72 h of treatment, an increased basal alveolar neutrophil apoptosis might contribute to downregulation of inflammation and to faster clinical stability.
Microvascular Integrity and the Time Course of Myocardial Sodium Accumulation After Acute Infarction
Authors: Carlos E. Rochitte, Raymond J. Kim, Hanns B. Hillenbrand, Enn-ling Chen, João A. C. Lima
Journal: Circulation Research (2000)

Abstract —Loss of membrane permeability caused by ischemia leads to cellular sodium accumulation and myocardial edema. This phenomenon has important implications to left ventricular structure and function in the first hours after myocardial infarction. We hypothesized that during this period of time, after prolonged coronary occlusion and complete reflow, the rate of myocardial sodium accumulation is governed by microvascular integrity. We used 3-dimensional 23 Na MRI to monitor myocardial sodium content changes over time in an in vivo closed-chest canine model (n=13) of myocardial infarction and reperfusion. Infarcts with microvascular obstruction (MO) defined by both radioactive microspheres and contrast-enhanced 1 H MRI showed a slower rate of sodium accumulation as well as lower blood flow at 20 minutes and 6 hours after reperfusion. Conversely, the absence of MO was associated with faster rates of sodium accumulation and greater blood flow restoration. In addition, infarct size by 23 Na MRI correlated best with infarct size by triphenyltetrazolium chloride and contrast-enhanced 1 H MRI at 9 hours after reperfusion. We conclude that in reperfused myocardial infarction, sodium accumulation is dependent on microvascular integrity and is slower in regions of MO compared with those with patent microvasculature. Finally, 23 Na MRI can be a useful tool for monitoring in vivo myocardial sodium content in acute myocardial infarction.
C<scp>ELL</scp>B<scp>IOLOGY OF THE</scp>P<scp>RESYNAPTIC</scp>T<scp>ERMINAL</scp>
Authors: Venkatesh N. Murthy, Pietro De Camilli
Journal: Annual Review of Neuroscience (2003)

The chemical synapse is a specialized intercellular junction that operates nearly autonomously to allow rapid, specific, and local communication between neurons. Focusing our attention on the presynaptic terminal, we review the current understanding of how synaptic morphology is maintained and then the mechanisms in synaptic vesicle exocytosis and recycling.
Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial): a multicentre, randomised, placebo-controlled trial
Authors: Chinedu Nwokoro, Hitesh Pandya, Stephen Turner, Sandra Eldridge, Christopher J Griffiths, Tom Vulliamy, David Price, Marek Sanak, John W Holloway, Rossa Brugha, Lee Koh, Iain Dickson, Clare Rutterford, Jonathan Grigg
Journal: The Lancet Respiratory Medicine (2014)

The effectiveness of intermittent montelukast for wheeze in young children is unclear. We aimed to assess whether intermittent montelukast is better than placebo for treatment of wheeze in this age group. Because copy numbers of the Sp1-binding motif in the arachidonate 5-lipoxygenase (ALOX5) gene promoter (either 5/5, 5/x, or x/x, where x does not equal 5) modifies response to montelukast in adults, we stratified by this genotype.We did this multicentre, parallel-group, randomised, placebo-controlled trial between Oct 1, 2010, and Dec 20, 2013, at 21 primary care sites and 41 secondary care sites in England and Scotland. Children aged 10 months to 5 years with two or more wheeze episodes were allocated to either a 5/5 or 5/x+x/x ALOX5 promoter genotype stratum, then randomly assigned (1:1) via a permuted block schedule (size ten), to receive intermittent montelukast or placebo given by parents at each wheeze episode over a 12 month period. Clinical investigators and parents were masked to treatment group and genotype strata. The primary outcome was number of unscheduled medical attendances for wheezing episodes. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01142505.We randomly assigned 1358 children to receive montelukast (n=669) or placebo (n=677). Consent was withdrawn for 12 (1%) children. Primary outcome data were available for 1308 (96%) children. There was no difference in unscheduled medical attendances for wheezing episodes between children in the montelukast and placebo groups (mean 2·0 [SD 2·6] vs 2·3 [2·7]; incidence rate ratio [IRR] 0·88, 95% CI: 0·77-1·01; p=0·06). Compared with placebo, unscheduled medical attendances for wheezing episodes were reduced in children given montelukast in the 5/5 stratum (2·0 [2·7] vs 2·4 [3·0]; IRR 0·80, 95% CI 0·68-0·95; p=0·01), but not in those in the 5/x+x/x stratum (2·0 [2·5] vs 2·0 [2·3]; 1·03, 0·83-1·29; p=0·79, pinteraction=0·08). We recorded one serious adverse event, which was a skin reaction in a child allocated to placebo.Our findings show no clear benefit of intermittent montelukast in young children with wheeze. However, the 5/5 ALOX5 promoter genotype might identify a montelukast-responsive subgroup.Medical Research Council (UK) and National Institute for Health Research.
Effects of antiplatelet agents on pulmonary haemodynamic response to fMLP in endotoxin primed rats
Authors: C Song
Journal: Thorax (2003)

<b>Background:</b> The interaction between neutrophils and platelets may be important in the modulation of pulmonary haemodynamics under systemic inflammatory conditions. A study was undertaken to examine whether antiplatelet agents inhibit platelet-neutrophil adherence and ameliorate the pulmonary haemodynamic response to fMLP by inhibiting thromboxane release in endotoxin primed lungs. fMLP stimulates neutrophils but not platelets; however, thromboxane synthesis in neutrophils is very low. <b>Methods:</b> Rats were pretreated with either cilostazol (300 mg/kg) or aspirin (50 mg/kg) before endotoxin priming (5 mg/kg). Platelets in the lung were identified by fluorescent immunohistochemistry. Platelet-neutrophil adherence was analysed by flow cytometry of the lung vascular flush. The effect of fMLP (10<sup>−6</sup> M) on thromboxane release, lung weight (an indicator of pulmonary vasoconstriction), and lung filtration coefficient was determined in an isolated lung system perfused at a constant pressure difference. <b>Results:</b> Endotoxin induced platelet accumulation and platelet-neutrophil adherence in the lung capillary were completely inhibited by cilostazol and aspirin while neutrophil recruitment was not affected. The fMLP challenge caused a significant increase in thromboxane B<sub>2</sub> levels in endotoxin primed lungs. The fMLP induced decrease in lung weight was enhanced by endotoxin priming (from −4.9 to −63.9 mg, 95% CI of mean difference −99.5 to −10.5 mg, p&lt;0.05). The fMLP induced increase in the lung filtration coefficient was also enhanced by endotoxin priming (from 0.63 to 2.40 mg/min/cm H<sub>2</sub>O/g, 95% CI of mean difference 1.17 to 2.37 mg/min/cm H<sub>2</sub>O/g, p&lt;0.05). Treatment with cilostazol and aspirin completely inhibited the enhanced pulmonary haemodynamic response to fMLP. <b>Conclusion:</b> The neutrophil–platelet interaction is of critical importance in the modulation of pulmonary haemodynamics via thromboxane.