Adenosine A1 receptor activation attenuates lung ischemia–reperfusion injury

ObjectivesIschemia–reperfusion injury contributes significantly to morbidity and mortality in lung transplant patients. Currently, no therapeutic agents are clinically available to prevent ischemia–reperfusion injury, and treatment strategies are limited to maintaining oxygenation and lung function. Adenosine can modulate inflammatory activity and injury by binding to various adenosine receptors; however, the role of the adenosine A1 receptor in ischemia–reperfusion injury and inflammation is not well understood. The present study tested the hypothesis that selective, exogenous activation of the A1 receptor would be anti-inflammatory and attenuate lung ischemia–reperfusion injury.MethodsWild-type and A1 receptor knockout mice underwent 1 hour of left lung ischemia and 2 hours of reperfusion using an in vivo hilar clamp model. An A1 receptor agonist, 2-chloro-N6-cyclopentyladenosine, was administered 5 minutes before ischemia. After reperfusion, lung function was evaluated by measuring airway resistance, pulmonary compliance, and pulmonary artery pressure. The wet/dry weight ratio was used to assess edema. The myeloperoxidase and cytokine levels in bronchoalveolar lavage fluid were measured to determine the presence of neutrophil infiltration and inflammation.ResultsIn the wild-type mice, 2-chloro-N6-cyclopentyladenosine significantly improved lung function and attenuated edema, cytokine expression, and myeloperoxidase levels compared with the vehicle-treated mice after ischemia–reperfusion. The incidence of lung ischemia–reperfusion injury was similar in the A1 receptor knockout and wild-type mice; and 2-chloro-N6-cyclopentyladenosine had no effects in the A1 receptor knockout mice. In vitro treatment of neutrophils with 2-chloro-N6-cyclopentyladenosine significantly reduced chemotaxis.ConclusionsExogenous A1 receptor activation improves lung function and decreases inflammation, edema, and neutrophil chemotaxis after ischemia and reperfusion. These results suggest a potential therapeutic application for A1 receptor agonists for the prevention of lung ischemia–reperfusion injury after transplantation

BMP7 Gene Transfer via Gold Nanoparticles into Stroma Inhibits Corneal Fibrosis In Vivo

This study examined the effects of BMP7 gene transfer on corneal wound healing and fibrosis inhibition in vivo using a rabbit model. Corneal haze in rabbits was produced with the excimer laser performing -9 diopters photorefractive keratectomy. BMP7 gene was introduced into rabbit keratocytes by polyethylimine-conjugated gold nanoparticles (PEI2-GNPs) transfection solution single 5-minute topical application on the eye. Corneal haze and ocular health in live animals was gauged with stereo- and slit-lamp biomicroscopy. The levels of fibrosis [α-smooth muscle actin (αSMA), F-actin and fibronectin], immune reaction (CD11b and F4/80), keratocyte apoptosis (TUNEL), calcification (alizarin red, vonKossa and osteocalcin), and delivered-BMP7 gene expression in corneal tissues were quantified with immunofluorescence, western blotting and/or real-time PCR. Human corneal fibroblasts (HCF) and in vitro experiments were used to characterize the molecular mechanism mediating BMP7’s anti-fibrosis effects. PEI2-GNPs showed substantial BMP7 gene delivery into rabbit keratocytes in vivo (2×10[superscript 4] gene copies/ug DNA). Localized BMP7 gene therapy showed a significant corneal haze decrease (1.68±0.31 compared to 3.2±0.43 in control corneas; p88%; p<0.0001), and immunoblotting of BMP7-transefected HCFs grown in the presence of TGFβ demonstrated significantly enhanced pSmad-1/5/8 (95%; p<0.001) and Smad6 (53%, p<0.001), and decreased αSMA (78%; p<0.001) protein levels. These results suggest that localized BMP7 gene delivery in rabbit cornea modulates wound healing and inhibits fibrosis in vivo by counter balancing TGFβ1-mediated profibrotic Smad signaling.National Institutes of Health (U.S.) (RO1EB000244)Mason Eye Institute (Research to Prevent Blindness Unrestricted Grant

BMP7 Gene Transfer via Gold Nanoparticles into Stroma Inhibits Corneal Fibrosis \u3cem\u3ein vivo\u3c/em\u3e

This study examined the effects of BMP7 gene transfer on corneal wound healing and fibrosis inhibition in vivo using a rabbit model. Corneal haze in rabbits was produced with the excimer laser performing -9 diopters photorefractive keratectomy. BMP7 gene was introduced into rabbit keratocytes by polyethylimine-conjugated gold nanoparticles (PEI2- GNPs) transfection solution single 5-minute topical application on the eye. Corneal haze and ocular health in live animals was gauged with stereo- and slit-lamp biomicroscopy. The levels of fibrosis [a-smooth muscle actin (aSMA), F-actin and fibronectin], immune reaction (CD11b and F4/80), keratocyte apoptosis (TUNEL), calcification (alizarin red, vonKossa and osteocalcin), and delivered-BMP7 gene expression in corneal tissues were quantified with immunofluorescence, western blotting and/or real-time PCR. Human corneal fibroblasts (HCF) and in vitro experiments were used to characterize the molecular mechanism mediating BMP7’s anti-fibrosis effects. PEI2-GNPs showed substantial BMP7 gene delivery into rabbit keratocytes in vivo (26104 gene copies/ug DNA). Localized BMP7 gene therapy showed a significant corneal haze decrease (1.6860.31 compared to 3.260.43 in control corneas; p,0.05) in Fantes grading scale. Immunostaining and immunoblot analyses detected significantly reduced levels of aSMA (4665% p,0.001) and fibronectin proteins (4865% p,0.01). TUNEL, CD11b, and F4/80 assays revealed that BMP7 gene therapy is nonimmunogenic and nontoxic for the cornea. Furthermore, alizarin red, vonKossa and osteocalcin analyses revealed that localized PEI2-GNP-mediated BMP7 gene transfer in rabbit cornea does not cause calcification or osteoblast recruitment. Immunofluorescence of BMP7-transefected HCFs showed significantly increased pSmad-1/5/8 nuclear localization (.88%; p,0.0001), and immunoblotting of BMP7-transefected HCFs grown in the presence of TGFb demonstrated significantly enhanced pSmad-1/5/8 (95%; p,0.001) and Smad6 (53%, p,0.001), and decreased aSMA (78%; p,0.001) protein levels. These results suggest that localized BMP7 gene delivery in rabbit cornea modulates wound healing and inhibits fibrosis in vivo by counter balancing TGFb1-mediated profibrotic Smad signaling

FORMULATION AND EVALUATION OF SUBLINGUAL TABLET CONTAINING ANTIEMETIC DRUG

The aim of the present research is to formulate a sublingual tablet of antiemetic drug. Doxylamine succinate is an antihistaminic commonly used for the prevention and treatment of nausea and vomiting. Oral bioavailability of doxylamine succinate is low and shows extensive hepatic metabolism. The Objective of the present research is to formulate doxylamine succinate sublingual tablet to avoid hepatic first-pass metabolism and to improve its bioavailability. Sublingual route not only overcome the problem of dysphagia but also giving the rapid onset of action by enhancing permeability through site of administration Keywords: Sublingual tablet, Doxylamine succinate, Antiemetic, Dysphagia, Bioavailabilit

Identification of faults in rotating machines using high precision FBG vibration sensor: a case study on PM schemes

Predictive maintenance (PM) is a data-driven approach to performing proactive maintenance by analyzing the condition of the equipment in any industrial setting. The high-precision sensors are widely adapted to meticulously analyze critical maintenance conditions using such a data-driven approach. In a similar context, a fiber brag grating (FBG) sensor is a passive and high-precision sensor that is widely used in industries where conventional sensors are not preferred. Broadly, this article presents four sub elements of the proposed integrated system such as the design of the sensor element, signal processing scheme (SPS), machine learning (ML) model for predicting anomalies, and decision support system (DSS) to suggest maintenance actions. Also, this article highlights an experimental case study on vibration monitoring and analysis of real-time signals for making proactive maintenance decisions. An FBG vibration sensor of center wavelength 1,550 nm is designed and utilized to acquire real-time vibration signatures of a rotating machine under test. A piezoelectric vibration sensor is used with the FBG sensor to compare the vibration response obtained during the test. Pre-processing of raw signals is performed using a moving average filter (MAV) followed by a low pass filter to nullify the effect of noise. To obtain proactive maintenance decisions, a DSS model is prepared by considering the processed vibration signatures. Various maintenance conditions are tested during the experimental analysis and detailed results analysis are presented

Modulation of metoprolol pharmacokinetics and hemodynamics by diphenhydramine coadministration during exercise testing in healthy premenopausal women

Premenopausal women may be most vulnerable to acute coronary syndromes at a point in their menstrual cycle when their plasma estrogen levels are the lowest during and immediately after menstruation. Metoprolol is a first-line drug in the management of patients with acute coronary syndrome; however, when metoprolol was marketed in 1982, women were largely excluded from clinical trials. Furthermore, the over-the-counter antihistamine diphenhydramine inhibited the metabolism of the CYP2D6 substrate metoprolol in healthy, young men with pharmacokinetic and pharmacodynamic consequences. The pharmacokinetics and pharmacodynamics of metoprolol and its interaction with diphenhydramine were investigated in a randomized, double-blind, crossover, placebo-controlled manner in healthy, premenopausal extensive (EM; n = 16) and poor metabolizer (PM; n = 4) women immediately after menstruation. During the placebo phase, EMs had between 5.2- and 8.4-fold higher total clearance (CL/F) of R- and S-metoprolol compared with PMs, whereas the latter had a 35% greater area under the effect curve (AUEC) and 60% greater EC(50) value for heart rate reduction than EMs (all P < 0.05). Diphenhydramine coadmininstration caused a 2.2- to 3.2-fold decrease in CL/F of metoprolol enantiomers with a resulting 21% increase in AUEC and 29% increase in EC(50) value for heart rate reduction in EMs (all P < 0.05). This is the first study to report an in-depth elucidation of metoprolol's pharmacokinetics and hemodynamics in premenopausal EM and PM women at a point in their menstrual cycle when vulnerability for acute coronary events may be greatest. Caution is warranted when the over-the-counter antihistamine diphenhydramine is part of a chronic therapeutic regime

Tissue-derived proinflammatory effect of adenosine A2B receptor in lung ischemia–reperfusion injury

ObjectiveIschemia–reperfusion injury after lung transplantation remains a major source of morbidity and mortality. Adenosine receptors have been implicated in both pro- and anti-inflammatory roles in ischemia–reperfusion injury. This study tests the hypothesis that the adenosine A2B receptor exacerbates the proinflammatory response to lung ischemia–reperfusion injury.MethodsAn in vivo left lung hilar clamp model of ischemia–reperfusion was used in wild-type C57BL6 and adenosine A2B receptor knockout mice, and in chimeras created by bone marrow transplantation between wild-type and adenosine A2B receptor knockout mice. Mice underwent sham surgery or lung ischemia–reperfusion (1 hour ischemia and 2 hours reperfusion). At the end of reperfusion, lung function was assessed using an isolated buffer-perfused lung system. Lung inflammation was assessed by measuring proinflammatory cytokine levels in bronchoalveolar lavage fluid, and neutrophil infiltration was assessed via myeloperoxidase levels in lung tissue.ResultsCompared with wild-type mice, lungs of adenosine A2B receptor knockout mice were significantly protected after ischemia–reperfusion, as evidenced by significantly reduced pulmonary artery pressure, increased lung compliance, decreased myeloperoxidase, and reduced proinflammatory cytokine levels (tumor necrosis factor-α; interleukin-6; keratinocyte chemoattractant; regulated on activation, normal T-cell expressed and secreted; and monocyte chemotactic protein-1). Adenosine A2B receptor knockout→adenosine A2B receptor knockout (donor→recipient) and wild-type→ adenosine A2B receptor knockout, but not adenosine A2B receptor knockout→wild-type, chimeras showed significantly improved lung function after ischemia–reperfusion.ConclusionsThese results suggest that the adenosine A2B receptor plays an important role in mediating lung inflammation after ischemia–reperfusion by stimulating cytokine production and neutrophil chemotaxis. The proinflammatory effects of adenosine A2B receptor seem to be derived by adenosine A2B receptor activation primarily on resident pulmonary cells and not bone marrow-derived cells. Adenosine A2B receptor may provide a therapeutic target for prevention of ischemia–reperfusion-related graft dysfunction in lung transplant recipients

SAHA : FDA approved histone deacetylase inhibitor demonstrates exceptionally high inhibition of corneal haze following PRK surgery in rabbit model [abstract]

TGF[beta] induces the transformation of corneal keratocytes into fibroblasts and myofibroblasts resulting in the formation of corneal haze (scar) following injury. We investigated whether epigenetic modifications can prevent development of corneal haze in vivo using a rabbit model

India

This article surveys significant legal developments in India during the year 2014

A Parallel Military Dog based Algorithm for Clustering Big data in Cognitive Industrial Internet of Things

With the advancement of wireless communication, internet of things, and big data, high performance data analytic tools and algorithms are required. Data clustering, a promising analytic technique is widely used to solve the IoT and big data based problems, since it does not require labeled datasets. Recently, meta-heuristic algorithms have been efficiently used to solve various clustering problems. However, to handle big data sets produced from IoT devices, these algorithm fail to respond within desired time due to high computation cost. This paper presents a new meta-heuristic based clustering method to solve the big data problems by leveraging the strength of MapReduce. The proposed methods leverages the searching potential of military dog squad to find the optimal centroids and MapReduce architecture to handle the big data sets. The optimization efficacy the proposed method is validated against 17 benchmark functions and the results are compared with 5 other recent algorithms namely, bat, particle swarm optimization, artificial bee colony, multiverse optimization, and whale optimization algorithm. Further, a parallel version of the proposed method is introduced using MapReduce (MR-MDBO) for clustering the big datasets produced from industrial IoT. Moreover, the performance of MR-MDBO is studied on 2 benchmark UCI datasets and 3 real IoT based datasets produced from industry. The F-measure and computation time of the MR-MDBO is compared with the 6 other state-of-the-art methods. The experimental results witness that the proposed MR-MDBO based clustering outperforms the other considered algorithms in terms of clustering accuracy and computation times