Targeted Delivery of Surface Modified Nanoparticles: Modulation of Inflammation for Acute Lung Injury

The objective of the study is to demonstrate alleviation of pulmonary inflammation associated with acute lung injury (ALI) using novel surface modified nanoparticles. ALI is characterized by three main pathological events: I) pulmonary edema, II) excessive pro-inflammatory cytokines and chemokines production from alveolar epithelial and endothelial cells and III) leukocyte migration from blood circulation into alveoli. Currently, there is no FDA approved pharmacological treatment available except the supportive mechanical ventilation therapy. Numerous clinical trials involving pharmacological therapies aimed at different pathological targets turned unsuccessful. National Institute of Heart Lung and Blood Institute (NHLBI) cited underappreciation of drug delivery systems as one of the attributed drawbacks. During ALI, the αvβ6/αvβ5 integrins of alveolar epithelium and endothelium, respectively play a critical role in mediating pulmonary edema in interleukin-1b (IL-1b) stimulated ALI models. A transient blockade of both integrins by antibodies (Ab) or small Arg-Gly-Asp (RGD) peptide sequences may provide new causal therapies for pulmonary edema. A transcription factor, nuclear factor-kB (NF-kB) is associated with the regulation of a battery of genes that encode for pro-inflammatory cytokines, chemokines and cell adhesion molecules (CAMs). Glucocorticoids (GCs) exert their anti-inflammatory effects by NF-kB transcriptional interference mechanisms. Besides the above inflammatory mechanisms, leukocyte migration is another hallmark feature responsible for part of ALI pathogenesis. Leukocyte migration is dictated by sequential activation of adhesion molecules and their ligands on both leukocytes and endothelial cells (ECs). Intercellular adhesion molecule-1 (ICAM-1) located on alveolar endothelium plays a significant role in the recruitment of leukocytes into alveoli. Blockade of ICAM-1 receptors using anti-ICAM-1 antibodies may impede leukocyte migration into alveoli. In view of high mortality associated with ALI, there is an urgent need for a drug delivery system that inhibits majority of pathological events. In drug targeting research, liposomes are considered as versatile for their ability to carry drug payloads and flexible enough to modulate their surface for targeting purposes. In the current investigation, I developed surface modified stable liposome formulation for delivery of methylprednisolone succinate (a glucocorticoid; MPS) to the lung. Liposomes were targeted to the disease sites through different routes of administration to avail the spatial expression of the receptors in response to IL-1b stimulus. MPS-LcRGD targeted to avb6 integrins of alveolar epithelium attenuated pulmonary edema. MPS-LAb were able to modulate neutrophil migration. Moreover, MPS released from targeted liposomes inhibited the expression of pro-inflammatory cytokines and chemokines. The research work demonstrated the concept of using drug encapsulated and surface modified nanoparticles for therapeutic intervention of ALI

On a Generalized Goal in Fixed-Sample Ranking and Selection Problems

1 online resource (PDF, 90 pages

Investigation of Selected Medicinal Plants and Marketed Formulation for their Anti-inflammatory and Anti-Osteoarthritis Activity

There are several herbs used in the indigenous system of medicine for the treatment of inflammation and joint disorders. As per the literature survey information, the plant Strobilanthes callosus (Family-Acanthaceae) a traditional herb reported for anti-inflammatory and anti-arthritic activity. Due to a strong chemotaxonomical relationship among species of Genus Strobiolanthes, the two species i.e., Strobilanthes kunthianus (Family -Acanthaceae) and Strobilanthes cuspidatus (Family -Acanthaceae) were selected for the present study. The leaves of S. kunthianus and S. cuspidatus were collected from Kalliti, Nilgiri hills. The effects of ethanolic extracts of S. kunthianus (100 mg/kg and 200 mg/kg) and S. cuspidatus (100 mg/kg and 200 mg/kg) for their analgesic, anti-inflammatory, and anti-osteoarthritic activity were studied in different animal models using Wistar albino rats and Swiss albino mice in vivo and in vitro assays such as human RBC membrane stabilization and rabbit cartilage explants culture were also performed. The extracts SKE and SCE produced various changes in abdominal constriction (wriths), tolerance to pain, paw volume, granuloma formation and cartilage lesions when tested in vivo and also produced changes in lysis of human RBC and glycosaminoglycan release when tested in vitro. The extracts SKE and SCE were also studied for their safety in acute and sub acute toxicity models using Wistar rats, both the extracts did not produced any adverse effects or death in acute toxicity study and also there were no hematological changes, biochemical changes, pathological changes and death in sub acute toxicity study. This indicates that the extracts SKE and SCE were safe to use. The results obtained in the present investigation are consistent with the ethno medical claim made for the use of genus Strobilanthes in inflammation and joint disorders. Interestingly, shallaki showed lesser analgesic, anti-inflammatory and antiosteoarthritis activity when compared to SKE and SCE. The potential therapeutic activity of the extracts Strobilanthes kunthianus and Strobilanthes cuspidatus may be attributed to the presence of multiple phytoconstituents such as flavonoids, phytosterols, triterpenoids and tannins. Although more wide-cut understanding of the mechanism by which SKE and SCE mediates their beneficial effects needs further investigation on the action of prostaglandins, cycloxygenases, lipoxygenases, matrix-metalloproteases and reactive oxygen species, other animal models (Collagenase induced osteoarthritis and incapacitence test) and to isolate the phytoconstituents from the ethanolic extracts which are responsible for the therapeutic activity. Studies with varying dose levels and isolated phytoconstituents can also be performed. Work in this direction is progress in the institution

DOES FREE DISTRIBUTION OF MOSQUITO NETS AFFECT SUBSIDIZED NET SALES? EVIDENCE FROM A NATIONWIDE CAMPAIGN IN TANZANIA

Randomized controlled trials (RCTs) are increasingly popular for assessing development programmes. This study investigates the validity of extrapolating RCT results to large-scale programmes, using the example of the national bed net subsidy programme in Tanzania that later added a free distribution campaign. Although the RCTs suggest steady sales of nets throughout, an interrupted time series model reveals a 34 per cent monthly decline immediately after the campaign compared to 'normal' sales. After 6months, the total unsold nets reached 45 per cent of normal sales, or 347000 nets nationwide. We hypothesize that these differences in results arise from various scale and spillover effects. © 2013 John Wiley & Sons, Ltd

An Alternative Subset Approach to the Ranking and Selection Problem

1 online resource (PDF, 24 pages

Phenomenological theory of phase transitions in epitaxial BaxSr(1-x)TiO3 thin films

A phenomenological thermodynamic theory of BaxSr(1-x)TiO3 (BST-x) thin films epitaxially grown on cubic substrates is developed using the Landau-Devonshire approach. The eighth-order thermodynamic potential for BT single crystal and modified fourth-order potential for ST single crystal were used as starting potentials for the end-members of the solid solution with the aim to develop potential of BST-$x$ solid solution valid at high temperatures. Several coefficients of these potentials for BT were changed to obtain reasonable agreement between theory and experimental phase diagram for BST-x (x > 0.2) solid solutions. For low Ba content we constructed the specific phase diagram where five phases converge at the multiphase point (T_N2 = 47 K, x = 0.028) and all transitions are of the second order. The "concentration-misfit strain" phase diagrams for BST-x thin films at room temperature and "temperature-misfit strain" phase diagrams for particular concentrations are constructed and discussed. Near T_N2 coupling between polarization and structural order parameter in the epitaxial film is modified considerably and large number of new phases not present in the bulk materials appear on the phase diagram.Comment: 8 pages 5 figure

Electronic structure and ferroelectricity in SrBi2Ta2O9

The electronic structure of SrBi2Ta2O9 is investigated from first-principles, within the local density approximation, using the full-potential linearized augmented plane wave (LAPW) method. The results show that, besides the large Ta(5d)-O(2p) hybridization which is a common feature of the ferroelectric perovskites, there is an important hybridization between bismuth and oxygen states. The underlying static potential for the ferroelectric distortion and the primary source for ferroelectricity is investigated by a lattice-dynamics study using the Frozen Phonon approach.Comment: 17 pages, 7 figures. Phys. Rev. B, in pres