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1.  Anti-inflammatory activity of nanocrystalline silver-derived solutions in porcine contact dermatitis 
Nanocrystalline silver dressings have anti-inflammatory activity, unlike solutions containing Ag+ only, which may be due to dissolution of multiple silver species. These dressings can only be used to treat surfaces. Thus, silver-containing solutions with nanocrystalline silver properties could be valuable for treating hard-to-dress surfaces and inflammatory conditions of the lungs and bowels. This study tested nanocrystalline silver-derived solutions for anti-inflammatory activity.
Inflammation was induced on porcine backs using dinitrochlorobenzene. Negative and positive controls were treated with distilled water. Experimental groups were treated with solutions generated by dissolving nanocrystalline silver in distilled water adjusted to starting pHs of 4 (using CO2), 5.6 (as is), 7, and 9 (using Ca(OH)2). Solution samples were analyzed for total silver. Daily imaging, biopsying, erythema and oedema scoring, and treatments were performed for three days. Biopsies were processed for histology, immunohistochemistry (for IL-4, IL-8, IL-10, TNF-α, EGF, KGF, KGF-2, and apoptotic cells), and zymography (MMP-2 and -9). One-way ANOVAs with Tukey-Kramer post tests were used for statistical analyses.
Animals treated with pH 7 and 9 solutions showed clear visual improvements. pH 9 solutions resulted in the most significant reductions in erythema and oedema scores. pH 4 and 7 solutions also reduced oedema scores. Histologically, all treatment groups demonstrated enhanced re-epithelialisation, with decreased inflammation. At 24 h, pMMP-2 expression was significantly lowered with pH 5.6 and 9 treatments, as was aMMP-2 expression with pH 9 treatments. In general, treatment with silver-containing solutions resulted in decreased TNF-α and IL-8 expression, with increased IL-4, EGF, KGF, and KGF-2 expression. At 24 h, apoptotic cells were detected mostly in the dermis with pH 4 and 9 treatments, nowhere with pH 5.6, and in both the epidermis and dermis with pH 7. Solution anti-inflammatory activity did not correlate with total silver content, as pH 4 solutions contained significantly more silver than all others.
Nanocrystalline silver-derived solutions appear to have anti-inflammatory/pro-healing activity, particularly with a starting pH of 9. Solutions generated differently may have varying concentrations of different silver species, only some of which are anti-inflammatory. Nanocrystalline silver-derived solutions show promise for a variety of anti-inflammatory treatment applications.
PMCID: PMC2841158  PMID: 20170497
2.  Synthesis, Characterization, and In Vivo Efficacy of Shell Cross-Linked Nanoparticle Formulations Carrying Silver Antimicrobials as Aerosolized Therapeutics 
ACS Nano  2013;7(6):4977-4987.
The use of nebulizable, nanoparticle-based antimicrobial delivery systems can improve efficacy and reduce toxicity for treatment of multi-drug-resistant bacteria in the chronically infected lungs of cystic fibrosis patients. Nanoparticle vehicles are particularly useful for applying broad-spectrum silver-based antimicrobials, for instance, to improve the residence time of small-molecule silver carbene complexes (SCCs) within the lung. Therefore, we have synthesized multifunctional, shell cross-linked knedel-like polymeric nanoparticles (SCK NPs) and capitalized on the ability to independently load the shell and core with silver-based antimicrobial agents. We formulated three silver-loaded variants of SCK NPs: shell-loaded with silver cations, core-loaded with SCC10, and combined loading of shell silver cations and core SCC10. All three formulations provided a sustained delivery of silver over the course of at least 2–4 days. The two SCK NP formulations with SCC10 loaded in the core each exhibited excellent antimicrobial activity and efficacy in vivo in a mouse model of Pseudomonas aeruginosa pneumonia. SCK NPs with shell silver cation-load only, while efficacious in vitro, failed to demonstrate efficacy in vivo. However, a single dose of core SCC10-loaded SCK NPs (0.74 ± 0.16 mg Ag) provided a 28% survival advantage over sham treatment, and administration of two doses (0.88 mg Ag) improved survival to 60%. In contrast, a total of 14.5 mg of Ag+ delivered over 5 doses at 12 h intervals was necessary to achieve a 60% survival advantage with a free-drug (SCC1) formulation. Thus, SCK NPs show promise for clinical impact by greatly reducing antimicrobial dosage and dosing frequency, which could minimize toxicity and improve patient adherence.
PMCID: PMC4287418  PMID: 23718195
shell cross-linked knedel-like polymeric nanoparticles; silver carbene complexes; cystic fibrosis; nebulizable nanoparticles; multi-drug-resistant bacteria; Pseudomonas aeruginosa pneumonia
3.  Nano-silver in drinking water and drinking water sources: stability and influences on disinfection by-product formation 
Nano-silver is increasingly used in consumer products from washing machines and refrigerators to devices marketed for the disinfection of drinking water or recreational water. The nano-silver in these products may be released, ending up in surface water bodies which may be used as drinking water sources. Little information is available about the stability of the nano-silver in sources of drinking water, its fate during drinking water disinfection processes, and its interaction with disinfection agents and disinfection by-products (DBPs). This study aims to investigate the stability of nano-silver in drinking water sources and in the finished drinking water when chlorine and chloramines are used for disinfection and to observe changes in the composition of DBPs formed when nano-silver is present in the source water. A dispersion of nano-silver particles (10 nm; PVP-coated) was used to spike untreated Ottawa River water, treated Ottawa River water, organic-free water, and a groundwater at concentrations of 5 mg/L. The diluted dispersions were kept under stirred and non-stirred conditions for up to 9 months and analyzed weekly using UV absorption to assess the stability of the nano-silver particles. In a separate experiment, Ottawa River water containing nano-silver particles (at 0.1 and 1 mg/L concentration, respectively) was disinfected by adding sodium hypochlorite (a chlorinating agent) in sufficient amounts to maintain a free chlorine residual of approximately 0.4 mg/L after 24 h. The disinfected drinking water was then quenched with ascorbic acid and analyzed for 34 neutral DBPs (trihalomethanes, haloacetonitriles, haloacetaldehydes, 1,1 dichloro-2-propanone, 1,1,1 trichloro-2-propanone, chloropicrin, and cyanogen chloride). The results were compared to the profile of DBPs obtained under the same conditions in the absence of nano-silver and in the presence of an equivalent concentration of Ag+ ions (as AgNO3). The stability of the nano-silver dispersions in untreated Ottawa River water, with a dissolved organic carbon concentration of 6 mg/L, was significantly higher than the stability of the nano-silver dispersions in distilled, organic-free water. Nano-silver particles suspended in the groundwater agglomerated and were quickly and quantitatively removed from the solution. Our data confirm previous observations that natural dissolved organic matter stabilizes nano-silver particles, while the high-ionic strength of groundwater appears to favor their agglomeration and precipitation. As expected, nano-silver was not stable in Ottawa River water through the chlorination process, but survived for many days when added to the Ottawa River water after treatment with chlorine or chloramines. Stirring appeared to have minimal effect on nano-silver stability in untreated and treated Ottawa River water. The profile of DBPs formed in the presence of nAg differed significantly from the profile of DBPs formed in the absence of nAg only at the 1 mg/L nAg concentration. The differences observed consisted mainly in reduced formation of some brominated DBPs and a small increase in the formation of cyanogen chloride. The reduced formation of brominated congeners may be explained by the decrease in available bromide due to the presence of Ag+ ions. It should be noted that a concentration of 1 mg/L is significantly higher than nAg concentrations that would be expected to be present in surface waters, but these results could be significant for the disinfection of some wastewaters with comparably high nano-silver concentrations.
PMCID: PMC4177100  PMID: 24458938
Nano-silver; Drinking water; Surface water; Chlorination; Disinfection by-products; Stability
4.  Silver nanoparticle toxicity in Drosophila: size does matter 
Consumer nanotechnology is a growing industry. Silver nanoparticles are the most common nanomaterial added to commercially available products, so understanding the influence that size has on toxicity is integral to the safe use of these new products. This study examined the influence of silver particle size on Drosophila egg development by comparing the toxicity of both nanoscale and conventional-sized silver particles.
The toxicity assays were conducted by exposing Drosophila eggs to particle concentrations ranging from 10 ppm to 100 ppm of silver. Size, chemistry, and agglomeration of the silver particles were evaluated using transmission electron microscopy, X-ray photoelectron spectroscopy, and dynamic light scattering.
This analysis confirmed individual silver particle sizes in the ranges of 20–30 nm, 100 nm, and 500–1200 nm, with similar chemistry. Dynamic light scattering and transmission electron microscope data also indicated agglomeration in water, with the transmission electron microscopic images showing individual particles in the correct size range, but the dynamic light scattering z-average sizes of the silver nanoparticles were 782 ± 379 nm for the 20–30 nm silver nanoparticles, 693 ± 114 nm for the 100 nm silver nanoparticles, and 508 ± 32 nm for the 500–1200 nm silver particles. Most importantly, here we show significantly more Drosophila egg toxicity when exposed to larger, nonnanometer silver particles. Upon exposure to silver nanoparticles sized 20–30 nm, Drosophila eggs did not exhibit a statistically significant (P < 0.05) decrease in their likelihood to pupate, but eggs exposed to larger silver particles (500–1200 nm) were 91% ± 18% less likely to pupate. Exposure to silver nanoparticles reduced the percentage of pupae able to emerge as adults. At 10 ppm of silver particle exposure, only 57% ± 48% of the pupae exposed to 20–30 nm silver particles became adults, whereas 89% ± 25% of the control group became adults, and 94% ± 52% and 91% ± 19% of the 500–1200 nm and 100 nm group, respectively, reached adulthood.
This research provides evidence that nanoscale silver particles (<100 nm) are less toxic to Drosophila eggs than silver particles of conventional (>100 nm) size.
PMCID: PMC3044187  PMID: 21383859
Drosophila; silver; nanoparticle; toxicity
5.  Small changes in lung function in runners with marathon‐induced interstitial lung edema 
Physiological Reports  2014;2(6):e12056.
The purpose of this study was to assess lung function in runners with marathon‐induced lung edema. Thirty‐six (24 males) healthy subjects, 34 (SD 9) years old, body mass index 23.7 (2.6) kg/m2 had posterior/anterior (PA) radiographs taken 1 day before and 21 (6) minutes post marathon finish. Pulmonary function was performed 1–3 weeks before and 73 (27) minutes post finish. The PA radiographs were viewed together, as a set, and evaluated by two experienced readers separately who were blinded as to time the images were obtained. Radiographs were scored for edema based on four different radiological characteristics such that the summed scores for any runner could range from 0 (no edema) to a maximum of 8 (severe interstitial edema). Overall, the mean edema score increased significantly from 0.2 to 1.0 units (P <0.01), and from 0.0 to 2.9 units post exercise in the six subjects that were edema positive (P = 0.03). Despite a 2% decrease in forced vital capacity (FVC, P =0.024) and a 12% decrease in alveolar‐membrane diffusing capacity for carbon monoxide (DmCO, P =0.01), there was no relation between the change in the edema score and the change in DmCO or FVC. In conclusion, (1) mild pulmonary edema occurs in at least 17% of subjects and that changes in pulmonary function cannot predict the occurrence or severity of edema, (2) lung edema is of minimal physiological significance as marathon performance is unaffected, exercise‐induced arterial hypoxemia is unlikely, and postexercise pulmonary function changes are mild.
This study assessed lung function in runners with marathon‐induced interstitial lung edema. Pulmonary function tests and chest radiographs were obtained pre‐ and post marathon finish. Seventeen percent of subjects developed edema but the edema was of minimal physiological importance.
PMCID: PMC4208648  PMID: 24973330
Endurance; exercise; lung fluid; lung function; pulmonary; water
6.  In Vivo Human Time-Exposure Study of Orally Dosed Commercial Silver Nanoparticles 
Nanomedicine : nanotechnology, biology, and medicine  2013;10(1):10.1016/j.nano.2013.06.010.
Human biodistribution, bioprocessing and possible toxicity of nanoscale silver receives increasing health assessment.
We prospectively studied commercial 10- and 32-ppm nanoscale silver particle solutions in a single-blind, controlled, cross-over, intent-to-treat, design. Healthy subjects (n=60) underwent metabolic, blood counts, urinalysis, sputum induction, and chest and abdomen magnetic resonance imaging. Silver serum and urine content was determined.
No clinically important changes in metabolic, hematologic, or urinalysis measures were identified. No morphological changes were detected in the lungs, heart or abdominal organs. No significant changes were noted in pulmonary reactive oxygen species or pro-inflammatory cytokine generation.
In vivo oral exposure to these commercial nanoscale silver particle solutions does not prompt clinically important changes in human metabolic, hematologic, urine, physical findings or imaging morphology. Further study of increasing time exposure and dosing of silver nanoparticulate silver, and observation of additional organ systems is warranted to assert human toxicity thresholds.
PMCID: PMC3877176  PMID: 23811290
biological activity – nanoparticles; nanotechnology; nanotoxicology – oral ingestion; safety research
7.  Synthesis, characterization, and antimicrobial activity of silver carbene complexes derived from 4,5,6,7-tetrachlorobenzimidazole against antibiotic resistant bacteria† 
Silver N-heterocyclic carbene complexes have been shown to have great potential as antimicrobial agents, affecting a wide spectrum of both Gram-positive and Gram-negative bacteria. A new series of three silver carbene complexes (SCCs) based on 4,5,6,7-tetrachlorobenzimidazole has been synthesized, characterized, and tested against a panel of clinical strains of bacteria. The imidazolium salts and their precursors were characterized by elemental analysis, mass spectrometry, 1H and 13C NMR spectroscopy, and single crystal X-ray diffraction. The silver carbene complexes, SCC32, SCC33, and SCC34 were characterized by elemental analysis, 1H and 13C NMR spectroscopy, and single crystal X-ray diffraction. These complexes proved highly efficacious with minimum inhibitory concentrations (MICs) ranging from 0.25 to 6 μg mL−1. Overall, the complexes were effective against highly resistant bacteria strains, such as methicillin-resistant Staphylococcus aureus (MRSA), weaponizable bacteria, such as Yersinia pestis, and pathogens found within the lungs of cystic fibrosis patients, such as Pseudomonas aeruginosa, Alcaligenes xylosoxidans, and Burkholderia gladioli. SCC33 and SCC34 also showed clinically relevant activity against a silver-resistant strain of Escherichia coli based on MIC testing.
PMCID: PMC3703457  PMID: 22402409
8.  Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetate 
The study investigated the distribution of silver after 28 days repeated oral administration of silver nanoparticles (AgNPs) and silver acetate (AgAc) to rats. Oral administration is a relevant route of exposure because of the use of silver nanoparticles in products related to food and food contact materials.
AgNPs were synthesized with a size distribution of 14 ± 4 nm in diameter (90% of the nanoparticle volume) and stabilized in aqueous suspension by the polymer polyvinylpyrrolidone (PVP). The AgNPs remained stable throughout the duration of the 28-day oral toxicity study in rats. The organ distribution pattern of silver following administration of AgNPs and AgAc was similar. However the absolute silver concentrations in tissues were lower following oral exposure to AgNPs. This was in agreement with an indication of a higher fecal excretion following administration of AgNPs. Besides the intestinal system, the largest silver concentrations were detected in the liver and kidneys. Silver was also found in the lungs and brain. Autometallographic (AMG) staining revealed a similar cellular localization of silver in ileum, liver, and kidney tissue in rats exposed to AgNPs or AgAc.
Using transmission electron microscopy (TEM), nanosized granules were detected in the ileum of animals exposed to AgNPs or AgAc and were mainly located in the basal lamina of the ileal epithelium and in lysosomes of macrophages within the lamina propria. Using energy dispersive x-ray spectroscopy it was shown that the granules in lysosomes consisted of silver, selenium, and sulfur for both AgNP and AgAc exposed rats. The diameter of the deposited granules was in the same size range as that of the administered AgNPs. No silver granules were detected by TEM in the liver.
The results of the present study demonstrate that the organ distribution of silver was similar when AgNPs or AgAc were administered orally to rats. The presence of silver granules containing selenium and sulfur in the intestinal wall of rats exposed to either of the silver forms suggests a common mechanism of their formation. Additional studies however, are needed to gain further insight into the underlying mechanisms of the granule formation, and to clarify whether AgNPs dissolve in the gastrointestinal system and/or become absorbed and translocate as intact nanoparticles to organs and tissues.
PMCID: PMC3123173  PMID: 21631937
9.  PVP-coated, negatively charged silver nanoparticles: A multi-center study of their physicochemical characteristics, cell culture and in vivo experiments 
PVP-capped silver nanoparticles with a diameter of the metallic core of 70 nm, a hydrodynamic diameter of 120 nm and a zeta potential of −20 mV were prepared and investigated with regard to their biological activity. This review summarizes the physicochemical properties (dissolution, protein adsorption, dispersability) of these nanoparticles and the cellular consequences of the exposure of a broad range of biological test systems to this defined type of silver nanoparticles. Silver nanoparticles dissolve in water in the presence of oxygen. In addition, in biological media (i.e., in the presence of proteins) the surface of silver nanoparticles is rapidly coated by a protein corona that influences their physicochemical and biological properties including cellular uptake. Silver nanoparticles are taken up by cell-type specific endocytosis pathways as demonstrated for hMSC, primary T-cells, primary monocytes, and astrocytes. A visualization of particles inside cells is possible by X-ray microscopy, fluorescence microscopy, and combined FIB/SEM analysis. By staining organelles, their localization inside the cell can be additionally determined. While primary brain astrocytes are shown to be fairly tolerant toward silver nanoparticles, silver nanoparticles induce the formation of DNA double-strand-breaks (DSB) and lead to chromosomal aberrations and sister-chromatid exchanges in Chinese hamster fibroblast cell lines (CHO9, K1, V79B). An exposure of rats to silver nanoparticles in vivo induced a moderate pulmonary toxicity, however, only at rather high concentrations. The same was found in precision-cut lung slices of rats in which silver nanoparticles remained mainly at the tissue surface. In a human 3D triple-cell culture model consisting of three cell types (alveolar epithelial cells, macrophages, and dendritic cells), adverse effects were also only found at high silver concentrations. The silver ions that are released from silver nanoparticles may be harmful to skin with disrupted barrier (e.g., wounds) and induce oxidative stress in skin cells (HaCaT). In conclusion, the data obtained on the effects of this well-defined type of silver nanoparticles on various biological systems clearly demonstrate that cell-type specific properties as well as experimental conditions determine the biocompatibility of and the cellular responses to an exposure with silver nanoparticles.
PMCID: PMC4222445  PMID: 25383306
aerosols; biological properties; cell biology; nanoparticles; nanotoxicology; silver
10.  Gold-silver alloy nanoshells: a new candidate for nanotherapeutics and diagnostics 
Nanoscale Research Letters  2011;6(1):554.
We have developed novel gold-silver alloy nanoshells as magnetic resonance imaging (MRI) dual T1 (positive) and T2 (negative) contrast agents as an alternative to typical gadolinium (Gd)-based contrast agents. Specifically, we have doped iron oxide nanoparticles with Gd ions and sequestered the ions within the core by coating the nanoparticles with an alloy of gold and silver. Thus, these nanoparticles are very innovative and have the potential to overcome toxicities related to renal clearance of contrast agents such as nephrogenic systemic fibrosis. The morphology of the attained nanoparticles was characterized by XRD which demonstrated the successful incorporation of Gd(III) ions into the structure of the magnetite, with no major alterations of the spinel structure, as well as the growth of the gold-silver alloy shells. This was supported by TEM, ICP-AES, and SEM/EDS data. The nanoshells showed a saturation magnetization of 38 emu/g because of the presence of Gd ions within the crystalline structure with r1 and r2 values of 0.0119 and 0.9229 mL mg-1 s-1, respectively (Au:Ag alloy = 1:1). T1- and T2-weighted images of the nanoshells showed that these agents can both increase the surrounding water proton signals in the T1-weighted image and reduce the signal in T2-weighted images. The as-synthesized nanoparticles exhibited strong absorption in the range of 600-800 nm, their optical properties being strongly dependent upon the thickness of the gold-silver alloy shell. Thus, these nanoshells have the potential to be utilized for tumor cell ablation because of their absorption as well as an imaging agent.
PMCID: PMC3212091  PMID: 21995302
11.  Oxidative stress mediated cytotoxicity of biologically synthesized silver nanoparticles in human lung epithelial adenocarcinoma cell line 
Nanoscale Research Letters  2014;9(1):459.
The goal of the present study was to investigate the toxicity of biologically prepared small size of silver nanoparticles in human lung epithelial adenocarcinoma cells A549. Herein, we describe a facile method for the synthesis of silver nanoparticles by treating the supernatant from a culture of Escherichia coli with silver nitrate. The formation of silver nanoparticles was characterized using various analytical techniques. The results from UV-visible (UV-vis) spectroscopy and X-ray diffraction analysis show a characteristic strong resonance centered at 420 nm and a single crystalline nature, respectively. Fourier transform infrared spectroscopy confirmed the possible bio-molecules responsible for the reduction of silver from silver nitrate into nanoparticles. The particle size analyzer and transmission electron microscopy results suggest that silver nanoparticles are spherical in shape with an average diameter of 15 nm. The results derived from in vitro studies showed a concentration-dependent decrease in cell viability when A549 cells were exposed to silver nanoparticles. This decrease in cell viability corresponded to increased leakage of lactate dehydrogenase (LDH), increased intracellular reactive oxygen species generation (ROS), and decreased mitochondrial transmembrane potential (MTP). Furthermore, uptake and intracellular localization of silver nanoparticles were observed and were accompanied by accumulation of autophagosomes and autolysosomes in A549 cells. The results indicate that silver nanoparticles play a significant role in apoptosis. Interestingly, biologically synthesized silver nanoparticles showed more potent cytotoxicity at the concentrations tested compared to that shown by chemically synthesized silver nanoparticles. Therefore, our results demonstrated that human lung epithelial A549 cells could provide a valuable model to assess the cytotoxicity of silver nanoparticles.
PMCID: PMC4167841  PMID: 25242904
Adenocarcinoma cells A549; Reactive oxygen species generation (ROS); Lactate dehydrogenase (LDH); Mitochondrial transmembrane potential (MTP); Silver nanoparticles (AgNP)
12.  Imaging in detecting sites of pulmonary fibrosis induced by paraquat 
The most common cause of death from paraquat (PQ) poisoning is respiratory failure from pulmonary fibrosis, which develops through pathological overproduction of extracellular matrix proteins such as collagens. In this study, a MicroCT system was used to observe dynamic changes of pulmonary fibrosis in rats with PQ poisoning, and find the characteristics of interstitial lung diseases via density-based and texture-based analysis of CT images of the lung structure.
A total of 15 male SD rats were randomly divided into a control group (n=5) and a PQ poisoning group (n=10). The rats in the poisoning group were intraperitoneally administered with 4 mg/ mL PQ at 14 mg/kg, and the rats in the control group were administered with the same volume of saline. The signs of pulmonary fibrosis observed by the MicroCT included ground-glass opacity, nodular pattern, subpleural interstitial thickening, consolidation honeycomb-like shadow of the lung.
Compared with the control group, the rats with acute PQ poisoning had different signs of pulmonary fibrosis. Ground-glass opacity and consolidation of the lung appeared at the early phase of pulmonary fibrosis, and subpleural interstitial thickening and honeycomb-like shadow developed at the middle or later stage. MicroCT images showed that fibrotic lung tissues were denser than normal lungs, and their density was up-regulated with pulmonary fibrosis. There was no difference in the progress of pulmonary fibrosis between the right lung and the left lung (P>0.05), but there were differences in fibrosis degree at different sites in the lung (P<0.05 or P<0.01). Pulmonary fibrosis was mainly seen in the exterior area of the middle-lower part of the lung.
Imaging can show the development of pulmonary fibrosis in PQ poisoning rats, and this method may help to administer drugs more reasonably in treating pulmonary fibrosis.
PMCID: PMC4129732  PMID: 25214982
MicroCT; CT value; Paraquat; Pulmonary fibrosis; Region of interest
13.  Alveolar-Membrane Diffusing Capacity Limits Performance in Boston Marathon Qualifiers 
PLoS ONE  2012;7(9):e44513.
(1) to examine the relation between pulmonary diffusing capacity and marathon finishing time, and (2), to evaluate the accuracy of pulmonary diffusing capacity for nitric oxide (DLNO) in predicting marathon finishing time relative to that of pulmonary diffusing capacity for carbon monoxide (DLCO).
28 runners [18 males, age = 37 (SD 9) years, body mass = 70 (13) kg, height = 173 (9) cm, percent body fat = 17 (7) %] completed a test battery consisting of measurement of DLNO and DLCO at rest, and a graded exercise test to determine running economy and aerobic capacity prior to the 2011 Steamtown Marathon (Scranton, PA). One to three weeks later, all runners completed the marathon (range: 2∶22:38 to 4∶48:55). Linear regressions determined the relation between finishing time and a variety of anthropometric characteristics, resting lung function variables, and exercise parameters.
In runners meeting Boston Marathon qualification standards, 74% of the variance in marathon finishing time was accounted for by differences in DLNO relative to body surface area (BSA) (SEE = 11.8 min, p<0.01); however, the relation between DLNO or DLCO to finishing time was non-significant in the non-qualifiers (p = 0.14 to 0.46). Whereas both DLCO and DLNO were predictive of finishing time for all finishers, DLNO showed a stronger relation (r2 = 0.30, SEE = 33.4 min, p<0.01) compared to DLCO when considering BSA.
DLNO is a performance-limiting factor in only Boston qualifiers. This suggests that alveolar-capillary membrane conductance is a limitation to performance in faster marathoners. Additionally, DLNO/BSA predicts marathon finishing time and aerobic capacity more accurately than DLCO.
PMCID: PMC3439386  PMID: 22984520
14.  Synthesis of silver nanoparticles and antibacterial property of silk fabrics treated by silver nanoparticles 
Nanoscale Research Letters  2014;9(1):216.
A silver nanoparticle solution was prepared in one step by mixing AgNO3 and a multi-amino compound (RSD-NH2) solution under ambient condition. RSD-NH2 was in-house synthesized by methacrylate and polyethylene polyamine in methanol, which has abundant amino and imino groups. However, the characterization of silver nanoparticles indicated that these nanoparticles are easy to agglomerate in solution. Therefore, an in situ synthesis method of silver nanoparticles on the silk fabrics was developed. The examined results confirmed that the in situ synthesized silver nanoparticles were evenly distributed on the surface of fibers. The inhibition zone test and the antibacterial rate demonstrated that the finished fabrics have an excellent antibacterial property against Staphylococcus aureus and Escherichia coli. Moreover, the nanosilver-treated silk fabrics were laundered 0, 5, 10, 20, and 50 times and still retained the exceptional antibacterial property. When the treated fabrics were washed 50 times, the antibacterial rate is more than 97.43% for S. aureus and 99.86% for E. coli. The excellent laundering durability may be attributed to the tight binding between silver nanoparticles and silk fibers through the in situ synthesis. This method provides an economic method to enhance the antibacterial capability of silk fabrics with good resistance to washings.
PMCID: PMC4022402  PMID: 24872803
Silver nanoparticle; Multi-amino compound (RSD-NH2); Antibacterial activity; Silk fabric
15.  Potential Theranostics Application of Bio-Synthesized Silver Nanoparticles (4-in-1 System) 
Theranostics  2014;4(3):316-335.
In this report, we have designed a simple and efficient green chemistry approach for the synthesis of colloidal silver nanoparticles (b-AgNPs) that is formed by the reduction of silver nitrate (AgNO3) solution using Olax scandens leaf extract. The colloidal b-AgNPs, characterized by various physico-chemical techniques exhibit multifunctional biological activities (4-in-1 system). Firstly, bio-synthesized silver nanoparticles (b-AgNPs) shows enhanced antibacterial activity compared to chemically synthesize silver nanoparticles (c-AgNPs). Secondly, b-AgNPs show anti-cancer activities to different cancer cells (A549: human lung cancer cell lines, B16: mouse melanoma cell line & MCF7: human breast cancer cells) (anti-cancer). Thirdly, these nanoparticles are biocompatible to rat cardiomyoblast normal cell line (H9C2), human umbilical vein endothelial cells (HUVEC) and Chinese hamster ovary cells (CHO) which indicates the future application of b-AgNPs as drug delivery vehicle. Finally, the bio-synthesized AgNPs show bright red fluorescence inside the cells that could be utilized to detect the localization of drug molecules inside the cancer cells (a diagnostic approach). All results together demonstrate the multifunctional biological activities of bio-synthesized AgNPs (4-in-1 system) that could be applied as (i) anti-bacterial & (ii) anti-cancer agent, (iii) drug delivery vehicle, and (iv) imaging facilitator. To the best of our knowledge, there is not a single report of biosynthesized AgNPs that demonstrates the versatile applications (4-in-1 system) towards various biomedical applications. Additionally, a plausible mechanistic approach has been explored for the synthesis of b-AgNPs and its anti-bacterial as well as anti-cancer activity. We strongly believe that bio-synthesized AgNPs will open a new direction towards various biomedical applications in near future.
PMCID: PMC3915094  PMID: 24505239
Bio-synthesis; Silver nanoparticle; Green Chemistry; Olax scandens; Multifunctional activities; Antibacterial; anti-cancer.
16.  Modeling the Response of a Biofilm to Silver-Based Antimicrobial 
Mathematical biosciences  2013;244(1):29-39.
Biofilms are found within the lungs of patients with chronic pulmonary infections, in particular patients with cystic fibrosis, and are the major cause of morbidity and mortality for these patients. The work presented here is part of a large interdisciplinary effort to develop an effective drug delivery system and treatment strategy to kill biofilms growing in the lung. The treatment strategy exploits silver-based antimicrobials, in particular, silver carbene complexes (SCC). This manuscript presents a mathematical model describing the growth of a biofilm and predicts the response of a biofilm to several basic treatment strategies. The continuum model is composed of a set of reaction-diffusion equations for the transport of soluble components (nutrient and antimicrobial), coupled to a set of reaction-advection equations for the particulate components (living, inert, and persister bacteria, extracellular polymeric substance, and void). We explore the efficacy of delivering SCC both in an aqueous solution and in biodegradable polymer nanoparticles. Minimum bactericidal concentration (MBC) levels of antimicrobial in both free and nanoparticle-encapsulated forms are estimated. Antimicrobial treatment demonstrates a biphasic killing phenomenon, where the active bacterial population is killed quickly followed by a slower killing rate, which indicates the presence of a persister population. Finally, our results suggest that a biofilm with a ready supply of nutrient throughout its depth has fewer persister bacteria and hence may be easier to treat than one with less nutrient.
PMCID: PMC3697101  PMID: 23628237
biofilm modeling; antimicrobial; silver; nanoparticle; drug delivery
17.  Attenuation of allergic airway inflammation and hyperresponsiveness in a murine model of asthma by silver nanoparticles 
The use of silver in the past demonstrated the certain antimicrobial activity, though this has been replaced by other treatments. However, nanotechnology has provided a way of producing pure silver nanoparticles, and it shows cytoprotective activities and possible pro-healing properties. But, the mechanism of silver nanoparticles remains unknown. This study was aimed to investigate the effects of silver nanoparticles on bronchial inflammation and hyperresponsiveness. We used ovalbumin (OVA)-inhaled female C57BL/6 mice to evaluate the roles of silver nanoparticles and the related molecular mechanisms in allergic airway disease. In this study with an OVA-induced murine model of allergic airway disease, we found that the increased inflammatory cells, airway hyperresponsiveness, increased levels of IL-4, IL-5, and IL-13, and the increased NF-κB levels in lungs after OVA inhalation were significantly reduced by the administration of silver nanoparticles. In addition, we have also found that the increased intracellular reactive oxygen species (ROS) levels in bronchoalveolar lavage fluid after OVA inhalation were decreased by the administration of silver nanoparticles. These results indicate that silver nanoparticles may attenuate antigen-induced airway inflammation and hyperresponsiveness. And antioxidant effect of silver nanoparticles could be one of the molecular bases in the murine model of asthma. These findings may provide a potential molecular mechanism of silver nanoparticles in preventing or treating asthma.
PMCID: PMC2950409  PMID: 20957173
allergic airway disease; NF-κB; oxidative stress; silver nanoparticles
18.  Regional Eradication of Mycoplasma hyopneumoniae From Pig Herds and Documentation of Freedom of the Disease 
Acta Veterinaria Scandinavica  2001;42(3):355-364.
The objectives of this study were to 1) screen all sow herds in a region for M. hyopneumoniae, 2) to effectuate an eradication programme in all those herds which were shown to be infected with M. hyopneumoniae, and 3) to follow the success of the screening and the eradication programmes. The ultimate goal was to eradicate M. hyopneumoniae from all member herds of a cooperative slaughterhouse (153 farrowing herds + 85 farrowing-to-finishing herds + 150 specialised finishing herds) before year 2000. During 1998 and 1999, a total of 5067 colostral whey and 755 serum samples (mean, 25 samples/herd) were collected from sow herds and analysed for antibodies to M. hyopneumoniae by ELISA. Antibodies were detected in 208 (3.6%) samples. Two farrowing herds (1.3%) and 20 farrowing-to-finishing herds (23.5%) were shown to be infected with M. hyopneumoniae. A programme to eradicate the infection from these herds was undertaken. During March 2000, a survey was made to prove the success of the screening and the eradication programmes. In total, 509 serum samples were collected randomly from slaughtered finishing pigs. Antibodies to M. hyopneumoniae were not detected in 506 of the samples, whereas 3 samples were considered suspicious or positive. Accordingly, 3 herds were shown to be infected. One of the herds was previously falsely classified as non-infected. Two of the herds were finishing herds practising continuous flow system (CF). Unlike finishing herds which practice all-in/all-out management routines on herd level, CF herds do not get rid of transmissible diseases spontaneously between batches, for which reason a screening was made in the rest of the CF herds (total n = 7). Consequently, 2 more infected herds were detected. In addition to the results of the survey, a decreasing prevalence of lung lesions at slaughter (from 5.2% to 0.1%) and lack of clinical breakdowns indicated that all member herds were finally free from M. hyopneumoniae in the end of year 2000.
PMCID: PMC2202326  PMID: 11887396
ELISA; colostrum; antibodies; all-in/all-out; lung lesions; screening; sampling; survey
19.  Subchronic oral toxicity of silver nanoparticles 
The antibacterial effect of silver nanoparticles has resulted in their extensive application in health, electronic, consumer, medicinal, pesticide, and home products; however, silver nanoparticles remain a controversial area of research with respect to their toxicity in biological and ecological systems.
This study tested the oral toxicity of silver nanoparticles (56 nm) over a period of 13 weeks (90 days) in F344 rats following Organization for Economic Cooperation and Development (OECD) test guideline 408 and Good Laboratory Practices (GLP). Five-week-old rats, weighing about 99 g for the males and 92 g for the females, were divided into four 4 groups (10 rats in each group): vehicle control, low-dose (30 mg/kg), middle-dose (125 mg/kg), and high-dose (500 mg/kg). After 90 days of exposure, clinical chemistry, hematology, histopathology, and silver distribution were studied. There was a significant decrease (P < 0.05) in the body weight of male rats after 4 weeks of exposure, although there were no significant changes in food or water consumption during the study period. Significant dose-dependent changes were found in alkaline phosphatase and cholesterol for the male and female rats, indicating that exposure to more than 125 mg/kg of silver nanoparticles may result in slight liver damage. Histopathologic examination revealed a higher incidence of bile-duct hyperplasia, with or without necrosis, fibrosis, and/or pigmentation, in treated animals. There was also a dose-dependent accumulation of silver in all tissues examined. A gender-related difference in the accumulation of silver was noted in the kidneys, with a twofold increase in female kidneys compared to male kidneys.
The target organ for the silver nanoparticles was found to be the liver in both the male and female rats. A NOAEL (no observable adverse effect level) of 30 mg/kg and LOAEL (lowest observable adverse effect level) of 125 mg/kg are suggested from the present study.
PMCID: PMC2928176  PMID: 20691052
20.  Pleurodesis Induction in Rats by Copaiba (Copaifera multijuga Hayne) Oil 
BioMed Research International  2014;2014:939738.
This study aims to assess and compare copaiba oleoresin of Copaifera multijuga and 0.5% silver nitrate for the induction of pleurodesis in an experimental model. Ninety-six male Wistar rats were divided into three groups: control (0.9% saline solution), copaiba (copaiba oil), and silver nitrate (0.5% silver nitrate). The substances were injected into the right pleural cavity and the alterations were observed macroscopically and microscopically at 24, 48, 72, and 504 h. The value of macroscopic alterations grade and acute inflammatory reaction grade means was higher in the 24 h copaiba group in relation to silver nitrate. Fibrosis and neovascularization means in the visceral pleura were higher in 504 h copaiba group in relation to the silver nitrate group. The grade of the alveolar edema mean was higher in the silver nitrate group in relation to the copaiba group, in which this alteration was not observed. The presence of bronchopneumonia was higher in the 24 h silver nitrate group (n = 4) in relation to the copaiba group (n = 0). In conclusion, both groups promoted pleurodesis, with better results in copaiba group and the silver nitrate group presented greater aggression to the pulmonary parenchyma.
PMCID: PMC4066724  PMID: 24999484
21.  Quantification of Lung Fibrosis and Emphysema in Mice Using Automated Micro-Computed Tomography 
PLoS ONE  2012;7(8):e43123.
In vivo high-resolution micro-computed tomography allows for longitudinal image-based measurements in animal models of lung disease. The combination of repetitive high resolution imaging with fully automated quantitative image analysis in mouse models of lung fibrosis lung benefits preclinical research. This study aimed to develop and validate such an automated micro-computed tomography analysis algorithm for quantification of aerated lung volume in mice; an indicator of pulmonary fibrosis and emphysema severity.
Mice received an intratracheal instillation of bleomycin (n = 8), elastase (0.25U elastase n = 9, 0.5U elastase n = 8) or saline control (n = 6 for fibrosis, n = 5 for emphysema). A subset of mice was scanned without intervention, to evaluate potential radiation-induced toxicity (n = 4). Some bleomycin-instilled mice were treated with imatinib for proof of concept (n = 8). Mice were scanned weekly, until four weeks after induction, when they underwent pulmonary function testing, lung histology and collagen quantification. Aerated lung volumes were calculated with our automated algorithm.
Principal Findings
Our automated image-based aerated lung volume quantification method is reproducible with low intra-subject variability. Bleomycin-treated mice had significantly lower scan-derived aerated lung volumes, compared to controls. Aerated lung volume correlated with the histopathological fibrosis score and total lung collagen content. Inversely, a dose-dependent increase in lung volume was observed in elastase-treated mice. Serial scanning of individual mice is feasible and visualized dynamic disease progression. No radiation-induced toxicity was observed. Three-dimensional images provided critical topographical information.
We report on a high resolution in vivo micro-computed tomography image analysis algorithm that runs fully automated and allows quantification of aerated lung volume in mice. This method is reproducible with low inherent measurement variability. We show that it is a reliable quantitative tool to investigate experimental lung fibrosis and emphysema in mice. Its non-invasive nature has the unique benefit to allow dynamic 4D evaluation of disease processes and therapeutic interventions.
PMCID: PMC3418271  PMID: 22912805
22.  Pneumocystis carinii pneumonia: detection of parasites in sputum and bronchoalveolar lavage fluid by monoclonal antibodies. 
BMJ : British Medical Journal  1988;297(6645):381-384.
Diagnosis of pneumocystis pneumonia is based on identifying Pneumocystis carinii cytochemically in material from the lung. The silver methenamine staining methods most commonly used are technically difficult and lack specificity. The diagnostic value of immunocytological identification of the parasite was evaluated by using mouse monoclonal antibody 3F6, specific for human pneumocystis, to identify P carinii in bronchoalveolar lavage fluid and sputum by immunofluorescence and was compared with that of other variables. Bronchoalveolar lavage was performed on 25 patients positive for HIV antibody with clinically suspected pneumocystis pneumonia and 40 patients negative for HIV antibody who presented with interstitial disorders of the lung. Lavage fluid showed pneumocystis only in the patients positive for antibody, the parasite being detected in 19 by immunofluorescence and in 17 by a modified silver methenamine staining method. Chest x ray films obtained at the time of bronchoscopy showed interstitial or alveolar shadowing in 17 of the 19 patients, but clinical symptoms and the presence of antibodies to pneumocystis did not seem to be predictive. Sputum samples were collected during 43 episodes of clinically suspected pneumocystis pneumonia in patients positive for HIV antibody. Pneumocystis was detected consistently more commonly by immunofluorescence than the silver strain in sputum collected routinely and induced by inhalation of saline. In 17 patients bronchoalveolar lavage followed sputum collection, and the sensitivity of detection of pneumocystis in immunofluorescence in sputum compared with lavage fluid was 57% (8/14). Immunofluorescence was suitable for specimens fixed in ethanol and seemed highly specific and more sensitive than the standard cytochemical methods for identifying pneumocystis.
PMCID: PMC1834294  PMID: 3044514
23.  Luminescent Properties of Eu(III) Chelates on Metal Nanorods 
In this article, we report the change of optical properties for europium chelates on silver nanorods by near-field interactions. The silver rods were fabricated in a seed-growth method followed by depositing thin layers of silica on the surfaces. The europium chelates were physically absorbed in the silica layers on the silver rods. The silver rods were observed to exhibit two plasmon absorption bands from longitudinal and transverse directions, respectively, centered at 394 and 675 nm, close to absorption and emission bands from the Eu(III) chelates. As a result, the immobilized Eu(III) chelates on the silver rods should have strong interactions with the silver nanorods and lead to greatly improved optical properties. The Eu–Ag rod complexes were observed to have enhanced emission intensity up to 240-fold in comparison with the Eu(III) chelates in the metal-free silica templates. This enhancement is much larger than the value for the Eu(III) chelates on the gold rods or silver spheres indicating the presence of stronger interactions for the Eu(III) chelates with the silver rods. The interactions of Eu(III) chelates with the silver rods were also proven by extremely reduced lifetime. Moreover, the Eu–Ag rod complexes exhibited a polarized emission, which was also due to strong interactions of the Eu(III) chelates with the silver rods. All of these features may promise that the Eu(III)–Ag rod complexes have great potential for use as fluorescence imaging agents in biological assays.
PMCID: PMC3868211  PMID: 24363816
24.  Evaluating Nanoparticle Breakthrough during Drinking Water Treatment 
Environmental Health Perspectives  2013;121(10):1161-1166.
Background: Use of engineered nanoparticles (NPs) in consumer products is resulting in NPs in drinking water sources. Subsequent NP breakthrough into treated drinking water is a potential exposure route and human health threat.
Objectives: In this study we investigated the breakthrough of common NPs—silver (Ag), titanium dioxide (TiO2), and zinc oxide (ZnO)—into finished drinking water following conventional and advanced treatment.
Methods: NPs were spiked into five experimental waters: groundwater, surface water, synthetic freshwater, synthetic freshwater containing natural organic matter, and tertiary wastewater effluent. Bench-scale coagulation/flocculation/sedimentation simulated conventional treatment, and microfiltration (MF) and ultrafiltration (UF) simulated advanced treatment. We monitored breakthrough of NPs into treated water by turbidity removal and inductively coupled plasma–mass spectrometry (ICP-MS).
Results: Conventional treatment resulted in 2–20%, 3–8%, and 48–99% of Ag, TiO2, and ZnO NPs, respectively, or their dissolved ions remaining in finished water. Breakthrough following MF was 1–45% for Ag, 0–44% for TiO2, and 36–83% for ZnO. With UF, NP breakthrough was 0–2%, 0–4%, and 2–96% for Ag, TiO2, and ZnO, respectively. Variability was dependent on NP stability, with less breakthrough of aggregated NPs compared with stable NPs and dissolved NP ions.
Conclusions: Although a majority of aggregated or stable NPs were removed by simulated conventional and advanced treatment, NP metals were detectable in finished water. As environmental NP concentrations increase, we need to consider NPs as emerging drinking water contaminants and determine appropriate drinking water treatment processes to fully remove NPs in order to reduce their potential harmful health outcomes.
Citation: Abbott Chalew TE, Ajmani GS, Huang H, Schwab KJ. 2013. Evaluating nanoparticle breakthrough during drinking water treatment. Environ Health Perspect 121:1161–1166;
PMCID: PMC3801469  PMID: 23933526
25.  Restrictive lung function and asbestos-induced pleural fibrosis. A quantitative approach. 
Journal of Clinical Investigation  1993;91(6):2685-2692.
To assess further the clinical significance of asbestos-induced pleural fibrosis, we used a computer algorithm to reconstruct images three dimensionally from the high-resolution computerized tomography (HRCT) scan of the chest in 60 asbestos-exposed subjects. Pulmonary function tests, chest radiographs, and HRCT scans were performed on all study subjects. The volume of asbestos-induced pleural fibrosis was computed from the three-dimensional reconstruction of the HRCT scan. Among those with pleural fibrosis identified on the HRCT scan (n = 29), the volume of the pleural lesion varied from 0.01% (0.5 ml) and 7.11% (260.4 ml) of the total chest cavity. To investigate the relationship between asbestos-induced pleural fibrosis and restrictive lung function, we compared the computer-derived estimate of pleural fibrosis to the total lung capacity and found that these measures were inversely related (r = -0.40; P = 0.002). After controlling for age, height, pack-years of cigarette smoking, and the presence of interstitial fibrosis on the chest radiograph, the volume of pleural fibrosis identified on the three-dimensional reconstructed image from the HRCT scan was inversely associated with the total lung capacity (P = 0.03) and independently accounted for 9.5% of the variance of this measure of lung volume. These findings further extend the scientific data supporting an independent association between pleural fibrosis and restrictive lung function.
PMCID: PMC443332  PMID: 8514875

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