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Antibiotic-loaded bone cement beads have been a reliable passive delivery system for the localized treatment of osteomyelitis; however, low, and unregulated drug release rates limit the ability of this system to maintain therapeutic concentrations. This problem is further amplified by drug-resistant pathogens that might invade or evolve under these conditions. Furthermore, currently available bone cements are incompatible with some antibiotics. The proposed device resembles conventional bone cement beads but contains an on-demand drug delivery magnetic sponge that provides actively controlled release of antibiotics. The slightly porous structure facilitates some drug diffusion while further drug release may be controlled remotely via magnetic actuation. Additionally, a combination of silver nitrate and gentamicin are used in the device as these agents are shown to display a synergistic antibacterial activity in vitro using checkerboard and time-kill assays. The device releases gentamicin and silver in both actuation and diffusion modes over 7 days. The in vitro bacterial studies demonstrate the efficacy of the released agents alone, and synergistically in combination, against Methicillin-resistant Staphylococcus aureus and Escherichia coli. The proposed device offers a facile fabrication process which allows control of the release profile by engineering hole configurations or manipulating magnetic field strength to provide the most effective therapy.

Epigallocatechin gallate (EGCG) and tannic acid (TA) are known to increase the aqueous solubility and cellular uptake of the hydrophobic drugs docetaxel, paclitaxel, amphotericin B, and curcumin. In this study the practical application of gallate-based solubilization phenomena for the uptake of these drugs into dermal and bladder tissue and of lidocaine for wound healing application was studied. The penetration of all these drugs into pig skin or docetaxel into pig bladder using EGCG or TA formulations was measured. Overall, EGCG and TA particulate or propylene glycol paste formulations of drugs allowed for greatly increased levels of drug uptake into skin as compared to control formulations. EGCG/propylene glycol pastes allowed for rapid lidocaine uptake into skin. EGCG and TA formulations of docetaxel allowed for approximately 10 fold increases in bladder tissue uptake of docetaxel over tween based solutions. Morphologically, both EGCG and TA caused a mild, dose dependent exfoliation of the bladder wall. Both EGCG and TA formed injectable viscous pastes with propylene glycol which solidified in water and degraded and released lidocaine over 2-35 days. These data support the use of EGCG and TA based formulations of certain drugs for improved dermal, bladder and wound applications.

Finasteride is used to treat benign prostatic hyperplasia (BPH) and pattern hair loss (androgenetic alopecia or APA). The local administration of formulations with increased solubility and controlled release of finasteride are proposed using gallate-containing compositions within embolic microparticles or paste. Finasteride solubility in either epigallocatechin gallate (EGCG) or tannic acid (TA) solutions was assessed using HPLC. Poly( dl -lactide-co-glycolide) (PLGA) or poly(methylmethacrylate) (PMMA) microspheres (100–400 μm) containing finasteride and EGCG or TA were effectively manufactured. Embolic particles were loaded with finasteride/EGCG/TA. Dermal uptake of TA/EGCG/finasteride topical compositions was measured in pig skin. The solubility of finasteride was dramatically increased using EGCG- or TA-based compositions. Finasteride loaded microspheres released over two months which was increased by EGCG or TA inclusion. Embolic particles soaked up finasteride and EGCG or TA and released the encapsulated drug over two weeks. Dermal uptake of finasteride from EGCG- or TA-based formulations was enhanced between 10 and 50 fold in layers as deep as 500 μm when compared to a generic control formulation. Gallate-based formulations of finasteride increase drug solubility and allow for effective release of the drug from embolic formulations. Paste or powder EGCG- or TA-based formulations of finasteride greatly increase dermal penetration of the drug.

Under summer-like photoperiods (15∶9 L∶D) with abundant high-quality food, larval growth and development of the baetid mayflies (Ephemeroptera) Cloeon dipterum-IS1 and C. dipterum-CT1 were ...

There is an urgent environmental need to remediate waste water. In this study, the use of surface-modified nanocrystalline cellulose (CNC) to remove polluting drugs or chemicals from waste water and oil sands tailing ponds has been investigated. CNC was modified by either surface adsorbing cationic or hydrophobic species or by covalent methods and integrated into membrane water filters. The removal of either diclofenac or estradiol from water was studied. Similar non-covalently modified CNC materials were used to flocculate clays from water or to bind naphthenic acids which are contaminants in tailing ponds. Estradiol bound well to hydrophobically modified CNC membrane filter systems. Similarly, diclofenac (anionic drug) bound well to covalently cationically modified CNC membranes. Non-covalent modified CNC effectively flocculated clay particles in water and bound two naphthenic acid chemicals (negatively charged and hydrophobic). Modified CNC integrated into water filter membranes may remove drugs from waste or drinking water and contaminants from tailing ponds water. Furthermore, the ability of modified CNC to flocculate clays particles and bind naphthenic acids may allow for the addition of modified CNC directly to tailing ponds to remove both contaminants. CNC offers an environmentally friendly, easily transportable and disposable novel material for water remediation purposes.

Focal therapy has emerged as a treatment option for low- to intermediate-risk localized prostate cancer (PCa) patients, to balance the risks for urinary and sexual morbidity of radical treatment with the psychological burden of active surveillance. In this context, we developed ST-4PC, an injectable, polymeric paste formulation containing docetaxel (dtx) and bicalutamide (bic) for image-guided focal therapy of PCa. The objective of this work was to evaluate the in vitro characteristics and in vivo toxicity and efficacy of ST-4PC. In vitro drug release was evaluated using high-performance liquid chromatography. In vivo toxicity of blank- and drug-loaded ST-4PC was assessed in mice and rats. Tumor growth inhibition was evaluated in LNCaP subcutaneous (s.c.) and LNCaP-luc orthotopic xenograft models. Using the s.c. model, mice were monitored weekly for weight loss, tumor volume (TV) and serum PSA. For the orthotopic model, mice were additionally monitored for bioluminescence as measure of tumor growth. ST-4PC demonstrated a sustained and steady release of incorporated drugs with 50% dtx and 20% bic being released after 14 days. While no systemic toxicity was observed, dose-dependent local side effects from dtx developed in the s.c. but not in the orthotopic model, illustrating the limitations of s.c. models for evaluating local cytotoxic therapy. In the s.c. model, 0.1%/4% and 0.25%/4% dtx/bic ST-4PC paste significantly reduced PSA progression, but did not have a significant inhibitory effect on TV. ST-4PC loaded with 1%/4% dtx/bic significantly reduced TV, serum PSA, and bioluminescence in the orthotopic xenograft model. Compared with drugs dissolved in DMSO, ST-4PC significantly delayed tumor growth. Image-guided focal therapy using ST-4PC demonstrated promising inhibition of PSA progression and orthotopic tumor growth in vivo without significant toxicity, and warrants further clinical evaluation.

Watershed restoration for mitigating or preventing impacts of human land use on aquatic ecosystems is now big business and is far more common and consumes far more financial resources than ...

The manufacturing of polymethylmethacrylate(PMMA) microspheres loaded with doxycycline(DOX) and/or silver sulfate(AgPMMA microspheres were manufactured with AgThe median diameter of 50 µm was obtained for microspheres. DOX was encapsulated at an efficiency of 8.3% using a theoretical loading of 15%DOX + 5%AgPMMA microspheres containing DOX and Ag

The prompt treatment of burn wounds is essential but can be challenging in remote parts of Africa, where burns from open fires are a constant hazard for children and suitable medical care may be far away. Consequently, there is an unmet need for an economical burn wound dressing with a sustained antimicrobial activity that might be manufactured locally at low cost. This study describes and characterizes the novel preparation of a silver nitrate-loaded/poly(vinyl alcohol) (PVA) film. Using controlled heating cycles, films may be crosslinked with in situ silver nanoparticle production using only a low heat oven and little technical expertise. Our research demonstrated that heat-curing of PVA/silver nitrate films converted the silver to nanoparticles. These films swelled in water to form a robust, wound-compatible hydrogel which exhibited controlled release of the antibacterial silver nanoparticles. An optimal formulation was obtained using 5% (w/w) silver nitrate in PVA membrane films that had been heated at 140 &deg, C for 90 min. Physical and chemical characterization of such films was complemented by in vitro studies that confirmed the effective antibacterial activity of the released silver nanoparticles against both gram positive and negative bacteria. Overall, these findings provide economical and simple methods to manufacture stable, hydrogel forming wound dressings that release antibiotic silver over prolonged periods suitable for emergency use in remote locations.

Introduction: We previously described the manufacture and characterization of hydrogel forming, thin film, anti-infective wound dressings made from Poly Vinyl Alcohol (PVA) and silver nanoparticles, crosslinked by heat. However, these films were designed to be inexpensive for simple manufacture locally in Africa. In this new study, we have further developed PVA dressings by manufacturing films or electrospun membranes, made from blends of PVA with different degrees of hydrolyzation, that contain silver salts and degrade in a controlled manner to release silver in a sustained manner over 12 days. Methods: Films were solvent cast as films or electrospun into nanofibre membranes using blends of 99 and 88% hydrolyzed PVA, containing 1% w/w silver sulphadiazine, carbonate, sulphate, or acetate salts. Dissolution was measured as weight loss in water and silver release was measured using inductively coupled plasma (ICP) analysis. Results: Cast films generally stayed intact at PVA 99: PVA 88% ratios greater than 40:60 whereas electrospun membranes needed ratios greater than 10:90. Films (40:60 blend ratio) and membranes (10:90) all released silver salts in a sustained fashion but incompletely and to different extents. Electrospun membranes gave more linear release patterns in the 2&ndash, 12 day period and all salts released well. Conclusion: Blended PVA cast films offer improved control over hydrogel dissolution and silver release without the need for high temperature crosslinking. Blended PVA electrospun membranes further improve membrane dissolution control and silver release profiles. These blended PVA films and membranes offer improved inexpensive systems for the manufacture of long lasting anti-infective hydrogel wound dressings.

There is an unmet need for biocompatible, anti-infective, and mechanically strong hydrogels. This study investigated the use of poly vinyl alcohol (PVA), polysaccharides, and nanocrystalline cellulose (CNC) to deliver silver in a controlled manner for possible use against oral or wound bacteria. Silver was included in solvent cast films as silver diammine fluoride (SDF) or as nitrate, sulphate, or acetate salts. Hydrogel formation was assessed by swelling determinations and silver release was measured using inductively coupled plasma methods. Antibacterial studies were performed using Gram-positive and negative bacteria turbidity assays. PVA formed homogenous, strong films with SDF and swelled gently (99% hydrolyzed) or vigorously with dissolution (88% hydrolyzed) and released silver slowly or quickly, respectively. CNC-SDF films swelled over a week and formed robust hydrogels whereas CNC alone (no silver) disintegrated after two days. SDF loaded CNC films released silver slowly over 9 days whereas films crosslinked with silver salts were less robust and swelled and released silver more quickly. All silver loaded films showed good antibacterial activity. CNC may be crosslinked with silver in the form of SDF (or any soluble silver salt) to form a robust hydrogel suitable for dental use such as for exposed periodontal debridement areas.

To better understand the effects of transient thermal stress in an aquatic insect, we first identified static temperatures associated with fitness deficits, and then reared larvae from egg hatch to adulthood under diurnally variable regimens including daily forays into deleterious temperatures. We sampled mature larvae at the coolest and warmest portions of their respective regimens for RNA-seq analysis. Few transcripts (28) were differentially expressed when larvae oscillated between favorable temperatures, while 614 transcripts were differentially expressed when experiencing daily transient thermal stress. Transcripts associated with N-glycan processing were downregulated while those associated with lipid catabolism and chitin turnover were significantly upregulated in heat stressed larvae. An across-regimen comparison of differentially expressed transcripts among organisms sampled at comparable temperatures demonstrated that the effects of daily thermal stress persisted even when larvae were sampled at a more optimal temperature (806 differentially expressed transcripts). The chronically stressed population had reduced expression of transcripts related to ATP synthesis, mitochondrial electron chain functions, gluconeogenesis and glycolytic processes while transcripts associated with cell adhesion, synaptic vesicle transport, regulation of membrane potential and lipid biosynthesis increased. Comparisons of constant vs. variable temperatures revealed that the negative consequences of time spent at stressful temperatures were not offset by more time spent at optimal temperatures.

We hypothesized that physiological and morphological responses to prescribed fire support the post-scorch foliage recovery and growth of young longleaf pine. Two studies conducted in central Louisiana identified three means of foliage regrowth after fire that included an increase in the gas exchange rate of surviving foliage for 3 to 4 months after fire. Saplings also exhibited crown developmental responses to repeated fire that reduced the risk of future crown scorch. Starch reserves were a source of carbon for post-scorch foliage regrowth when fire was applied in the early growing season. However, the annual dynamics of starch accumulation and mobilization restricted its effectiveness for foliage regrowth when fire was applied late in the growing season. As such, post-scorch foliage regrowth became increasingly dependent on photosynthesis as the growing season progressed. Additionally, the loss of foliage by fire late in the growing season interrupted annual starch dynamics and created a starch void between the time of late growing season fire and mid-summer of the next year. The occurrence of drought during both studies revealed barriers to foliage reestablishment and normal stem growth among large saplings. In study 1, spring water deficit at the time of May fire was associated with high crown scorch and poor foliage and stem growth among large saplings. We attribute this lag in stem growth to three factors: little surviving foliage mass, low fascicle gas exchange rates, and poor post-scorch foliage recovery. In study 2, May fire during a short window of favorable burning conditions in the tenth month of a 20-month drought also reduced stem growth among large saplings but this growth loss was not due to poor post-scorch foliage recovery. Application of this information to prescribed fire guidelines will benefit young longleaf pine responses to fire and advance efforts to restore longleaf pine ecosystems.

We describe the preparation of injectable polymeric paste (IPP) formulations for local and sustained release of drugs. Furthermore, we include the characterization and possible applications of such pastes. Particular attention is paid to characteristics relevant to the successful clinical formulation development, such as viscosity, injectability, degradation, drug release, sterilization, stability performance and pharmacokinetics. Paste injectability was characterized using measured viscosity and the Hagen-Poiseuille equation to determine injection forces. Drug degradation, release and formulation stability experiments were performed in vitro and drug levels were quantified using HPLC-UV methods. Pharmacokinetic evaluation of sustained-release lidocaine IPPs used five groups of six rats receiving increasing doses subcutaneously. An anti-cancer formulation was evaluated in a subcutaneous tumor xenograft mouse model. The viscosity and injectability of IPPs could be controlled by changing the polymeric composition. IPPs demonstrated good long-term stability and tunable drug-release with low systemic exposure in vivo in rats. Preliminary data in a subcutaneous tumor model points to a sustained anticancer effect. These IPPs are tunable platforms for local and sustained delivery of drugs and have potential for further clinical development to treat a number of diseases.

An inability to adequately meet tissue oxygen demands has been proposed as an important factor setting upper thermal limits in ectothermic invertebrates (especially aquatic species) as well as explaining the observed decline in adult size with increased rearing temperature during the immature stages (a phenomenon known as the Temperature Size Rule, or TSR). We tested this by rearing three aquatic insects (the mayflies Neocloeon triangulifer and two species of the Cloeon dipterum complex) through their entire larval life under a range of temperature and oxygen concentrations. Hyperoxia did not extend upper thermal limits, nor did it prevent the loss of size or fertility experienced near upper chronic thermal limits. At moderate temperatures, the TSR pattern was observed under conditions of hyperoxia, normoxia, and hypoxia, suggesting little or no influence of oxygen on this trend. However, for a given rearing temperature, adults were smaller and less fecund under hypoxia due to a lowering of growth rates. These mayflies greatly increased the size of their gills in response to lower dissolved oxygen concentrations but not under oxygen-saturated conditions over a temperature range yielding the classic TSR response. Using ommatidium diameter as a proxy for cell size we found the classic TSR pattern observed under moderate temperature conditions was due primarily to a change in the number of cells rather than cell size. We conclude overall that a failure to meet tissue oxygen demands is not a viable hypothesis for explaining either the chronic thermal limit or TSR pattern in these species.

Objective To investigate the effect of three anticancer drugs (mitomycin c (MMC), doxorubicin or gemcitabine) on bladder wall morphology and the uptake of paclitaxel or docetaxel following coadministration. The primary objective of this study was to measure the uptake of MMC, doxorubicin or gemcitabine with or without exposure of the tissue to amine terminated cationic nanoparticles (CNPs) and to investigate any possible exfoliation effects of the three drugs on intact bladder tissue. The secondary objective was to investigate the uptake of taxane drugs (docetaxel, DTX) and paclitaxel, (PTX) from surfactant micelle formulations in the presence of MMC, doxorubicin or gemcitabine. Materials and methods Sections of fresh pig bladder tissue were incubated in Franz diffusion cells with the urothelial side exposed to solutions of doxorubicin, MMC and gemcitabine containing radioactive drug for 90 min. Some tissue samples were simultaneously exposed to each of the three drugs in combination with the surfactant micelle formulations of PTX (Taxol) or DTX (Taxotere). Tissue sections were then cryostat sectioned for drug quantitation by liquid scintillation counting or fixed for scanning electron microscopy and haematoxylin and eosin staining. Results All three drugs caused exfoliation of the urothelial layer of bladder tissues. Drug uptake studies showed that all three drugs effectively penetrated the lamina propria through to the muscular layer over a 2-h incubation and these levels were unaffected by pre-treatment with CNPs. The uptake levels of the taxane drugs PTX and DTX were significantly enhanced following simultaneous treatment of bladders with MMC, doxorubicin or gemcitabine. Conclusion The exfoliation effects of MMC, doxorubicin and gemcitabine allow for good tissue penetration of these drugs with no additional effect from CNP treatment of bladders. The observed exfoliation effect of these amine-containing drugs probably arises from a cationic interaction with the mucus and urothelium cell layer in a manner similar to that previously reported for CNPs. These studies suggest that the lack of long-term clinical efficacy of these drugs may not arise from poor intravesical drug penetration but may result from a rapid diffusion of the drugs into the deeper vascularised muscular region with rapid drug clearance. The enhanced uptake of PTX or DTX following co-administration with MMC, doxorubicin or gemcitabine probably arises from the removal of the urothelial barrier by exfoliation allowing for improved taxane partitioning into superficial layers. These effects may allow for dual drug intravesical strategies offering greatly improved taxane uptake and potential additive drug effects for improved efficacy.

We reared Cloeon dipterum from egg hatch to adult at 10 constant temperatures (12.1–33.5°C) to test 3 hypotheses (thermal equilibrium hypothesis, temperature size rule [TSR], and O2- and ca...

Understanding species' thermal limits and their physiological determinants is critical in light of climate change and other human activities that warm freshwater ecosystems. Here, we ask whether oxygen limitation determines the chronic upper thermal limits in larvae of the mayfly Neocloeon triangulifer, an emerging model for ecological and physiological studies. Our experiments are based on a robust understanding of the upper acute (∼40°C) and chronic thermal limits of this species (>28°C, ≤30°C) derived from full life cycle rearing experiments across temperatures. We tested two related predictions derived from the hypothesis that oxygen limitation sets the chronic upper thermal limits: (1) aerobic scope declines in mayfly larvae as they approach and exceed temperatures that are chronically lethal to larvae; and (2) genes indicative of hypoxia challenge are also responsive in larvae exposed to ecologically relevant thermal limits. Neither prediction held true. We estimated aerobic scope by subtracting measurements of standard oxygen consumption rates from measurements of maximum oxygen consumption rates, the latter of which was obtained by treating with the metabolic uncoupling agent carbonyl cyanide-4-(trifluoromethoxy) pheylhydrazone (FCCP). Aerobic scope was similar in larvae held below and above chronic thermal limits. Genes indicative of oxygen limitation (LDH, EGL-9) were only upregulated under hypoxia or during exposure to temperatures beyond the chronic (and more ecologically relevant) thermal limits of this species (LDH). Our results suggest that the chronic thermal limits of this species are likely not driven by oxygen limitation, but rather are determined by other factors, e.g. bioenergetics costs. We caution against the use of short-term thermal ramping approaches to estimate critical thermal limits (CTmax) in aquatic insects because those temperatures are typically higher than those that occur in nature.

Background The vast majority of prostate cancer presents clinically localized to the prostate without evidence of metastasis. Currently, there are several modalities available to treat this particular disease. Despite radical prostatectomy demonstrating a modest prostate cancer specific mortality benefit in the PIVOT trial, several novel modalities have emerged to treat localized prostate cancer in patients that are either not eligible for surgery or that prefer an alternative approach. Methods Athymic nude mice were subcutaneously inoculated with prostate cancer cells. The mice were divided into four cohorts, one cohort untreated, two cohorts received docetaxel (10 mg/kg) either subcutaneously (SC) or intravenously (IV) and the fourth cohort was treated using the magnetically-actuated docetaxel delivery device (MADDD), dispensing 1.5 μg of docetaxel per 30 min treatment session. Treatment in all three therapeutic arms (SC, IV, and MADDD) was administered once weekly for 6 weeks. Treatment efficacy was measured once a week according to tumor volume using ultrasound. In addition, calipers were used to assess tumor volume. Results Animals implanted with the device demonstrated no signs of distress or discomfort, neither local nor systemic symptoms of inflammation and infection. Using an independent sample t-test, the tumor growth rate of the treated tumors was significant when compared to the control. Post hoc Tukey HSD test results showed that the mean tumor growth rate of our device cohort was significantly lower than SC and control cohorts. Moreover, IV cohort showed slight reduction in mean tumor growth rates than the ones from the device cohort, however, there was no statistical significance in tumor growth rate between these two cohorts. Furthermore, immunohistochemistry demonstrated an increased cellular apoptosis in the MADDD treated tumors and a decreased proliferation when compared to the other cohorts. In addition, IV cohort showed increased treatment side effects (weight loss) when compared to the device cohort. Finally, MADDD showed minimal expression of CD45 comparable to the control cohort, suggesting no signs of chronic inflammation. Conclusions In conclusion, this study showed for the first time that MADDD, clearly suppressed tumor growth in local prostate cancer tumors. This could potentially be a novel clinical treatment approach for localized prostate cancer.

Objective: To investigate the use of polymethyl methacrylate (PMMA) electrospun fiber mats containing different amounts of polyethylene oxide (PEO) as a doxycycline delivery system and to test antibacterial activity against an oral pathogen. Methodology: PMMA powders or PEO (mol wt 200 Kd) (10,20,30% w/w/) were dissolved in N, N-dimethylformamide (DMF) to obtain a final polymer concentration of 15% in DMF (w/v). 2% Doxycycline monohydrate was added to the solutions and submitted to vortex mixing. The solution was transferred to a plastic syringe and fit into a nanofiber electrospinning unit. The parameters applied were: voltage at 17.2 kV; distance of 20 cm between the needle tip and the collector plate; target speed at 2 m/min; and transverse speed at 1cm/min. Syringe pump speed was 0.15 mm/min. The drug release analysis was performed by removing aliquots of the drug-containing solution (in PBS) at specific periods. Doxycycline release was quantified using RP-HPLC. Fiber mats from all groups had their antibacterial action tested against S. mutans based on inhibition halos formed around the specimens. The experiments were performed in triplicate. Gravimetric analysis at specific periods was performed to determine any polymer loss. Morphological characterization of the electrospun fibers was completed under an optical microscope followed by SEM analysis. Results: The addition of PEO to the PMMA fibers did not affect the appearance and diameter of fibers. However, increasing the %PEO caused higher doxycycline release in the first 24 h. Fibers containing 30% PEO showed statistically significant higher release when compared with the other groups. Doxycycline released from the fibers containing 20% or 30% of PEO showed effective against S. mutans. Conclusion: The incorporation of PEO at 20% and 30% into PMMA fiber mat resulted in effective drug release systems, with detected antibacterial activity against S. mutans.

Low-cost, open-source data collectors and a suite of collaborative online tools are making big leaps in the field of watershed monitoring.

Background Intravesical instillation of chemo- or immunotherapy is commonly used in bladder cancer. Upper tract urothelial carcinoma (UTUC) shares similar pathological features, but current formulations are not suitable for direct instillation to the upper urinary tract. Objective To evaluate in vivo applicability, characteristics and toxicity of ST-UC, a mucoadhesive polymeric paste formulation of gemcitabine, for upper urinary tract instillation. Material and methods Three pigs received 10 ml of ST-UC (100 mg/ml gemcitabine) retrogradely into 1 renal pelvis for pharmacokinetic studies. Four days later, a second injection into the contralateral renal pelvis was followed by serial euthanasia of the pigs and nephroureterectomy after 1, 3, and 6 hours. Adverse effects were monitored. Urine, serum, and tissue gemcitabine concentrations were measured, along with histologic examination of the upper urinary tract. Results Retrograde instillation of ST-UC was well tolerated with mild, completely receding hydronephrosis. Urine gemcitabine concentrations were highest in the first 3-hour collection interval. Hundred percent of gemcitabine was recovered in the urine within 24 hours. Serum peak concentrations (cmax) of gemcitabine were low at 5.5 µg/ml compared to the 10 to 30 µg/ml levels observed after a single intravenous dose of 1,000 mg/m2 gemcitabine. The formulation was still traceable after one hour and gemcitabine tissue concentrations are supportive of this extended drug exposure. No major histopathological changes were observed. The main limitation of this study is the lack of antitumor activity data. Conclusion This preclinical evaluation of ST-UC demonstrated feasible instillation in the renal pelvis, no significant safety concerns, and sustained release of gemcitabine.

Hydrotropic solubilization of hydrophobic drugs requires supramolar amounts of hydrotropes with potential toxicity issues. We investigated the use of epigallocatechin gallate (EGCG) and tannic acid at millimolar concentrations, as hydrotrope-like solubilizing agents. Paclitaxel, docetaxel, amphotherecin B, curcumin, or rapamycin were dried down with EGCG or tannic acid from ethanol and then redissolved in aqueous media. Following centrifugation and filtration, the drug solubility was measured using HPLC. The uptake of docetaxel into cells from EGCG-based solutions was measured using radiolabeled drugs. Both EGCG and tannic acid effectively increased the aqueous solubility of all drugs from low levels (μg/mL) to high levels (mg/mL) in a concentration-dependent fashion at millimolar concentrations. Solutions were generally stable at room temperature over 24 h. Compared with micellar formulations, EGCG-based solutions of docetaxel demonstrated markedly improved drug uptake or transport levels in all cell lines. The use of these additives may provide improved formulation of various hydrophobic drugs using oral, parenteral, localized, or device-associated delivery systems.

SUMMARY 1 Competitive interactions are assumed to play a role in governing species distributions but are difficult to infer using observational data. In addition, morphological identification may overlook species, obscuring patterns of competitive exclusion. To address these limitations, we showcase a molecular (DNA barcoding) approach to species-unit delineation and sample stream insect communities at small spatial scales where environmental filtering and dispersal limitations are minimised. 2 Rocks from riffles were sampled for stream insects, in particular caddisfly (Trichoptera), beetle (Coleoptera) and blackfly (Simuliidae) larvae from filterer and grazer guilds at White Clay Creek, Pennsylvania, U.S.A. (20 June, 2013). Additive partitioning of species diversity was used to establish at which spatial scale(s) variation in the distribution of species occurs; this informed us of the spatial scale at which to conduct checkerboard analyses, which tested for signatures of species segregations (e.g. competitive exclusion). 3 Only a small portion of the total species diversity occurred at the smallest spatial level (mean = 30% on individual rocks). Distributional variation in species was greatest at the kilometre scale (where beta-diversity was 37% and 41% for filterers and grazers respectively). At the scale of White Clay Creek sampled (c. 3 km extent), species of filterers showed a strong tendency to segregate on individual rocks, while grazers showed random structure approaching aggregation. 4 This study demonstrates a potential approach to assessing the role of competition in structuring communities using observational data and highlights the importance of accurate species units for analysis (e.g. DNA barcoding). Using a combination of analyses, we were able to link patterns of segregation to competitive interactions among stream insect species in a filterer guild, while determining these interactions were not important in a grazer guild.

Numerous different delivery systems have been developed for local administration of drugs. However, their service lives generally depend on the payload depletion time and most of them are designed for one time use due to lack of drug replenishment abilities. To address this issue, a refillable magnetic porous polydimethylsiloxane (PDMS) capsule is proposed for remotely controlled drug delivery applications. An inner cavity is built in the sponge scaffold to provide space for drug storage and the refilling is accomplished by injecting drugs with a syringe. The rapid and reversible deformation of the magnetic porous structure under a magnetic field offers a controlled pumping force to push drugs out of the capsule. In this work, low molecular weight (methylene blue, MB, 320 g mol−1) and high molecular weight (bovine serum albumin, BSA, 67 000 g mol−1) molecules were used as model compounds to test and verify the operational principle. This proof-of-concept study has demonstrated the capability of the refillable porous capsule in controlled drug delivery under external magnetic stimuli.

A commercial bandage provides a quick solution to small cuts and bruises by absorbing excess blood and covering the wound. In this study, we propose a type of medical dressing using a polydimethylsiloxane (PDMS) membrane with significant potential to improve wound healing conditions. A thin soft Janus PDMS film with opposing porous and nonporous faces is fabricated and tested for qualities applicable to improve current bandages, such as the porosity, stretchability, and water-wettability. The PDMS film can be stretched to 150% of its original length to allow the bending of fingers or joints. The nonporous face of the PDMS film provides a natural waterproofing barrier against intrusion by microbes and contaminants. The porous face of the bandage with pore size between 100 μm and 400 μm provides abundant void space for the preloading of pharmaceuticals and allows a relatively quick drug release (over 50% in 5 min, over 80% in 30 min), while simultaneously improving water vapor permeability. Blood absorbed could be distributed within the film's pore network, reducing the chances of forming a large clot and hardened scab that may break the wound bed upon removal. All these improvements demonstrate that the Janus PDMS film will provide the performance needs as a new bandage for wound care.

We assessed water quality using physical, chemical, and biological characteristics in 37 streams between Puerto Maldonado and Cusco in Peru. Study sites ranged from ∼200 to 4000 m in elevation, with streams selected as pairs (control/natural vs. human impacted) along this gradient. In general, temperature decreased (R2 = 0.82) and other parameters increased [dissolved oxygen (R2 = 0.19), conductivity (R2 = 0.17), pH (R2 = 0.37)] with elevation. Macroinvertebrates were hand collected by professional entomologists and using leaf packs implemented by conservation workers. The professionals identified 213 unique taxa from the hand collections, with 80 species collected only one time. Data from control streams showed that as elevation increased, total richness (p = 0.008) and EPT richness (p = 0.050) decreased whereas Diptera richness increased (p = 0.002). NMS ordination indicated significant differences in macroinvertebrate assemblages when control streams from low and high elevations were contrasted. Hand collections also revealed significant differences between control and impact streams for total richness, EPT richness and % Diptera, but not for % EPT, % EPT richness, or % Diptera richness. The majority of the deployed leaf packs were successfully retrieved and contained many macroinvertebrates (Avg. = 141 individuals per pack). There were 98 unique taxa (family level or higher) identified from the leaf packs by the trained conservation workers. Fourteen of 15 macroinvertebrate community metrics (at the family level) were able to detect significant differences between control and impact sites. All of the family level metrics responded similarly across the elevation gradient except total richness, EPT richness, EPT count, and % Hydropsychids. Both the Costa Rica and the Virginia Save Our Stream Indexes were able to differentiate control from impacted streams using leaf pack data. Although the diversity of macroinvertebrates was higher for hand collections relative to leaf packs (due to greater habitats sampled and higher taxonomic resolution), leaf pack samples were better able to distinguish control from impacted streams. Specifically, leaf packs were able to discern impacts in streams at low elevation better than those at high elevation. Generally, macroinvertebrates indicated impact from urbanization to be worse than impacts from other human activities (i.e., gold mining and agriculture). Overall, hand collections will serve as an important reference of species diversity going forward while leaf packs processed by trained conservation workers are a viable method to monitor stream water quality in Peru and perhaps elsewhere.

The objective of this study was to use ultrasound in combination with nanoparticulate formulations of taxane drugs for an additive approach to overcome multidrug resistance (MDR). Polymeric nanoparticulate formulations containing both chemotherapeutic taxane drugs and a polymeric inhibitor (MePEG17-b-PCL5) of drug resistant proteins have been previously developed in an attempt to overcome MDR in cells. High frequency (>1 MHz) ultrasound has been shown to increase the uptake of cytotoxic drugs in MDR proliferating cells and has been suggested as a different way to overcome MDR, resensitize drug resistant cancer cells and allow for chemotherapeutic efficacy. MDCK-MDR cells were incubated with docetaxel (DTX) or paclitaxel (PTX) loaded, solid core, nanoparticles made from a 50:50 ratio of two diblock copolymers, MePEG114-b-PCL200 and MePEG17-b-PCL5 (PCL200/PCL5). The accumulation of drug in MDCK-MDR cells was measured using radiolabeled drug and the viability of cells was determined using an MTS cell proliferation assay. The effect of ultrasound (4 MHz, 32 W/cm2, 10 s, 25% duty cycle) on drug uptake and cell viability was studied. Using free DTX or PTX, MDCK-MDR cells were killed at sublethal doses of drug with the P-gp inhibitor (MePEG17-b-PCL5) present at a concentration of just 0.006% (m/v) and cell death began after just 3 h of incubation. Using sublethal incubation doses of PTX or DTX in PCL200/PCL5 nanoparticles for 90 min, followed by a second exposure to blank PCL200/PCL5 nanoparticles, cell viability dropped by approximately 60% at 24 h. Drug accumulation increased by 1.43–1.9 fold following five bursts of ultrasound applied at 90 min. Both, increased ultrasound exposure and increased concentrations of blank nanoparticles during the second incubation allowed for increased levels of cell death. The combined use of ultrasound with taxane and P-gp inhibitor loaded polymeric nanoparticles may allow for increased accumulation of drug and inhibitor which may then release both agents inside cells in a controlled manner to overcome drug resistance in MDR cells.

We develop a three-stage stochastic individual-based model for the phenology of the parthenogenetic mayfly Neocloeon triangulifer (Ephemeroptera: Baetidae). Mayflies are poikilothermic and develop at a rate dependent on the temperature of their aquatic environment. The model was built using development data for each aquatic stage from controlled laboratory studies to determine the variation in development rates present in the population and the development rate response curve to temperature. Variable temperature experiments simulating diel temperature changes were used to validate the model. The thermal input data for the model is based on average daily water temperature recordings from White Clay Creek from January 2007 to 2013. The model predicts a multivoltine life cycle with a mode of 3 generations per year that agrees well with field observations. An optimally timed quiescent period for larvae (triggered by day length) is shown to enhance synchronization of adult emergence. Any future stream temperature rise is predicted to increase the number of generations per year and desynchronize adult emergence, and these changes could lead to significant population decline in species that reproduce sexually.

Propagating and releasing freshwater mussels (Unionida) into the wild can contribute substantially to conservation and perhaps ecosystem restoration, but poorly conceived projects can waste money and public good will, and harm mussel populations and ecosystems. Moving from vague, emotional reactions about mussel restoration to more rigorous discussions and analyses can help focus efforts to where they do the most good. We suggest that: (i) projects to restore mussels for conservation goals to sites where known environmental problems have been eliminated or mitigated have good prospects for success; (ii) projects to restore mussels for conservation goals to sites where known environmental problems have not been eliminated or mitigated have poor prospects for success; (iii) projects to restore mussels for conservation goals to sites in the common situation in which the status of environmental problems is unknown have unknown prospects for success, but may be valuable as scientific experiments, if project performance is monitored properly; (iv) the value of population augmentation as a conservation tool is uncertain, and needs better theoretical and empirical analysis; (v) assisted migration of mussels as a conservation tool is controversial, and should be discussed thoroughly before we reach crises in which it is rejected or carried out carelessly; (vi) projects to restore ecosystem services face more stringent criteria for success than conservation projects, and some such projects being discussed seem unlikely to succeed. Monitoring data on how restoration projects perform typically are inadequately collected, reported, disseminated, and used to improve practice. This could be improved by setting up a clearinghouse to collect, hold, and disseminate data; providing training to restorationists; and opening conversations between restorationists and data managers and statisticians.

Salinity in freshwater ecosystems has increased significantly at numerous locations throughout the world, and this increase often reflects the use or production of salts from road de-icing, mining/oil and gas drilling activities, or agricultural production. When related to de-icing salts, highest salinity often occurs in winter when water temperature is often low relative to mean annual temperature at a site. Our study examined acute (96 h) responses to elevated salinity (NaCl) concentrations at five to seven temperature treatments (5–25°C) for four mayfly species (Baetidae: Neocloeon triangulifer , Procloeon fragile ; Heptageniidae: Maccaffertium modestum ; Leptophlebiidae: Leptophlebia cupida ) that are widely distributed across eastern North America. Based on acute LC50s at 20°C, P. fragile was most sensitive (LC50 = 767 mg l −1 , 1447 µS cm −1 ), followed by N. triangulifer (2755 mg l −1 , 5104 µS cm −1 ), M. modestum (2760 mg l −1 , 5118 µS cm −1 ) and L. cupida (4588 mg l −1 , 8485 µS cm −1 ). Acute LC50s decreased as temperature increased for all four species ( n = 5–7, R 2 = 0.65–0.88, p = 0.052–0.002). Thus, acute salt toxicity is strongly temperature dependent for the mayfly species we tested, which suggests that brief periods of elevated salinity during cold seasons or in colder locations may be ecologically less toxic than predicted by standard 20 or 25°C laboratory bioassays. This article is part of the theme issue ‘Salt in freshwaters: causes, ecological consequences and future prospects’.

We demonstrate an implantable MEMS drug delivery device to conduct controlled and on-demand, ex vivo drug transport to human eye tissue. Remotely operated drug delivery to human post-mortem eyes was performed via a MEMS device. The developed curved packaging cover conforms to the eyeball thereby preventing the eye tissue from contacting the actuating membrane. By pulsed operation of the device, using an externally applied magnetic field, the drug released from the device accumulates in a cavity adjacent to the tissue. As such, docetaxel (DTX), an antiangiogenic drug, diffuses through the eye tissue, from sclera and choroid to retina. DTX uptake by sclera and choroid were measured to be 1.93±0.66 and 7.24±0.37 μg/g tissue, respectively, after two hours in pulsed operation mode (10 s on/off cycles) at 23°C. During this period, a total amount of 192 ng DTX diffused into the exposed tissue. This MEMS device shows great potential for the treatment of ocular posterior segment diseases such as diabetic retinopathy by introducing a novel way of drug administration to the eye.

The ability of a plant to acclimate metabolically to thermal changes is necessary to maintain a positive carbon balance. It is likely that a plant’s acclimatory potential is a function of leaf nitrogen and/or leaf carbohydrate status. Two important issues assessed concerning leaf dark respiration (RD) were the effects of growth temperature, light, and fertilization on thermal respiratory acclimation and changes in respiratory parameters (indicative of acclimation) throughout the dark period. Soybean (Glycine max (L.) Merr.) plants were grown in greenhouses under a full factorial treatment arrangement of temperature, light, and nutrition. RD was measured at three temperatures to estimate respiratory parameters (cool respiration R13, warm respiration R25, and the temperature response of respiration EO) three times throughout the night (6 pm, 11 pm, and 4 am). Respiratory parameters did not differ throughout the night. Thermal acclimation was observed in warm grown plants under optimal growing conditions (i.e., high light and high fertilization); however, acclimation did not occur when limitations were imposed (i.e., shade or no fertilization). These findings suggest thermal acclimation will occur so long as plants do not undergo limitations. This may have major implications for natural ecosystems and may play a role in assessing an ecosystems resiliency to climate change.

A cylindrically shaped magnetically-actuated MEMS (microelectromechanical systems) drug delivery device for localized prostate cancer treatment is proposed in this work. The device is designed for implantation through a gauge 12 needle for minimally invasive procedures. The drug delivery device consists of a drug reservoir, a PDMS (polydimethylsiloxane) membrane, a magnetic block and a housing. Under external magnetic fields, the movement of the magnetic block deflects the membrane and discharges the drug through an aperture and into the housing. The housing has a large opening which allows the released drug to diffuse to the surrounding tissues while it prevents the tissues from touching the membrane. On-demand drug release with consistent release rates and device implantation using a needle into ex vivo porcine bladder tissue are demonstrated.

Nanoparticles composed of both high- and low-molecular-weight methoxy poly(ethylene glycol)-block-poly(caprolactone) (MePEG-b-PCL) diblock copolymers (termed “mixed molecular weight nanoparticles”) were investigated for the encapsulation and delivery of the taxane drugs paclitaxel (PTX) and docetaxel (DTX). These nanoparticles were prepared using nanoprecipitation and emulsion methods. These 80 nm nanoparticles were prepared with high yields, efficiently solubilized PTX and DTX up to 500 and 1300 μg/mL, respectively, and demonstrated controlled release of these drugs over 14 days. The taxane-sensitive (MDCKII) and taxane-resistant [P-glycoprotein (P-gp) overexpressing] MDCKII-MDR cell lines were used to establish the cytotoxic profiles of these nanoparticles. Because of the coencapsulation of the previously demonstrated P-gp inhibitor, a low–molecular-weight MePEG-b-PCL copolymer (MePEG 17 -b-PCL 5 ), these drug-loaded mixed molecular weight nanoparticles dramatically reduced the viability of P-gp overexpressing MDCKII-MDR cells and restored sensitivity to taxane drugs in these cells. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Well-organized composite formations such as hierarchical nested-network (NN) structure in bone tissue and reticular connective tissue present remarkable mechanical strength and play a crucial role in achieving physical and biological functions for living organisms. Inspired by these delicate microstructures in nature, an analogous scaffold of double network hydrogel was fabricated by creating a poly(2-hydroxyethyl methacrylate) (pHEMA) network in the porous structure of alginate hydrogels. The resulting hydrogel possessed hierarchical NN structure and showed significantly improved mechanical strength but still maintained high elasticity comparable to soft tissues due to a mutual strengthening effect between the two networks. The tough hydrogel is also self-lubricated, exhibiting a surface friction coefficient comparable with polydimethylsiloxane (PDMS) substrates lubricated by a commercial aqueous lubricant (K-Y Jelly) and other low surface friction hydrogels. Additional properties of this hydrogel include high hydrophilicity, good biocompatibility, tunable cell adhesion and bacterial resistance after incorporation of silver nanoparticles. Firm bonding of the hydrogel on silicone substrates could be achieved through facile chemical modification, thus enabling the use of this hydrogel as a versatile coating material for biomedical applications. Statement of Significance In this study, we developed a tough hydrogel by crosslinking HEMA monomers in alginate hydrogels and forming a well-organized structure of hierarchical nested network (NN). Different from most reported stretchable alginate-based hydrogels, the NN hydrogel shows higher compressive strength but retains comparable softness to alginate counterparts. This work further demonstrated the good integration of the tough hydrogel with silicone substrates through chemical modification and micropillar structures. Other properties including surface friction, biocompatibility and bacterial resistance were investigated and the hydrogel shows a great promise as a versatile coating material for biomedical applications.

Understanding species' thermal limits and their physiological determinants is critical in light of climate change and other human activities that warm freshwater ecosystems. Here, we ask whether oxygen limitation determines the chronic upper thermal limits in larvae of the mayfly

Ultrathin free-standing Janus films were fabricated at air-water interfaces using azopyridine derivatives and poly(acrylic acid) via multi-level self-assembly on molecular and microscopic scales, which showed distinct asymmetric water wetting abilities on different surfaces.

Species-level identifications are difficult or impossible for many larval aquatic macroinvertebrates. We described the taxonomic composition of macroinvertebrate communities from 5 coastal streams in 3 neighboring catchments in southern California. We compared taxonomic identifications based on deoxyribonucleic acid (DNA) barcoding (cytochrome c oxidase subunit I [COI]) with morphological identifications of the same specimens. We examined 5870 individuals, and barcodes with sequence lengths >350 base pairs (bp) for 91% of those specimens. We used the naturally occurring gaps in divergence frequencies for each order (usually 2% level of genetic divergence) to delimit putative species for all taxonomic groups except Simulium (3%) and Baetis (1%). We identified 200 species across these 5 streams. We identified 104 more species via barcodes than via morphology (200 vs 96, a 108% increase). Richness increases were greatest for Chironomidae (60 more species), Ephemeroptera (10 species), Acari (10 specie...