Solubilisation of drugs within liposomal bilayers:alternatives to cholesterol as a membrane stabilising agent

Objectives The aim of this work was to investigate the effect of cholesterol on the bilayer loading of drugs and their subsequent release and to investigate fatty alcohols as an alternative bilayer stabiliser to cholesterol. Methods The loading and release rates of four low solubility drugs (diazepam, ibuprofen, midazolam and propofol) incorporated within the bilayer of multilamellar liposomes which contained a range of cholesterol (0–33 mol/mol%) or a fatty alcohol (tetradecanol, hexadecanol and octadecanol) were investigated. The molecular packing of these various systems was also investigated in Langmuir monolayer studies. Key findings Loading and release of drugs within the liposome bilayer was shown to be influenced by their cholesterol content: increasing cholesterol content was shown to reduce drug incorporation and inclusion of cholesterol in the bilayer changed the release profile of propofol from zero-order, for phosphatidyl choline only liposomes, to a first-order model when 11 to 33 total molar % of cholesterol was present in the formulation. At higher bilayer concentrations substitution of cholesterol with tetradecanol was shown to have less of a detrimental impact on bilayer drug loading. However, the presence of cholesterol within the liposome bilayer was shown to reduce drug release compared with fatty alcohols. Monolayer studies undertaken showed that effective mean area per molecule for a 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) : cholesterol mixture deviated by 9% from the predicted area compared with 5% with a similar DSPC : tetradecanol mixture. This evidence, combined with cholesterol being a much more bulky structure, indicated that the condensing influence of tetradecanol was less compared with cholesterol, thus supporting the reduced impact of tetradecanol on drug loading and drug retention. Conclusions Liposomes can be effectively formulated using fatty alcohols as an alternative bilayer stabiliser to cholesterol. The general similarities in the characteristics of liposomes containing fatty alcohols or cholesterol suggest a common behavioural influence for both compounds within the bilayer.

Progress in the development of in vitro human-based alternatives to animal models

Editorial

Alternatives to steel grid bridge decks

Most of the moveable bridges use open grid steel decks, because these are factory assembled, light-weight, and easy to install. Open grid steel decks, however, are not as skid resistant as solid decks. Costly maintenance, high noise levels, poor riding comfort and susceptibility to vibrations are among the other disadvantages of these decks. The major objective of this research was to develop alternative deck systems which weigh no more than 25 lb/ft2, have solid riding surface, are no more than 4–5 in. thick and are able to withstand prescribed loading. Three deck systems were considered in this study: ultra-high performance concrete (UHPC) deck, aluminum deck and UHPC-fiber reinforced polymer (FRP) tube deck. UHPC deck was the first alternative system developed as a part of this project. Due to its ultra high strength, this type of concrete results in thinner sections, which helps satisfy the strict self-weight limit. A comprehensive experimental and analytical evaluation of the system was carried out to establish its suitability. Both single and multi-unit specimens with one or two spans were tested for static and dynamic loading. Finite element models were developed to predict the deck behavior. The study led to the conclusion that the UHPC bridge deck is a feasible alternative to open grid steel deck. Aluminum deck was the second alternative system studied in this project. A detailed experimental and analytical evaluation of the system was carried out. The experimental work included static and dynamic loading on the deck panels and connections. Analytical work included detailed finite element modeling. Based on the in-depth experimental and analytical evaluations, it was concluded that aluminum deck was a suitable alternative to open grid steel decks and is ready for implementation. UHPC-FRP tube deck was the third system developed in this research. Prestressed hollow core decks are commonly used, but the proposed type of steel-free deck is quite novel. Preliminary experimental evaluations of two simple-span specimens, one with uniform section and the other with tapered section were carried out. The system was shown to have good promise to replace the conventional open grid decks. Additional work, however, is needed before the system is recommended for field application.

Institutions, Innovation, and Grassroots Change: Alternatives to Transnational Governance in the Global South

Transnational governance has been advanced as a viable option for regulating commodities produced in emerging economies—where incapable or unwilling states may undersupply institutions requisite for overseeing supply chains consistent with the quality, safety, environmental, or social standards demanded by the global marketplace. Producers from these jurisdictions, otherwise left with few venues for securing market access and price premiums, ostensibly benefit from whatever pathways transnational actors offer to minimize barriers to entry—including voluntary certification for compliance with a panoply of public and private rules, such as those promulgated by NGOs like the Fair Trade Federation or multinational retailers like Wal-Mart. Yet, such transnational “sustainability” governance may neither be effective nor desirable. Regulatory schemes, like third-party certification, often privilege the interests of primary architects and beneficiaries—private business associations, governments, NGOs, and consumers in the global North—over regulatory targets—producers in the global South. Rather than engaging with the international marketplace via imported and externally-driven schemes, some producer groups are instead challenging existing rules and innovating homegrown institutions. These alternatives to commercialization adopt some institutional characteristics of their transnational counterparts yet deliver benefits in a manner more aligned with the needs of producers. Drawing on original empirical cases from Nicaragua and Mexico, this dissertation examines the role of domestic institutional alternatives to transnational governance in enhancing market access, environmental quality and rural livelihoods within producer communities. Unlike the more technocratic and expert-driven approaches characteristic of mainstream governance efforts, these local regulatory institutions build upon the social capital, indigenous identity, “ancestral” knowledge, and human assets of producer communities as new sources of power and legitimacy in governing agricultural commodities.

Greener Alternatives to Selected Organic Oxidation Reactions

The study of green chemistry is dedicated to eliminating or reducing toxic waste. One route to accomplish this goal is to explore alternative reaction conditions and parameters resulting in the development of more benign synthetic routes and reagents. The primary focus of this research is to find optimal reaction conditions for the oxidation of a primary alcohol to an aldehyde. As a case study, the oxidation of benzyl alcohol to benzaldehyde, a common industrial process, was examined. Traditionally carried out using the Jones Reagent, commonly referred to as chromium (IV) oxide or chromium trioxide (CrO3) in sulphuric acid, a great deal of research went into utilizing less toxic reagents, such as MnO2 or KMnO4 supported on a clay base. This research has led to an improvement on these alternatives, using a lithium chloride (LiCl) catalyst in a montmorillonite K10 clay solid phase, together with the oxidizing agent hydrogen peroxide, as even greener alternatives to these traditional oxidizing agents. Experiments were carried out to determine the lifetime of this LiCl/clay system as compared to MnO2 and KMnO4, to investigate its ability to catalyze the oxidation of other aromatic alcohols (such as 4-methoxybenzyl alcohol and diphenylmethanol), and to further improve the system’s adherence to green chemistry principles. Green solvent alternatives were examined by replacing the toluene solvent with dimethylcarbonate (DMC), and reaction conditions were optimized to improve product yield. It was determined that the LiCl/H2O2 system was, in most cases, equally as effective at catalyzing the oxidation of benzyl alcohol to benzaldehyde. Although the catalyst and oxidizing agent eliminated the toxic waste generated from chromium reagents, it offered significant challenges in product isolation, because of an aqueous-organic phase separation.

Role of organic acids and phytonutrients as natural alternatives to antibiotics in supporting intestinal functionality

The gastrointestinal tract (GIT) represents the major portion of the body that interfaces with the external environment, with the double function of food processing and line of defense of the body. Numerous components support and regulate the barrier function of the GIT, such as tight junctions (TJs), cytokines, commensal and pathogenic microorganisms, and other systems of the organism, as the endocannabinoid system (ECS). The ECS can control several gastrointestinal functions, as well as the regulation of intestinal inflammation. Failure of the intestinal barrier function triggers an increase of the concentration of pro-inflammatory cytokines and leads to a reduction in intestinal functionality. This thesis aimed to explore the potential of natural compounds as a new alternative approach to antibiotics not only as antimicrobial, but also supporting intestinal maturation and integrity, and as immune-boosting agents. Different experiments were performed to evaluate the potential of nature-identical compounds (NICs), organic acids (OAs), and essential oils (EOs) to support and fight various stressful stimuli. In vitro, a well characterized blend of NICs and OAs were able to improve TJs and transepithelial electrical resistance (TEER) in an intestinal cell line, exerting an anti-inflammatory potential. EOs enhanced TEER and TJs mRNA levels, with a reduction of paracellular permeability, showing antioxidant and antimicrobial properties. In vivo, thymol modulates the gene expression of ECS and gut chemosensing in the GIT of piglets, where the precise localization of the cannabinoid receptors was immunohistochemically confirmed, suggesting an anti-inflammatory potential. In conclusion, natural alternative molecules represent an effective alternative to support or replace the classical pharmacological prophylaxis. These alternative molecules act not only as antimicrobial agents, but also exerted a crucial role in supporting the intestinal barrier function, preventing oxidative stress, and reducing inflammation. Moreover, thymol seems able to modulate the ECS, representing a novel frontier to support animal health and productivity.

The Governor’s Task Force on African-Americans in Prison, 2001

Report produced by the Department of Corrections

Issue review : county jails and probation sentencing.

This issue review provides a description of the use and funding of county jails and the potential budget impact if the state were to fund the cost of housing probationers.

Issue review : community-based corrections funding.

This issue review examines the funding levels within the community-based corrections, or CBC, district departments compared to the offender populations, risk and supervision levels, and recidivism rates to consider whether current funding allocations are appropriate. The majority of offenders in corrections are supervised by the CBC-district departments.

El papel de la OEA en el establecimiento de los tribunales de tratamiento de drogas en Estados Unidos como mecanismo de reducción del daño (1989-2013)

La reducción de la demanda, específicamente por medios alternativos al sistema penal tradicional, ha sido uno de los componentes más discutidos en los análisis que abordan la lucha contra las drogas. Este artículo se propone determinar el papel de la Organización de Estados Americanos en el establecimiento de los Tribunales de Tratamiento de Drogas en Estados Unidos como mecanismo de reducción del daño en el periodo comprendido entre 1989 y 2013. Se sugiere que la organización internacional, a través de la CICAD, ha jugado un papel de promoción, y evaluación de los Tribunales de Tratamiento de Drogas en Estados Unidos, generando presión entre sus Estados miembro, dada la necesidad de instaurar alternativas legales de reducción del daño. Sin embargo, se presentan deficiencias en los mecanismos de evaluación, ya que las indicaciones realizadas no tienen un carácter obligatorio y por tanto las determinaciones de la CICAD no necesariamente son adoptadas.

Inferring the biggest and best: a measurement model for applying recognition to evoke consideration sets and judge between multiple alternatives

It has long been supposed that preference judgments between sets of to-be-considered possibilities are made by means of initially winnowing down the most promising-looking alternatives to form smaller “consideration sets” (Howard, 1963; Wright & Barbour, 1977). In preference choices with >2 options, it is standard to assume that a “consideration set”, based upon some simple criterion, is established to reduce the options available. Inferential judgments, in contrast, have more frequently been investigated in situations in which only two possibilities need to be considered (e.g., which of these two cities is the larger?) Proponents of the “fast and frugal” approach to decision-making suggest that such judgments are also made on the basis of limited, simple criteria. For example, if only one of two cities is recognized and the task is to judge which city has the larger population, the recognition heuristic states that the recognized city should be selected. A multinomial processing tree model is outlined which provides the basis for estimating the extent to which recognition is used as a criterion in establishing a consideration set for inferential judgments between three possible options.

Reexamining the Role of Incarceration and Stigma in Criminal Law

One of the ways by which the legal system has responded to different sets of problems is the blurring of the traditional boundaries of criminal law, both procedural and substantive. This study aims to explore under what conditions does this trend lead to the improvement of society's welfare by focusing on two distinguishing sanctions in criminal law, incarceration and social stigma. In analyzing how incarceration affects the incentive to an individual to violate a legal standard, we considered the crucial role of the time constraint. This aspect has not been fully explored in the literature on law and economics, especially with respect to the analysis of the beneficiality of imposing either a fine or a prison term. We observed that that when individuals are heterogeneous with respect to wealth and wage income, and when the level of activity can be considered a normal good, only the middle wage and middle income groups can be adequately deterred by a fixed fines alone regime. The existing literature only considers the case of the very poor, deemed as judgment proof. However, since imprisonment is a socially costly way to deprive individuals of their time, other alternatives may be sought such as the imposition of discriminatory monetary fine, partial incapacitation and other alternative sanctions. According to traditional legal theory, the reason why criminal law is obeyed is not mainly due to the monetary sanctions but to the stigma arising from the community’s moral condemnation that accompanies conviction or merely suspicion. However, it is not sufficiently clear whether social stigma always accompanies a criminal conviction. We addressed this issue by identifying the circumstances wherein a criminal conviction carries an additional social stigma. Our results show that social stigma is seen to accompany a conviction under the following conditions: first, when the law coincides with the society's social norms; and second, when the prohibited act provides information on an unobservable attribute or trait of an individual -- crucial in establishing or maintaining social relationships beyond mere economic relationships. Thus, even if the social planner does not impose the social sanction directly, the impact of social stigma can still be influenced by the probability of conviction and the level of the monetary fine imposed as well as the varying degree of correlation between the legal standard violated and the social traits or attributes of the individual. In this respect, criminal law serves as an institution that facilitates cognitive efficiency in the process of imposing the social sanction to the extent that the rest of society is boundedly rational and use judgment heuristics. Paradoxically, using criminal law in order to invoke stigma for the violation of a legal standard may also serve to undermine its strength. To sum, the results of our analysis reveal that the scope of criminal law is narrow both for the purposes of deterrence and cognitive efficiency. While there are certain conditions where the enforcement of criminal law may lead to an increase in social welfare, particularly with respect to incarceration and stigma, we have also identified the channels through which they could affect behavior. Since such mechanisms can be replicated in less costly ways, society should first try or seek to employ these legal institutions before turning to criminal law as a last resort.

Use of SECM to study the electrochemical behavior of DIN 1.4575 superferritic stainless steel aged at 475 degrees C

In order to lower the excessive costs of metallic prosthesis materia Is alternatives to Ti and Ti alloys have been searched. in this study, the corrosion resistance of the DIN 1.4575 superferritic stainless steel, either solution annealed or solution annealed and aged at 475 degrees C for periods varying from 100 to 1080 h, was investigated by electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization methods in Hanks` solution. The solution annealed and the aged for 1080 h samples were also tested using scanning electrochemical microscopy (SECM) in a 0.1 mol/L NaCl solution at 25 degrees C. The EIS results showed that the corrosion resistance of the DIN 1.4575 steel decreases with heat treatment time at 475 degrees C probably due to alpha prime formation. Besides the diminution of the overall impedance values, the low frequency limit of the Nyquist diagrams show a progressive change from an almost capacitive response to a resistive behavior as the heat treatment time increases. Pitting corrosion resistance also decreased with aging time at 475 degrees C.