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Background Hexavalent chromium has been found to increase the risk of lung cancer in occupational studies. It has been suggested that the relative risk of lung cancer may vary by age. Methods The cohort examined is the Baltimore cohort of chromium production workers. The effect of age on the lung cancer risk from hexavalent chromium exposure was examined using a conditional Poisson regression modeling approach of Richardson and Langholz (R&L) and Cox models with interaction terms of age and cumulative hexavalent chromium exposure. Results The inclusion of multiple age groups in the R&L approach suggests the existence of an age effect that is also supported by a Cox proportional hazard analysis. The hazard ratio in Cox models with age‐cumulative exposure interaction terms was significantly elevated for the youngest age group and significantly decreased for the oldest age group. Conclusions Our analyses are consistent with the observation that younger chromium production workers have a greater lung cancer risk than older workers.

Introduction: Respiratory syncytial virus (RSV) causes high morbidity and mortality rates among infants, young children, and the elderly worldwide. Unfortunately, a safe and effective vaccine is still unavailable. In 1966, a formalin-inactivated RSV vaccine failed and resulted in the death of two young children. This failure shifted research toward the development of subunit-based vaccines for pregnant women (to passively vaccinate infants) and the elderly. Among these subunit-based vaccines, the viral envelope glycoproteins show great potential as antigens. Areas covered: In this review, progress in the development of safe and effective subunit RSV vaccines based on the viral envelope glycoproteins and intended for pregnant women and the elderly, are reviewed and discussed. Studies published in the period 2012-2018 were included. Expert opinion: Researchers are close to bringing safe and effective subunit-based RSV vaccines to the market using the viral envelope glycoproteins as antigens. However, it remains a major challenge to elicit protective immunity, with a formulation that has sufficient (storage) stability. These issues may be overcome by using the RSV fusion protein in its pre-fusion conformation, and by formulating this protein as a dry powder. It may further be convenient to administer this powder via the pulmonary route.

The impact of foodborne metals on the burden of disease has been largely overlooked, in comparison to the attention on acute diseases associated with infectious foodborne agents. Four articles in this special section describe in detail the burden of disease from foodborne lead, methylmercury, arsenic, and cadmium. Ingested lead and methylmercury are causally associated with lifelong intellectual disability. Long term ingestion of arsenic is causally associated with an increased risk of cancer. Long term ingestion of cadmium is causally associated with an increased risk of late stage chronic kidney disease. This article presents an overview of the burden of disease from these four foodborne metals and discusses them in the context of the World Health Organization's initiative to estimate the global burden of foodborne disease. The results indicate that in 2015, ingestion of arsenic, methylmercury, lead, and cadmium resulted in more than 1 million illnesses, over 56,000 deaths, and more than 9 million disability-adjusted life years (DALYs) worldwide. The greatest impact on DALYs was in the Western Pacific B subregion. All of the metals were found to have high DALYs per case in comparison with other foodborne disease agents, including infectious and parasitic agents. In addition, lead, arsenic, and methylmercury were found to have high DALYs per 100,000 population in comparison to other foodborne disease agents.

Arsenic is a ubiquitous, naturally occurring metalloid that poses a significant risk for human cancer and non-cancer diseases. It is now evident that arsenic contamination in food, especially rice and grains, presents a significant exposure to hundreds of millions of individuals worldwide. However, the disease risk from chronic exposure to the low amounts of arsenic found in food remains to be established. Thus, this research estimates the global burdens of disease expressed as Disability-Adjusted Life Years (DALYs) for lung, skin and bladder cancers, as well as coronary heart disease (CHD) attributable to inorganic arsenic in food. To determine foodborne inorganic arsenic exposures worldwide, we used the World Health Organization (WHO) estimates of food consumption in 17 country clusters, in conjunction with the reported measurements of total and inorganic arsenic in different foods. We estimated cancer potency factors for arsenic related bladder and lung cancers, and from US Environmental Protection Agency risk estimates for skin cancer to calculate the cancer incidence in males and females within each of the WHO member states. Summary relative risk estimates and population attributable fractions were developed to estimate the YLD, YLL, and DALYs for arsenic-induced CHD. The findings indicate that, globally, each year the combined DALYs for all cancers attributable to inorganic arsenic in food are approximately 1.4 million with variation in global distribution based on population and food consumption patterns. The global burden of CHD attributable to foodborne inorganic arsenic also varied with WHO region and may contribute as much as 49 million DALYs. However, in contrast to cancer burden, there is a threshold effect for arsenic-associated CHD with no increased risk of heart disease at the expected lower bound of arsenic consumption in food. These estimates indicate that foodborne arsenic exposure causes a significant yet avoidable global burden of human disease.

Chronic exposures to cadmium (Cd) are associated with reduced glomerular filtration rate (GFR), increasing the risk of chronic kidney disease (CKD). In support of the World Health Organization (WHO)'s initiative to estimate the global burden of foodborne diseases, a risk assessment was performed to estimate the Disability-Adjusted Life Years (DALYs) due to late-stage CKD associated with dietary exposures to cadmium. Using the distribution of population GFRs, the prevalence of CKD was calculated as the proportion of humans whose GFR fall in the ranges corresponding to Stage 4 or Stage 5 CKD. The increase in the CKD prevalence due to cadmium exposure was simulated based on a previously reported pharmacokinetic model describing the relationship between dietary cadmium intake and urinary cadmium (UCd), as well as a previously published dose-response relationship between UCd and GFR. Cadmium-related incidence rate, calculated as the change in the prevalence during a one-year period, were used to compute the mortality and DALY in all WHO regions. It is estimated that dietary cadmium would result in a median of 12,224 stage 4 and stage 5 new CKD cases per year worldwide, resulting in 2064 global deaths and 70,513 DALYs. These data translate into a median global burden of 1.0 DALY per 100,000 population, which account for 0.2% of the global DALYs of CKD. While these results suggest that the overall impact of dietary cadmium exposure on global CKD is low, they do indicate that reasonable efforts to reduce dietary exposure will result a positive public health impact. This would be particularly the case in areas with elevated levels of dietary cadmium.

During the last decades the number of therapeutic proteins increased tremendously on the pharmaceutical market. However, due to their often poor stability and limitations of the administration route, the application of therapeutic proteins is a major challenge. The oral mucosa has been suggested as a possible route for protein delivery. In this study, we prepared protein loaded orodispersible films (ODFs), based on blends of trehalose/pullulan by air- and freeze-drying. These two carbohydrates were selected based on the excellent protein stabilizing capacity of trehalose and film-forming ability of pullulan. ODFs were loaded with three model proteins. Ovalbumin was used to study the effect of protein incorporation on the mechanical properties, disintegration time, uniformity of weight and thickness of the ODFs. Lysozyme and β-galactosidase were used to evaluate protein stability. Ovalbumin loading did not significantly influence the mechanical properties of freeze-dried ODFs, while incorporation of ovalbumine in air-dried ODFs led to a substantial reduction in tensile strength. The trehalose/pullulan ratio had no impact on the stability of lysozyme, while the stability of β-galactosidase increased with increasing trehalose/pullulan ratios. Furthermore, freeze-drying appeared to be favorable over air-drying for process stability while the reverse was found for storage stability. In conclusion, trehalose/pullulan-based ODFs are from a technical point promising for possible protein delivery via the oral cavity.

Development of biofilm associated candidemia for patients with implanted biomaterials causes an urgency to develop antimicrobial and biofilm inhibitive coatings in the management of recalcitrant Candida infections. Recently, there is an increase in the number of patients with biofilm formation and resistance to antifungal therapy. Therefore, there is a growing interest to use essential oils as coating agents in order to prevent biomaterial-associated Candida infections. Often high costs, complicated and laborious technologies are used for both applying the coating and determination of the antibiofilm effects hampering a rapid screening of essential oils. In order to determine biofilm formation of Candida on essential oil coated surfaces easier, cheaper and faster, we developed an essential oil (lemongrass oil) coated surface (silicone- rubber) by using a hypromellose ointment/essential oil mixture. Furthermore, we modified the "crystal violet binding assay" to quantify the biofilm mass of Candida biofilm formed on the lemongrass oil coated silicone rubber surface. The essential oil coating and the biomass determination of biofilms on silicone rubber can be easily applied with simple and accessible equipment, and will therefore provide rapid information about whether or not a particular essential oil is antiseptic, also when it is used as a coating agent.

Nonphotochemical laser-induced nucleation (NPLIN) is a promising primary nucleation control method, yet its underlying mechanism remains elusive. To contribute to the discussion on whether the polarization of laser irradiation in NPLIN experiments influences the polymorphic outcome, we revisit NPLIN experiments with aqueous glycine solutions with supersaturations ranging between S = 1.5 and S = 1.7 irradiated by nanosecond pulses (∼7 ns) of near-infrared wavelength (1064 nm). Systematically altering laser light excitation properties, including the number of pulses and type of polarization, we quantified the nucleation kinetics and characterized the polymorphic form that crystallized upon laser irradiation. Due to the stochasticity of the nucleation process, a large number of samples (>100 per each experimental point) were studied under carefully controlled experimental conditions such as the ambient temperature, cooling rate, and aging period. We observed significant differences among laser-irradiated, spontaneously nucleated, and crash-cooled samples in terms of nucleation kinetics and polymorphic form. This result indicates that laser irradiation provides a different polymorph-forming pathway in comparison to crash-cooling and spontaneous nucleation. However, no clear dependence between the polymorphic form and the polarization of laser irradiation is observed. We discuss our results in the context of previous reports supported thorough quantification of sample heating in NPLIN experiments.

A droplet-based microfluidic platform is presented to study the nucleation kinetics of calcium oxalate monohydrate (COM), the most common constituent of kidney stones, while carefully monitoring the pseudo-polymorphic transitions. The precipitation kinetics of COM is studied as a function of supersaturation and pH as well as in the presence of inhibitors of stone formation, magnesium ions (Mg(2+)), and osteopontin (OPN). We rationalize the trends observed in the measured nucleation rates leveraging a solution chemistry model validated using isothermal solubility measurements. In equimolar calcium and oxalate ion concentrations with different buffer solutions, dramatically slower kinetics is observed at pH 6.0 compared to pHs 3.6 and 8.6. The addition of both Mg(2+) and OPN to the solution slows down kinetics appreciably. Interestingly, complete nucleation inhibition is observed at significantly lower OPN, namely, 3.2 × 10(−8) M, than Mg(2+) concentrations, 0.875 × 10(−4) M. The observed inhibition effect of OPN emphasizes the often-overlooked role of macromolecules on COM nucleation due to their low concentration presence in urine. Moreover, analysis of growth rates calculated from observed lag times suggests that inhibition in the presence of Mg(2+) cannot be explained solely on altered supersaturation. The presented study highlights the potential of microfluidics in overcoming a major challenge in nephrolithiasis research, the overwhelming physiochemical complexity of urine.

To better understand how the sulfate (SO42&minus, ) anion may contribute to the adverse effects associated with elevated ionic strength or salinity in freshwaters, we measured the uptake and efflux of SO42&minus, in four freshwater species: the fathead minnow (Pimephales promelas, Teleostei: Cyprinidae), paper pondshell (Utterbackia imbecillis, Bivalvia: Unionidae), red swamp crayfish (Procambarus clarkii, Crustacea: Cambaridae), and two-lined mayfly (Hexagenia bilineata, Insecta: Ephemeridae). Using &delta, (34S/32S) stable isotope ratios and the concentrations of S and SO42&minus, we measured the SO42&minus, influx rate (Jin), net flux (Jnet), and efflux rate (Jout) during a 24 h exposure period. For all four species, the means of Jin for SO42&minus, were positive, and Jin was significantly greater than 0 at both target SO42&minus, concentrations in the fish and mollusk and at the lower SO42&minus, concentration in the crayfish. The means of Jout and Jnet were much more variable than those for Jin, but several species by target SO42&minus, concentration combinations for Jout and Jnet, were negative, which suggests the net excretion of SO42&minus, by the animals. The results of our experiments suggest a greater regulation of SO42&minus, in freshwater animals than has been previously reported.

Most influenza vaccines are administered via injection, which is considered as user-unfriendly. Vaccination via oral cavity using an orodispersible film (ODF) might be a promising alternative. To maintain the antigenicity of the vaccine during preparation and subsequent storage of these ODFs, sugars such as trehalose and pullulan can be employed as stabilizing excipients for the antigens. In this study, first, &beta, galactosidase was used as a model antigen. Solutions containing &beta, galactosidase and sugar (trehalose or trehalose/pullulan blends) were pipetted onto plain ODFs and then either air- or vacuum-dried. Subsequently, sugar ratios yielding the highest &beta, galactosidase stability were used to prepare ODFs containing H5N1 whole inactivated influenza virus vaccine (WIV). The stability of the H5N1 hemagglutinin was assessed by measuring its hemagglutination activity. Overall, various compositions of trehalose and pullulan successfully stabilized &beta, galactosidase and WIV in ODFs. WIV incorporated in ODFs showed excellent stability even at challenging storage conditions (60 &deg, C/0% relative humidity or 30 &deg, C/56% relative humidity) for 4 weeks. Except for sugars, the polymeric component of ODFs, i.e., hypromellose, possibly improved stability of WIV as well. In conclusion, ODFs may be suitable for delivering of WIV to the oral cavity and can possibly serve as an alternative for injections.

Accurate Calcium Oxalate Monohydrate (COM) solubility measurements are essential for elucidating the physiochemical mechanism behind the formation of kidney stones, nephrolithiasis. Yet the reported solubility values of COM in ultrapure water, arguably the simplest solvent relevant for nephrolithiasis, vary significantly depending on implemented method. To address this variation, we present an experimental study of the solubility of COM validated by a model based on the Debye&ndash, H&uuml, ckel theory describing the solution chemistry and the complex formation. We also carefully monitor potential pseudopolymorphic/hydrate transitions during the solubility measurements with in-situ and ex-situ methods. Our results indicate that the solubility of COM in ultrapure water is a weak function of temperature. However, the measured solubility varies significantly in buffer solutions across physiologically relevant pH values at body temperature. The proposed model explains observed trends as a combined effect of ionic strength, protonation reactions, and soluble complex formation. Moreover, it predicts solubility of COM in buffer solutions remarkably well using our measurements in ultrapure water as input, demonstrating the consistency of presented approach. The presented study parleying experiments and modelling provides a solid stepping stone to extend the physiochemical understanding of nephrolithiasis to more realistic solutions laden with biological complexity.

Background Several acylcarnitines used as primary markers on dried blood filter papers (DBS) for newborn screening lack specificity and contribute to a higher false positive rate. The analysis of urine acylglycines is useful in the diagnosis of inborn errors of metabolism (IEM) including medium chain acyl-CoA dehydrogenase deficiency (MCADD), isovaleric acidemia, and beta-ketothiolase deficiency (BKTD). Currently, no method for analyzing acylglycines from DBS has been published. Methods Acylglycines were extracted from two 3.2 mm DBS punches and butylated using Butanol-HCl. Ultra Performance Liquid Chromatography (UPLC-MS/MS) with run time of 10 min permits resolution and quantitation of 15 acylglycines; including several isobaric. Method development was completed. Reference intervals (n = 573) were established for four birth weight groups. Furthermore, samples from patients with a confirmed IEM (n = 11), and false positive screens (n = 78) were analyzed to validate the interpretation obtained from the newly established reference intervals. Results Calibration curves were linear from 0.005 to 25.0 μM. Ion suppression was evaluated as minimal (2 to 10%). Samples from known patients were used to validate the reference intervals. For C5OH-related disorders, tiglylglycine (TG), TG/acetylglycine (AG) ratio, 3methylcrotonylglycine (3MCG) and 3MCG/AG ratio increased specificity. Propionylglycine (PG) and PG/acetylglycine ratio were two discriminatory markers in the investigation of C3-related disorders. Hexanoylglycine (HG), octanoylglycine (OG), suberylglycine (SG), and the ratios HG/AG, OC/AG and SG/AG were excellent markers of MCADD deficiency. Conclusion This method shows potential application as a second tier screen in order to reduce the false positive rate for a number of IEM targeted by newborn screening.

The addition of enalapril maleate to a casting solution for orodispersible films (ODFs) containing hypromellose and carbomer 974P as film forming agents (standard casting solution, SCS) caused a dose dependent reduction of the viscosity. This phenomenon was a serious problem in the preparation of ODFs with an increased enalapril load (> 1 mg per ODF) when using the solvent casting method.The aim of the present work was twofold. Firstly, the influence of enalapril on the viscosity of SCS was studied in more detail. Secondly, two methods for increasing the enalapril load of an ODF were investigated that did not negatively influence the properties of SCS. The casting height was increased and the preparation of bilayered ODF, using the double-casting method, was explored. In the framework of the bilayered ODFs the compatibility between the film forming agents hydroxypropyl cellulose (HPC), sodium alginate (SA), hydroxyethyl cellulose (HEC) and the combination hypromellose-carbomer 974P (SCS) was investigated.Results and conclusions: We found that enalapril concentration dependently reduced the pH, thereby negatively influencing the gel formation and the viscosity of SCS.An increased casting height did not result in a proportionally increased enalapril load.The enalapril load could be doubled when a bilayered ODF containing two layers of SCS was produced.Finally, not all combinations of film forming agents could be used for the preparation of bilayered ODFs. Besides, the sequence in which the different polymer layers were casted affected the appearance of the ODFs. In conclusion, the best formulations were produced with the polymer combinations SCS/SCS and SCS/HPC.

This study aimed at optimizing the immunocapture (IC) and simple-direct-tube (SDT) -reverse transcriptase polymerase chain reaction (RT-PCR) techniques for detection of Rice yellow mottle virus (RYMV) in order to avoid the extraction of high quality RNA required for molecular methods and avoid costs involved. Rice yellow mottle virus strains and phylotypes were obtained from infected rice leaf samples collected from Morogoro, Arusha and Kilimanjaro regions. The efficacy and sensitivity of IC and SDT methods was demonstrated using the aliquots from infected plant sap obtained by grinding rice leaves and binding onto PCR tube using coating buffer and in phosphate buffer saline with 0.5% Tween-20 (PBST 1X), respectively, and assayed by RT-PCR with RYMVIIIF/RYMVIIR primers. Analysis of the PCR product was performed by electrophoresis on 1% agarose gel, pre-stained with 2.5 μl of ethidium bromide (10 µg of ethidium bromide per ml of 0.5x Tris-acetate-ethylenediaminetetraacetic acid (TAE) buffer) at 100 V cm-1 for 30 min and visualized under UV light. The results indicate that SDT-RT-PCR and IC-RT-PCR detected RYMV in all tested infected leaf samples at the expected band size of 720 bp and had the same sensitivity as virus extraction RNA-RT PCR technique, implying that the methods can be useful for detection of wide range of RYMV strains. The negative control did not yield any amplicons. The results also show that these techniques are rapid methods for characterization of RYMV strains and may be recommended for use soon after periodical surveys to quickly identify new strains for breeding purposes at low cost. However, SDT protocol was easier and faster than IC and it was also cost-effective in terms of reagents for the detection of RYMV. Key words: Rice yellow mottle virus, detection, immunocapture-RT-PCR, simple-direct-tube-RT-PCR.

The mechanosensitive channels of large conductance (MscL) are bacterial membrane proteins that serve as last resort emergency release valves in case of severe osmotic downshock. Sensing bilayer tension, MscL channels are sensitive to changes in the bilayer environment and are, therefore, an ideal test case for exploring membrane protein coupling. Here, we use high-throughput coarse-grained molecular dynamics simulations to characterize MscL gating kinetics in different bilayer environments under the influence of alcohols. We performed over five hundred simulations to obtain sufficient statistics to reveal the subtle effects of changes in the membrane environment on MscL gating. MscL opening times were found to increase with the addition of the straight chain alcohols ethanol, octanol, and to some extent dodecanol but not with hexadecanol. Increasing concentration of octanol increased the impeding effect, but only up to 10-20 mol %. Our in silico predictions were experimentally confirmed using reconstituted MscL in a liposomal fluorescent efflux assay. Our combined data reveal that the effect of alcohols on MscL gating arises not through specific binding sites but through a combination of the alcohol-induced changes to a number of bilayer properties and their alteration of the MscL bilayer interface. Our work provides a key example of how extensive molecular simulations can be used to predict the functional modification of membrane proteins by subtle changes in their bilayer environment.

A hollow fiber membrane module was assessed for its potential in assisting crystallization processes. The membrane module was characterized in the sweeping gas membrane distillation configuration considering various solution and sweeping gas flow rates, temperatures and solution concentrations. A model, coupling mass and heat transfer, was developed to predict the membrane flux. The effect of the process conditions on the membrane flux was experimentally determined and the results were used to validate the model. Feed temperature and air flow rate were found to have a significant effect on the membrane flux. Having found the optimal process conditions for membrane distillation process, batch seeded crystallization experiment were performed to confirm the potential of membrane distillation in the generation of adequate rate and level of supersaturation. Since the desired supersaturation level could be maintained in the crystallizer while seeds were growing, it is confirmed that membrane distillation can be an efficient alternative to conventional supersaturation generation processes. Finally, comparing the modelling results with experiments confirms the acceptable accuracy and predictability capability of the developed model.

Background Active optical crop sensors have been gaining importance to determine in-season nitrogen (N) fertilization requirements for on-the-go variable rate applications. Although most of these active in-field crop sensors have been evaluated in maize (Zea mays L.) and wheat (Triticum aestivum L. emend. Thell.), these sensors have not been evaluated in soybean [Glycine max (L.) Merr.] production systems in North Dakota, USA. Recent research from both South Dakota and North Dakota, USA indicate that in-season N application in soybean can increase soybean yield under certain conditions. Results The study revealed that OptRx™ sensor reading did not show any significant differences from early to midway through the growing season. The NDRE (normalized difference red edge) index data collected towards the end of the growing season showed significantly higher values for some of the N treatments as compared to others in both years. The NDRE values were strongly correlated to grain yield for both years under tiled (r = 0.923) and non-tiled (r = 0.901) drainage conditions. Certain soybean varieties displayed significantly higher NDRE values over both years. The three varieties tested across years, under both tiled and non-tiled conditions, showed a significant linear relationship between late August NDRE values and yield (R2 = 0.85 for tiled and R2 = 0.81 for non-tiled). Conclusion In this research, the study results show that the OptRx™ sensor has the potential to work for soybean as well, though later in the crop growing season. Further investigation is needed to confirm the use of OptRx™ sensor for variable rate in-season N applications in soybeans. © 2019 Society of Chemical Industry.

Phthalates are ubiquitous chemical compounds, and two—di-ethyl phthalate (DEP) and di-isobutyl phthalate (DiBP)—are not currently regulated by the U.S. Congress or the European Union. While many reviews of phthalates have been published, none have examined bone health, inflammation, or oxidative stress; anogenital distance was most recently reviewed in 2014. The objective of this paper is to determine if an association exists between mono-ethyl phthalate (MEP) or mono-isobutyl phthalate (MiBP), metabolites of DEP and DiBP, respectively, and the four outcomes indicated above. We conducted a literature search of PubMed through December 2017 and included 29 observational epidemiologic studies published in English that assessed MEP and/or MiBP in relation to one of the above four health outcomes in humans. Two authors rated each paper using a modified Downs and Black (DB) assessment tool; a third author settled score disagreements. A single author extracted information related to the study population, exposure and outcome assessment, covariates, and significant results from each article. Ten studies were identified on anogenital distance, four on bone health, five on inflammation, and thirteen on oxidative stress. Score percentages (total points given out of total possible points) were calculated for each study. The current research suggests a positive association between MiBP and two measures of oxidative stress, 8-hydroxydeoxyguanosine (8-OHdG) and 8-isoprostane. MEP is potentially associated with 8-OHdG as well, although the evidence is limited by fewer high-quality studies. There does not appear to be an association between anogenital distance and MEP or MiBP, and it is unclear if relationships exist between these phthalate metabolites and bone health and inflammation. Given the role that oxidative stress plays in a number of diseases and the ubiquity of MEP and MiBP, it is important that individuals be aware of potential sources of exposure to these chemicals.

Soybean [Glycine max (L.) Merr.] seed composition and yield are a function of genetics (G), environment (E), and management (M) practices, but contribution of each factor to seed composition and yield are not well understood. The goal of this synthesis-analysis was to identify the main effects of G, E, and M factors on seed composition (protein and oil concentration) and yield. The entire dataset (13,574 data points) consisted of 21 studies conducted across the United States (US) between 2002 and 2017 with varying treatments and all reporting seed yield and composition. Environment (E), defined as site-year, was the dominant factor accounting for more than 70% of the variation for both seed composition and yield. Of the crop management factors: (i) delayed planting date decreased oil concentration by 0.007 to 0.06% per delayed week (R 2∼0.70) and a 0.01 to 0.04 Mg ha-1 decline in seed yield per week, mainly in northern latitudes (40-45 N); (ii) crop rotation (corn-soybean) resulted in an overall positive impact for both seed composition and yield (1.60 Mg ha-1 positive yield difference relative to continuous soybean); and (iii) other management practices such as no-till, seed treatment, foliar nutrient application, and fungicide showed mixed results. Fertilizer N application in lower quantities (10-50 kg N ha-1) increased both oil and protein concentration, but seed yield was improved with rates above 100 kg N ha-1. At southern latitudes (30-35 N), trends of reduction in oil and increases in protein concentrations with later maturity groups (MG, from 3 to 7) was found. Continuing coordinated research is critical to advance our understanding of G × E × M interactions.

Objectives To determine the feasibility of preparing a long-term stable ready-to-use parenteral amiodarone formulation using cyclodextrins as dissolution enhancer.Methods A preformulation study was performed with different molar ratios of hydroxypropyl-beta-cyclodextrin (HP-BCD) or sulfobutylether-beta-cyclodextrin (SBE-BCD) to amiodarone in order to investigate enhancement of amiodarone's water solubility. Further, effects of pH and temperature on the dissolution rate during production were investigated. Shelf`-life was determined for a ready-to- use iso-osmotic preparation of 1.8 mg/mL amiodarone with SBE-BCD in a molar ratio of 1: 3. Amiodarone content was assessed using a validated high-pressure liquid chromatography ultraviolet method.Results Amiodarone-SBE-BCD in a molar ratio of 1: 3 at pH 4.0-5.0 yielded the best results in terms of increased solubility and dissolution time (90 min). With SBE-BCD, a smaller molar ratio to amiodarone was needed than with HP-BCD. The amiodarone content of the final formulation stored 12 months at 21 degrees C in daylight remained unchanged.Conclusions A ready-to-use or ready-to-administer amiodarone product, prepared in a hospital pharmacy, for intravenous application in an acute clinical setting is a feasible option from a chemical, physical and microbiological point of view. The availability of such a product will have a significant impact on medication safety, and production should therefore be considered.

Direct nucleation control (DNC) is a feedback control strategy, based on an in situ measurement of the number of particles. In batch cooling crystallization processes, the DNC approach utilizes temperature cycling to control the supersaturation profile during the batch. As a result of this cycling, product crystals with a large mean size and a narrow size distribution can be achieved due to the dissolution of undesired fines. However, implementing the temperature cycles may come at the expense of significantly prolonged batch times due to conventional heat transfer limitations and practical limitations for implementing actuation for both conventional heating and cooling. In this work, microwave heating in combination with DNC is presented to eliminate limitations of conventional heating and further improve the effectiveness of DNC. The results show a very rapid response when using microwave heating, which allowed for improved effectiveness of DNC. In particular, batch times under DNC could be reduced by 5...

We describe analyses to estimate the global burden of disease associated with methylmercury (MeHg). An intelligence quotient

Various mechanisms have been proposed to explain the nonphotochemical laser-induced nucleation (NPLIN). Identifying the dominant mechanism requires addressing a large set of experimental parameters with a statistically significant number of samples, forced by the stochastic nature of nucleation. In this study, with aqueous KCl system, we focus on the nucleation probability as a function of laser wavelength, laser intensity, and sample supersaturation, whereas the influence of filtration and the laser-induced radiation pressure on NPLIN activity is also studied. To account for the nucleation stochasticity, we used 80-100 samples. The NPLIN probability showed an increase with increasing laser intensity. The results are different from the previous report, as a supersaturation independent intensity threshold is not observed. No dependence of the NPLIN probability on the laser wavelength (355, 532, and 1064 nm) was observed. Filtration of samples reduced the nucleation probability suggesting a pronounced role of impurities on NPLIN. The magnitude and the propagation velocity of the laser-induced radiation pressure were quantified using a pressure sensor under laser intensities ranging from 0.5 to 80 MW/cm2. No correlation was found between the radiation pressure and NPLIN at our unfocused laser beam intensities ruling out the radiation pressure as a possible cause for nucleation.

Orodispersible films (ODFs) are promising drug delivery systems for customized small scale pharmacy preparations. The aim of the present study was to develop a versatile casting solution suitable for the extemporaneous production of ODFs to which active pharmaceutical ingredients (APIs) can be added. Different combinations of film forming agents and other excipients and different casting heights were tested for their suitability for production of ODFs. The best suitable casting solution contained hypromellose, carbomer, glycerol, disodium EDTA and trometamol. This casting solution was used to prepare ODFs containing water-soluble APIs (enalapril maleate and prednisolone disodium phosphate) and a poorly water-soluble API (diazepam) for which ethanol 96% was used as co-solvent.The water-soluble APIs as well as ethanol influenced the viscosity of the casting solution, mechanical properties and disintegration time of the ODFs. All ODFs containing API met the requirements on uniformity of mass and uniformity of content set by the European Pharmacopoeia (2014) (Ph. Eur.) 8th edition. In conclusion, ODFs of good pharmaceutical quality can be prepared on small scale. Hereby opening the perspective of using ODFs for individualized pharmacotherapy.

METIS is the “Mid-infrared ELT Imager and Spectrograph” for the European Extremely Large Telescope (E-ELT) that will cover the thermal/mid-infrared wavelength range from 3-14 micron. Starting from a pumped nitrogen line at 70K, it requires cryogenic cooling of detectors and optics at 40K (1.4W), 25K (1.1W), and 8K (0.4W). A vibration-free cooling technology for this instrument based on sorption coolers is under development at the University of Twente in collaboration with Dutch Space. We propose a sorption-based cooler with three cascaded Joule-Thomson coolers of which the sorption compressors are all heat sunk at the 70K platform. A helium-operated cooler is used to obtain the 8K level with a cooling power of 0.4W. Here, three pre-cooling stages are used at 40K, 25K and 15K. The latter two levels are provided by a hydrogen-based cooler, whereas the 40K level is realized by a neon-based sorption cooler. Based on our space-cooler heritage, our preliminary design used sorption compressors equipped with gas-gap heat switches. These have maximum efficiency, but the gas-gap switches add significantly to the complexity of the system. Since in METIS relatively high cooling powers are required, and thus a high number of compressor cells, manufacturability is an important issue. We, therefore, developed an alternative cylindrical compressor design that uses short-pulse heating establishing a thermal wave in radial direction. This allows to omit the gas-gap heat switch. The paper discusses the adapted cell design and two METIS cooler demonstrator setups that are currently under construction.

Resurrection species are a group of land plants that can tolerate extreme desiccation of their vegetative tissues during harsh drought stress, and still quickly – often within hours – regain normal physiological and metabolic functions following rehydration. At the molecular level, this desiccation tolerance is attributed to basal cellular mechanisms including the constitutive expression of stress-associated genes and high levels of protective metabolites present already in the absence of stress, as well as to transcriptome and metabolome reconfigurations rapidly occurring during the initial phases of drought stress. Parts of this response are conferred by unique metabolites, including a diverse array of sugars, phenolic compounds, and polyols, some of which accumulate to high concentrations within the plant cell. In addition to drought stress, these metabolites are proposed to contribute to the protection against other abiotic stresses and to an increased oxidative stress tolerance. Recently, extracts of resurrection species and particular secondary metabolites therein were reported to display biological activities of importance to medicine, with e.g. antibacterial, anticancer, antifungal, and antiviral activities, rendering them possible candidates for the development of novel drug substances as well as for cosmetics. Herein, we provide an overview of the metabolite composition of resurrection species, summarize the latest reports related to the use of natural products from resurrection plants, and outline their potential for medical applications.

Quality assurance and quality control of the crude drug and its preparations should be based on the major groups of secondary metabolites. Pharmacopoeial aspects for the crude drug include a definition, and macroscopical and microscopical description of the crude drug, identity and purity reactions, and an assay for a quantitative determination. Tinctures are obtained using 1 part of drug and 10 parts of extraction solvent or 1 part of drug and 5 parts of extraction solvent. The titration of valepotriates was performed by opening the epoxide ring with hydrobromic acid using a methylene chloride extract of the crude drug. According to the European Pharmacopoeia 2nd edn, the crude drug should be stored in a well-closed container, protected from light. For quality control of the crude drug and of phytomedicines prepared from valerian, monographs of the European Pharmacopoeia 2nd edn can be used, but additional analyses are necessary.

Incorporation of therapeutic proteins in a matrix of sugar glass is known to enhance protein stability, yet protection is often lost when exposed to high relative humidity (RH). We hypothesized that especially in these conditions the use of binary glasses of a polysaccharide and disaccharide might yield advantages for protein stability. Therefore, different amounts of the polysaccharide pullulan were introduced in freeze-dried trehalose glasses. In these homogeneous blends, the presence of pullulan above 50 weight % prevented crystallization of trehalose when exposed to high RH. Storage stability testing up to 4 weeks of the model protein β-galactosidase incorporated in pullulan/trehalose blends showed superior behavior of pure trehalose at 30°C/0% RH, while pullulan/trehalose blends yielded the best stability at 30°C/56% RH. In conclusion, binary glasses of pullulan and trehalose may provide excellent stability of proteins under storage conditions that may occur in practice, namely high temperature and high RH.

Despite the wide use of the real adsorbed solution theory to predict multicomponent adsorption equilibrium, the models used for the adsorbed phase activity coefficients are usually borrowed from the gas–liquid phase equilibria. In this work, the accuracy of the Wilson and NRTL models for evaluating adsorbed phase activity coefficients is tested using a 2D-lattice model. An accurate model for adsorbed-phase activity coefficients should have no problem in fitting adsorption data obtained using this simple lattice model. The results, however, show that the commonly used Wilson and NRTL models cannot describe the adsorbed phase activity coefficients for slightly non-ideal to strong non-ideal mixtures. Therefore, until new models for adsorbed phase activity coefficients are developed, we should use existing models for liquids with care. In the second part of this work, the use of Monte Carlo simulations on a segregated 2D-lattice model, for predicting adsorption of mixtures is investigated. The segregated model assumes that the competition for adsorption occurs at isolated adsorption sites, and that the molecules from each adsorption site interact with the bulk phase independently. Two binary mixtures in two adsorbent materials were used as case studies for testing the predictions of the segregated 2D-lattice model: the binary system CO2–N2 in the hypothetical pure silica zeolite PCOD8200029, with isolated adsorption sites and normal preference for adsorption, and the binary system CO2–C3H8 in pure silica mordenite (MOR), with isolated adsorption sites and inverse site preference. The segregated 2D-lattice model provides accurate predictions for the system CO2–N2 in PCOD8200029 but fails in predicting the adsorption behaviour of CO2–C3H8 in pure silica MOR. The predictions of the segregated ideal adsorbed solution theory model are superior to those of the 2D-lattice model.

Background: Mercury (Hg) is used in gold mining to extract gold from ore by forming “amalgam”—a mixture composed of approximately equal parts mercury and gold. Approximately 15 million people, incl...

BACKGROUND Metal sulfide recovery in sulfate reducing bioreactors is a challenge due to the formation of small precipitates with poor settling properties. The size of the metal sulfide precipitates with the change in operational parameters such as pH, sulfide concentration and reactor configuration has been previously studied. The effect of the hydraulic retention time (HRT) on the metal precipitate characteristics such as particle size for settling has not yet been addressed. RESULTS The change in size of the metal (Cu, Zn, Pb and Cd) sulfide precipitates as a function of the HRT was studied in two sulfate reducing inversed fluidized bed (IFB) reactors operating at different chemical oxygen demand concentrations to produce high and low sulfide concentrations. The decrease of the HRT from 24 to 9 h in both IFB reactors affected the contact time of the precipitates formed, thus making differences in aggregation and particle growth regardless of the differences in sulfide concentration. Further HRT decrease to 4.5 h affected the sulfate reducing activity for sulfide production and hence, the supersaturation level and solid phase speciation. Metal sulfide precipitates affected the sulfate reducing activity and community in the biofilm, probably because of the stronger local supersaturation causing metal sulfides accumulation in the biofilm. CONCLUSIONS This study shows that the HRT is an important factor determining the size and thus the settling rate of the metal sulfides formed in bioreactors. © 2013 Society of Chemical Industry

The dose-response analyses of cancer and noncancer health effects of aldrin and dieldrin were evaluated using current methodology, including benchmark dose analysis and the current U.S. Environmental Protection Agency (U.S. EPA) guidance on body weight scaling and uncertainty factors. A literature review was performed to determine the most appropriate adverse effect endpoints. Using current methodology and information, the estimated reference dose values were 0.0001 and 0.00008 mg/kg-day for aldrin and dieldrin, respectively. The estimated cancer slope factors for aldrin and dieldrin were 3.4 and 7.0 (mg/kg-day)(-1), respectively (i.e., about 5- and 2.3-fold lower risk than the 1987 U.S. EPA assessments). Because aldrin and dieldrin are no longer used as pesticides in the United States, they are presumed to be a low priority for additional review by the U.S. EPA. However, because they are persistent and still detected in environmental samples, quantitative risk assessments based on the best available methods are required. Recent epidemiologic studies do not demonstrate a causal association between aldrin and dieldrin and human cancer risk. The proposed reevaluations suggest that these two compounds pose a lower human health risk than currently reported by the U.S. EPA.

Soil and house dust collected in and around Hg mines and a processing facility in Horlivka, a mid-sized city in the Donets Basin of southeastern Ukraine, have elevated As and Hg levels. Surface soils collected at a former Hg-processing facility had up to 1300 mg kg−1 As and 8800 mg kg−1 Hg; 1M HCl extractions showed 74–93% of the total As, and 1–13% of the total Hg to be solubilized, suggesting differential environmental mobility between these elements. In general, lower extractability of As and Hg was seen in soil samples up to 12 km from the Hg-processing facility, and the extractable (1M HCl, synthetic precipitation, deionized water) fractions of As are greater than those for Hg, indicating that Hg is present in a more resistant form than As. The means (standard deviation) of total As and Hg in grab samples collected from playgrounds and public spaces within 12 km of the industrial facility were 64 (±38) mg kg−1 As and 12 (±9.4) mg kg−1 Hg; all concentrations are elevated compared to regional soils. Th...

The adsorption of traces of five volatile organic compounds (VOCs) comprising butanal, 2-ethyl-2-hexenal, 2,6-dimethylcyclohexanone, 2,4,6-trimethylanisole, and 2,4,6-trimethylphenol from liquid toluene was investigated. Twenty-one commercial adsorbents of different classes were tested in batch adsorption experiments using the six-component mixture. The Na form of FAU zeolite (NaY) performed by far the best for the overall removal of these compounds from toluene, although removal of all six compounds to very low concentrations (

When applied to a pure component suspension in an apolar solvent, a strong inhomogeneous electric field induces particle movement, and the particles are collected at the surface of one of the two electrodes. This new phenomenon was used to separately isolate two organic crystalline compounds, phenazine and caffeine, from their suspension in 1,4-dioxane. First, crystals of both compounds were collected at different electrodes under the influence of an electric field. Subsequent cooling crystallization enabled the immobilization and growth of the particles on the electrodes, which were separately collected after the experiment with purities greater than 91 %. This method can be further developed into a technique for crystal separation and recovery in complex multicomponent suspensions of industrial processes.

Salts of chiral molecules, which originally crystallize as racemic compounds, could form conglomerates. The utilization of such conglomerate salts, as intermediates for the deracemization of corresponding racemic compounds, expands the theoretical application range of Viedma Ripening by roughly 10-fold. In the present study, the use of temperature cycling on conglomerate forming salts as an alternative technique for Viedma Ripening was studied. The racemic compound Phenylalanine (Phe) was successfully deracemized via its conglomerate-forming salt with 2,5-xylenesulfonic acid (XSA) by continuous heating-cooling cycles applied to its suspension in glacial acetic acid, coupled with a solution racemization reaction. In addition, the dependence of the deracemization rate on the operational parameters was studied. Enhanced racemization reaction kinetics, either by a larger amount of free amino acid or by a higher concentration of catalyst, was shown to accelerate the deracemization process. It seems to indicate that a concentration difference between the two enantiomers, which could be diminished by a faster racemization rate, behaves as one of the major rate-limiting factors for the deracemization process. A larger mass fraction of solid dissolving and recrystallizing in the heating-cooling cycles, achieved by either a larger temperature swing or a smaller dry mass concentration, also leads to a faster deracemization. A change in cooling rate does not affect the deracemization rate significantly within the range tested, indicating a limited presence of secondary nucleation of the minor enantiomers. The results can be used as a preliminary foundation for process optimization as well as mechanisms investigation. The advantages and disadvantages of temperature cycling and Viedma Ripening, as deracemization methods in an industrial setting, are discussed.

The Metastable Zone Width (MSZW) is the difference between the saturation temperature and the temperature at which crystals are detected under constant cooling rate. The MSZW is conventionally treated as a reproducible, deterministic, volume independent property and is commonly used to characterize crystal nucleation and to determine the crystallization process operation window. In this paper we investigate the volume dependency of the MSZW both experimentally and theoretically. MSZW measurements were performed for paracetamol–water and isonicotinamide–ethanol model systems at four different volumes between 500 mL and 1 L. A stochastic model developed based on the Single Nucleus Mechanism and a deterministic population balance were used to theoretically study the effect of volume on MSZW. It was experimentally observed that the MSZW is not a reproducible point at small volumes but a spread which increases roughly inversely proportional to the volume. The dependency on volume of the MSZW cannot be explained by the deterministic population balance model but can be explained by the stochastic model based on the single nucleus mechanism. The knowledge of the MSZW behaviour at a certain volume and nucleation rate would help in identifying a process operating window limited by the saturation temperature on one side and the smallest MSZ limit on the other for a particular concentration. The knowledge of the process window at given conditions of volume and concentration would lead to better crystalline product quality as controlled seeding can be performed without the influence of crystals appearing as a result of a primary nucleation event.