tbuckley/cabot-search huggingface dataset:
Fcγ receptor profile of monocytes and macrophages from rheumatoid arthritis patients and their response to immune complexes formed with autoantibodies to citrullinated proteins
Authors: Lætitia Laurent, Cyril Clavel, Olivia Lemaire, Florence Anquetil, Martin Cornillet, Laurent Zabraniecki, Leonor Nogueira, Bernard Fournié, Guy Serre, Mireille Sebbag
Journal: Annals of the Rheumatic Diseases (2011)

Objective To analyse Fcγ receptor (FcγR) expression on monocytes and macrophages from rheumatoid arthritis (RA) patients versus healthy controls (HC), and to compare their responses to immune complexes containing RA-specific anti-citrullinated proteins auto antibodies (ACPA). Methods Monocytes and monocyte-derived macrophages were obtained from the peripheral blood of 34 RA patients and 69 HC. FcγR expression was studied by flow cytometry. Cells were stimulated with ACPA-containing immune complexes, and tumour necrosis factor alpha (TNFα) was assayed in culture supernatants. Results Variations distinguished RA from HC monocytes, corresponding to a 5% and 6% decrease in the percentages of monocytes expressing FcγRI and FcγRII, respectively, and a 7% increase in the proportion of FcγRIII-positive monocytes. Although in both HC and RA patients macrophage differentiation was accompanied by a dramatic increase in the percentage of FcγRIII-expressing cells (72% vs 74.5%), the parallel decline in the proportion of FcγRI-positive cells was markedly smaller in RA (7% vs 43%). Monocytes and macrophages from patients were responsive to ACPA-containing immune complexes but TNFα production in both cell types neither differed from that observed with the corresponding cells from HC, nor correlated with FcγR expression or clinical or biological data. In RA as in HC, ACPA-containing immune complexes induced secretions of more TNFα in macrophages than in paired monocytes (ninefold). Finally, the proinflammatory potential of ACPA-containing immune complexes was confirmed in CD14-positive monocyte macrophages from the synovial fluid of four RA patients. Conclusions ACPA-containing immune complexes induce TNFα secretion by blood and synovial fluid-derived macrophages from RA patients, fitting with their probable involvement in RA pathophysiology.
Embryonic Stem-Cell Research — The Case for Federal Funding
Authors: Jeffrey M. Drazen
Journal: New England Journal of Medicine (2004)

In the debate between those who support federal funding for embryonic stem-cell research and those who do not, a critical point has been overlooked. Research using this technology is strongly supported in a number of countries, including Australia, Israel, the Czech Republic, Singapore, Korea, and the United Kingdom. Others in the world appreciate the potential of this technology. If we continue to prevent federal funds from being used to support this research in the United States, the ability of our biomedical scientists to compete with other research teams throughout the world will be undermined. No matter how hard we try, . . .
Discontinuous Conduction in Mouse Bundle Branches Is Caused by Bundle-Branch Architecture
Authors: Toon A.B. van Veen, Harold V.M. van Rijen, Marjan J.A. van Kempen, Lucile Miquerol, Tobias Opthof, Daniel Gros, Marc A. Vos, Habo J. Jongsma, Jacques M.T. de Bakker
Journal: Circulation (2005)

Background— Recordings of the electrical activity of mouse bundle branches (BBs) suggest reduced conduction velocity (CV) in the midseptal compared with the proximal part of the BB. The present study was performed to elucidate the mechanism responsible for this slowing of conduction. Methods and Results— Hearts of 16 mice were isolated and Langendorff perfused. After the right and left ventricular free walls were removed, the extracellular activity of the BB was mapped with a 247-point electrode. Premature stimulation was used to estimate CV restitution in the BBs. Expression/distribution of connexin40 (Cx40), Cx43, and Cx45 was determined. Morphology of the conduction system was assessed by whole-mount acetylcholine esterase staining and in Cx40 +/KI-GFP hearts. Effective CV in the midseptal part of the left and right BBs was reduced by 50% compared with the proximal BB. CV restitution in the proximal and midseptal parts of the BBs was similar. Myocytes labeled positive for Cx40 and Cx45 in the entire BB. Cx43 colocalized with Cx40 and Cx45 only in the very distal BB. Subcellular distribution of gap junctions differed between proximal and distal BBs. Geometry of the midseptal and distal BBs revealed on both sides a profuse network of interlacing fibers, whereas the proximal BB consisted of a single (right BB) or multiple (left BB) parallel fibers. Conclusions— Comparison of connexin expression/distribution, geometry of the BBs, and CV characteristics suggests that increased path length for activation resulting from BB geometry is responsible for the apparently reduced CV in the midseptal BB of the mouse heart.
The pharmacokinetics (PK) and pharmacodynamics (PD) of the fluticasone furoate (FF) and vilanterol (VI) combination in subjects with severe renal impairment
Authors: Ann Allen, Kelly Hardes, Rodger Kempsford, Lee Tombs
Journal: European Respiratory Journal (2012)

Introduction: A combination of the novel corticosteroid FF and long-acting beta2 agonist VI (FF/VI) is being developed as a once-daily inhaled treatment for asthma and COPD.

Objectives: To investigate the effect of severe renal impairment on FF and VI PK and PD.

Methods: Open-label, parallel group study of repeat dose once-daily FF/VI 200/25mcg (7 days) in 9 subjects with severe renal impairment (CrCl<30mL/min) and 9 matched control healthy subjects (by gender, ethnicity, age (±5 years) and BMI (±15%)). FF and VI PK parameters were assessed on Day 7. PK parameter point estimates (90% confidence interval [CI]) were constructed for the ratio of geometric means (renally impaired:healthy subjects). Non-inferiority was to be concluded if the upper 90% CI for the ratio was <2 for the Day 7 comparison. Systemic PD effects of FF (0–24h serum cortisol) and VI (0–4h heart rate and serum potassium) were assessed on Day 7.

Results: For FF AUC(0–24) and Cmax the geometric mean ratio [90% CI] for renal:healthy was 0.91 [0.60, 1.38] and 0.96 [0.57, 1.61], respectively. For VI AUC(0–24) and Cmax the geometric mean ratio [90% CI] for renal: healthy was 1.56 [1.27, 1.92] and 0.70 [0.49, 1.00], respectively. Administration of FF/VI 200/25mcg to subjects with severe renal impairment did not result in significantly greater effects on serum cortisol, heart rate or serum potassium compared with healthy subjects.

Conclusions: There was no evidence of clinically relevant increases in FF or VI systemic exposure or systemic pharmacodynamic effects in subjects with severe renal impairment compared with healthy subjects.

Funded by GSK (HZA113970; [NCT01266980][1]).

 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01266980&atom=%2Ferj%2F40%2FSuppl_56%2FP2151.atom
Long-Term, High-Dosage Candesartan Suppresses Inflammation and Injury in Chronic Kidney Disease
Authors: Chen Yu, Rujun Gong, Abdlla Rifai, Evelyn M. Tolbert, Lance D. Dworkin
Journal: Journal of the American Society of Nephrology (2007)

Recent evidence suggests that higher-than-usual antihypertensive dosages of renin-angiotensin-aldosterone system blockers may provide additional protection from progression of chronic renal disease; however, there have been few long-term studies, and the underlying mechanisms remain uncertain. This study examined the effects of long-term (14 mo) administration of ultrahigh dosages of the angiotensin receptor blocker candesartan on the progression of renal injury in spontaneously hypertensive rats (SHR). Beginning 8 wk after birth, SHR underwent unilateral nephrectomy and were given vehicle (control), or candesartan at a standard 5 mg/kg per d (T5), high 25 mg/kg per d (T25), or ultrahigh 75 mg/kg per d dosage (T75). After 2 wk, BP was reduced in all treated groups; however, it was better controlled in the high-dosage groups (T25 and T75). Urinary protein was significantly reduced in T75 after 2 wk of treatment and was also declined in the other two treatment groups but only after 2 mo. Exogenous angiotensin II test showed that complete angiotensin receptor blockade was achieved only in the high-dosage groups. Renal inflammation and macrophage (ED-1) infiltration were significantly ameliorated in both T25 and T75 but not in T5 rats. This was associated with the changes of tubular expression of monocyte chemoattractant protein-1, RANTES (regulated upon expression normal T cell expressed and secreted), and the phosphorylated NF-kappaB, a marker for activation. Suppression of ED-1, monocyte chemoattractant protein-1, and RANTES expression and NF-kappaB activation were greater in T75 as compared with T25. These findings suggest that candesartan has dosage-dependent, anti-inflammatory effects that are mediated by suppression of NF-kappaB activation and chemokine expression. Renal protection with high-dosage therapy may depend on these nonhemodynamic effects.
Drug excipients allergy
Authors: Vipulkumar Shah
Journal: European Respiratory Journal (2012)

INTRODUCTION: 

Because of its rarity, drug excipients allergy is often unsuspected by the doctors. Some times the active drug is blamed and discontinued unnecessarily when the real culprit is drug excipients.

This was suspected when patients reported exacerbation of urticaria with anti histaminic which are actually used for treating urticaria. After suspecting drug excipient as the cause of allergy.

MATERIAL: 

To know actual cause it was decided to do patch testing with common drug excipients. The common excipient selected were Yellow Tartrazine, Titanium Dioxide, Sunset Yellow, Brilliant Blue, Quinolone Yellow, Talcum, and Ponaceue 4R.

METHOD: 

Patch testing material were prepared by using the basic material and suitable vehicle. 24 patients were selected for patch testing. Patch was put on patients back after 48 hrs reading were taken to confirm the skin sensitivities.

RESULT: 

Out of 24 patients 15 patients were positive for Yellow Tartrazine only, 3 patients showed positive to Titanium Dioxide. 2 patients were positive to Quinolone Yellow and Talcum. 2 were positive with Brilliant blue. 3 patients were positive Yellow Tartrazine, Sunsets Yellow and Talcum.

CONCLUSION: 

Drug excipients play an important role in causation is required to be standardised for patch testing. This type of patients should be treated in view of such investigations and preferably treated with drug without excipients.
The 1.688 Repetitive DNA of Drosophila: Concerted Evolution at Different Genomic Scales and Association with Genes
Authors: Gustavo C. S. Kuhn, Heinrich Küttler, Orlando Moreira-Filho, John S. Heslop-Harrison
Journal: Molecular Biology and Evolution (2011)

Concerted evolution leading to homogenization of tandemly repeated DNA arrays is widespread and important for genome evolution. We investigated the range and nature of the process at chromosomal and array levels using the 1.688 tandem repeats of Drosophila melanogaster where large arrays are present in the heterochromatin of chromosomes 2, 3, and X, and short arrays are found in the euchromatin of the same chromosomes. Analysis of 326 euchromatic and heterochromatic repeats from 52 arrays showed that the homogenization of 1.688 repeats occurred differentially for distinct genomic regions, from euchromatin to heterochromatin and from local arrays to chromosomes. We further found that most euchromatic arrays are either close to, or are within introns of, genes. The short size of euchromatic arrays (one to five repeats) could be selectively constrained by their role as gene regulators, a situation similar to the so-called "tuning knobs."
Role of shear rate and platelets in promoting fibrin formation on rabbit subendothelium. Studies utilizing patients with quantitative and qualitative platelet defects.
Authors: H J Weiss, V T Turitto, H R Baumgartner
Journal: Journal of Clinical Investigation (1986)

The deposition of platelets on subendothelium of rabbit aortic segments exposed to non-anticoagulated human blood increased progressively with increasing wall shear rates (50-2,600 s-1), whereas fibrin deposition decreased. Studies in normal subjects and patients with platelet disorders suggested that, under the conditions used, platelets were essential for fibrin deposition at intermediate (650 s-1) but not low (50 s-1) shear rates. Fibrin deposition was markedly diminished in a patient with Scott syndrome whose platelets have a diminished capacity to bind Factor Xa and activate Factors IX and II. In glycoprotein IIb-IIIa deficiency, fibrin deposition was normal (or somewhat increased), whereas in glycoprotein Ib deficiency the association of fibrin with platelets, but not subendothelium, was decreased. The findings indicate that platelets, perhaps through surface localization of coagulation proteins, promote fibrin deposition on subendothelium at arterial shear rates and suggest that agents directed against platelet coagulant properties could be antithrombotic.
Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesisin a mouse model
Authors: Akihiko Taguchi, Toshihiro Soma, Hidekazu Tanaka, Takayoshi Kanda, Hiroyuki Nishimura, Hiroo Yoshikawa, Yoshitane Tsukamoto, Hiroyuki Iso, Yoshihiro Fujimori, David M. Stern, Hiroaki Naritomi, Tomohiro Matsuyama
Journal: Journal of Clinical Investigation (2004)

Thrombo-occlusive cerebrovascular disease resulting in stroke and permanent neuronal loss is an important cause of morbidity and mortality. Because of the unique properties of cerebral vasculature and the limited reparative capability of neuronal tissue, it has been difficult to devise effective neuroprotective therapies in cerebral ischemia. Our results demonstrate that systemic administration of human cord blood–derived CD34+ cells to immunocompromised mice subjected to stroke 48 hours earlier induces neovascularization in the ischemic zone and provides a favorable environment for neuronal regeneration. Endogenous neurogenesis, suppressed by an antiangiogenic agent, is accelerated as a result of enhanced migration of neuronal progenitor cells to the damaged area, followed by their maturation and functional recovery. Our data suggest an essential role for CD34+ cells in promoting directly or indirectly an environment conducive to neovascularization of ischemic brain so that neuronal regeneration can proceed.
Leukocyte Chemoattractant Receptors in Human Disease Pathogenesis
Authors: Brian A. Zabel, Alena Rott, Eugene C. Butcher
Journal: Annual Review of Pathology Mechanisms of Disease (2014)

Combinations of leukocyte attractant ligands and cognate heptahelical receptors specify the systemic recruitment of circulating cells by triggering integrin-dependent adhesion to endothelial cells, supporting extravasation, and directing specific intratissue localization via gradient-driven chemotaxis. Chemoattractant receptors also control leukocyte egress from lymphoid organs and peripheral tissues. In this article, we summarize the fundamental mechanics of leukocyte trafficking, from the evolution of multistep models of leukocyte recruitment and navigation to the regulation of chemoattractant availability and function by atypical heptahelical receptors. To provide a more complete picture of the migratory circuits involved in leukocyte trafficking, we integrate a number of nonchemokine chemoattractant receptors into our discussion. Leukocyte chemoattractant receptors play key roles in the pathogenesis of autoimmune diseases, allergy, inflammatory disorders, and cancer. We review recent advances in our understanding of chemoattractant receptors in disease pathogenesis, with a focus on genome-wide association studies in humans and the translational implications of mechanistic studies in animal disease models.
The antiphospholipid syndrome: a syndrome in evolution.
Authors: R A Asherson, R Cervera
Journal: Annals of the Rheumatic Diseases (1992)

The antiphospholipid syndrome: a syndrome in evolution Since the original description and definition of the 'anti- phospholipid syndrome' (APS)' a number of distinct clinical manifestations related to it have been reported.Most of these may be ascribed to the hypercoagulable state, of which antiphospholipid antibodies seem either to be 'markers' or intimately connected in some way with the highly complex coagulation mechanisms resulting in thrombotic occlusions.Here, we bring these 'expanded' clinical mani- festations together and examine specifically those situations which may now also be included under the broad umbrella of the APS.Although less common than deep vein thrombosis, recurrent fetal loss, or stroke (the well recognised manifesta- tions of the APS), these additional manifestations may occur not only in association with a defined systemic lupus erythematosus (SLE) or 'lupus-like' disease but also in the 'primary' APS.We may further subdivide patients with these lesser known associations into (a) those in whom coagulopathy and thrombosis have been adequately demon- strated as the underlying mechanisms (table 1); and (b) those in whom the association remains unproved or indefinite because no radiological or histopathological evidence of vascular occlusions is available (table 2).Table I Proved associations with thrombosis 1 Hepatic 2 Adrenal
Lung surfactant, there is more to it than just surface tension
Authors: Eline Hermans, M. Saad Bhamla, Gerald G. Fuller, Jan Vermant
Journal: European Respiratory Journal (2014)

Introduction: Since the first description of lung surfactant (1), the lowering of surface tension has been the main function ascribed to it9s presence. Synthetic surfactants still are not as effective as animal surfactant, in spite of similar effects on surface tension. Additionally, the malfunctioning of the surfactant in ARDS, attributed to HSA, cannot be explained by solely considering the changes in surface tension.  Aim: The fluid dynamical properties of lung surfactant are investigated: drainage and wetting on lung epithelial cells, interfacial rheology in shear and dilation, and adsorption to the liquid/air interface. In addition, the effect of HSA on these properties is investigated.  Method: Curosurf® (Chiesi) is compared to Survanta® (Abbott) at a concentration of 0.8 mg/ml phospholipids. HSA (Sigma Aldrich) is studied at 40 mg/ml. Measurements were performed in a langmuir trough with state of the art techniques for characterizing drainage (2), interfacial shear (3,4) and dilatational (5) rheology.  Results: Interfacial rheology of both surfactants differ by an order of magnitude, resulting in significantly different timescales of fluid mobility. Survanta® spreads slower than Curosurf®. HSA mobility seems similar to Curosurf®. However, its adsorption dynamics are rather slow in comparison to the other surfactants.  Conclusion: Interfacial rheology largely affects the spreading of the surfactant in the lung. As a result it should be considered as an important design parameter for lung surfactant mixtures.  (1) R.E. Pattle, Nature, 1955.  (2) M.S. Bhamla et al., Soft Matter, 2014.  (3) S. Reynaert et al., J Rheol, 2008.  (4) S. Vandebrill et al., Rheol Acta, 2010.  (5) T. Verwijlen et al., Adv Colloid Interface Sci, 2014.
Metabolic Syndrome Biomarkers Predict Lung Function Impairment
Authors: Bushra Naveed, Michael D. Weiden, Sophia Kwon, Edward J. Gracely, Ashley L. Comfort, Natalia Ferrier, Kusali J. Kasturiarachchi, Hillel W. Cohen, Thomas K. Aldrich, William N. Rom, Kerry Kelly, David J. Prezant, Anna Nolan
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Cross-sectional studies demonstrate an association between metabolic syndrome and impaired lung function.To define if metabolic syndrome biomarkers are risk factors for loss of lung function after irritant exposure.A nested case-control study of Fire Department of New York personnel with normal pre-September 11th FEV(1) and who presented for subspecialty pulmonary evaluation before March 10, 2008. We correlated metabolic syndrome biomarkers obtained within 6 months of World Trade Center dust exposure with subsequent FEV(1). FEV(1) at subspecialty pulmonary evaluation within 6.5 years defined disease status; cases had FEV(1) less than lower limit of normal, whereas control subjects had FEV(1) greater than or equal to lower limit of normal.Clinical data and serum sampled at the first monitoring examination within 6 months of September 11, 2001, assessed body mass index, heart rate, serum glucose, triglycerides and high-density lipoprotein (HDL), leptin, pancreatic polypeptide, and amylin. Cases and control subjects had significant differences in HDL less than 40 mg/dl with triglycerides greater than or equal to 150 mg/dl, heart rate greater than or equal to 66 bpm, and leptin greater than or equal to 10,300 pg/ml. Each increased the odds of abnormal FEV(1) at pulmonary evaluation by more than twofold, whereas amylin greater than or equal to 116 pg/ml decreased the odds by 84%, in a multibiomarker model adjusting for age, race, body mass index, and World Trade Center arrival time. This model had a sensitivity of 41%, a specificity of 86%, and a receiver operating characteristic area under the curve of 0.77.Abnormal triglycerides and HDL and elevated heart rate and leptin are independent risk factors of greater susceptibility to lung function impairment after September 11, 2001, whereas elevated amylin is protective. Metabolic biomarkers are predictors of lung disease, and may be useful for assessing risk of impaired lung function in response to particulate inhalation.
An automated image analysis method to measure regularity in biological patterns: a case study in a Drosophila neurodegenerative model
Authors: Sergio Diez-Hermano, Jorge Valero, Cristina Rueda, Maria D Ganfornina, Diego Sanchez
Journal: Molecular Neurodegeneration (2015)

The fruitfly compound eye has been broadly used as a model for neurodegenerative diseases. Classical quantitative techniques to estimate the degeneration level of an eye under certain experimental conditions rely either on time consuming histological techniques to measure retinal thickness, or pseudopupil visualization and manual counting. Alternatively, visual examination of the eye surface appearance gives only a qualitative approximation provided the observer is well-trained. Therefore, there is a need for a simplified and standardized analysis of fruitfly eye degeneration extent for both routine laboratory use and for automated high-throughput analysis. We have designed the freely available ImageJ plugin FLEYE, a novel and user-friendly method for quantitative unbiased evaluation of neurodegeneration levels based on the acquisition of fly eye surface pictures. The incorporation of automated image analysis tools and a classification algorithm sustained on a built-in statistical model allow the user to quickly analyze large sample size data with reliability and robustness. Pharmacological screenings or genetic studies using the Drosophila retina as a model system may benefit from our method, because it can be easily implemented in a fully automated environment. In addition, FLEYE can be trained to optimize the image detection capabilities, resulting in a versatile approach to evaluate the pattern regularity of other biological or non-biological samples and their experimental or pathological disruption.