A novel hanging spherical drop system for the generation of cellular spheroids and high throughput combinatorial drug screening

We propose a novel hanging spherical drop system for anchoring arrays of droplets of cell suspension based on the use of biomimetic superhydrophobic flat substrates, with controlled positional adhesion and minimum contact with a solid substrate. By facing down the platform, it was possible to generate independent spheroid bodies in a high throughput manner, in order to mimic in vivo tumour models on the lab-on-chip scale. To validate this system for drug screening purposes, the toxicity of the anti-cancer drug doxorubicin in cell spheroids was tested and compared to cells in 2D culture. The advantages presented by this platform, such as feasibility of the system and the ability to control the size uniformity of the spheroid, emphasize its potential to be used as a new low cost toolbox for high-throughput drug screening and in cell or tissue engineering.

Biodegradable drug-eluting stents: Targeting urothelial tumors of upper urinary tract

INTRODUCTION & OBJECTIVES: Urothelial tumors of upper urinary tract are ranked among the most common types of cancers worldwide. The current standard therapy to prevent recurrence is intravesical Bacillus Calmetteâ Guerin (BCG) immunotherapy, but it presents several disadvantages such as BCG failure and intolerance. Another way is to use chemotherapy, which is generally better tolerated that BCG. In this case, drugs such as epirubicin, doxorubicin, paclitaxel and gemcitabine are used. Nevertheless, intravesical chemotherapy only prevents recurrence in the short-term. These failings can be partially attributed to the short residence time and low bioavailability of the drug within the upper urinary tract and the cancer cells, resulting in a need for frequent drug instillation. To avoid these problems, biodegradable ureteral stents impregnated by supercritical fluid CO2 (SCF) with each of the four anti-cancer drugs were produced. MATERIAL & METHODS: Four formulations with different concentrations of gelatin and alginate and crosslink agent were tested and bismuth was added to confer radiopaque properties to the stent. The preliminary in vivo validation studies in female domestic pigs was conducted at the University of Minho, Braga, after formal approval by the institutionâ s review board and in accordance with its internal ethical protocol for animal experiments. Paclitaxel, epirubicin, doxorubicin and gemcitabine were impregnated in the stents and the release kinetics was measured in artificial urine solution (AUS) for 9 days by UV spectroscopy in a microplate reader. The anti-tumoral effect of the developed stents in transitional cell carcinoma (TCC) and HUVEC primary cells, used as control, was evaluated. RESULTS: The in vivo validation of this second-generation of ureteral stents performed was herein demonstrated. Biodegradable ureteral stents were placed in the ureters of a female pigs, following the normal surgical procedure. The animals remained asymptomatic, with normal urine flow. The in vitro release study in AUS of the stent impregnated showed a higher release in the first 72h for the four anti-cancer drugs impregnated after this time the plateau was achieved and the stent degraded after 9 days. The direct and indirect contact of the anti-cancer biodegradable stents with the TCC and HUVEC cell lines confirm the anti-tumor effect of the stents impregnated with the four anti-cancer drugs, reducing around 75% of the viability of the TCC cell line after 72h and no killing effect in the HUVEC cells. CONCLUSIONS: The use of biodegradable ureteral stent in urology clinical practice not only reduce the stent-related symptoms but also open new treatment therapyâ s, like in urothelial tumors of upper urinary tract. Furthermore, we have demonstrated the clinical validation in vivo pig model. This study has thus shown the killing efficacy of the anti-cancer drug eluting biodegradable stents in vitro for the TCC cell line, with no toxicity observed in the control, non-cancerous cells.The direct and indirect contact of the anti-cancer biodegradable stents with the TCC and HUVEC cell lines confirm the anti-tumor effect of the stents impregnated with the four anti-cancer drugs, reducing around 75% of the viability of the TCC cell line after 72h and no killing effect in the HUVEC cells. This study has thus shown the killing efficacy of the anti-cancer drug eluting biodegradable stents in vitro for the TCC cell line, with no toxicity observed in the control, non-cancerous cells.

Development of a poly(L-Lactic acid) based drug release system

Dissertação de mestrado em Biofísica e Bionanossistemas

Odour nuisance in Ireland and the potential use of olfactometry for the control of odours

Odour nuisance in other European countries has led to the development of techniques which employ panels of human assessors for the determination of environmental odours. Odour measurement is not widely practised in Ireland, yet local authorities are frequently in receipt of odour derived public complaints. This dissertation examines the fundamentals of odour nuisance in terms of how we perceive odours, common sources of environmental odours, the principles of odour measurement (in particular the Sutch pre-standard on olfactometry) and the extent to which odour nuisance is a problem in Ireland. The intention is to provide a reference document for use by those interested parties in the country who may be variously involved in policy making, legislative development, enforcement of environmental law or any person who has an interest in odours and the public nuisance they can give rise to. In particular the aim was to provide previously undocumented information on the prevalence of odour nuisance in Ireland, the exercision of the available powers to control odours, and the possible value of odour measurement as part of a regulatory process. A questionnaire was circulated to all local authorities in the country and 82% responded with information on their experiences and views on the subject of odours. The results of the survey are presented in summary and detailed form.

Role Of MMP-2 and MMP-9 in Resistance to Drug Therapy in Patients with Resistant Hypertension

AbstractBackground:Despite the increased evidence of the important role of matrix metalloproteinases (MMP-9 and MMP‑2) in the pathophysiology of hypertension, the profile of these molecules in resistant hypertension (RHTN) remains unknown.Objectives:To compare the plasma levels of MMP-9 and MMP-2 and of their tissue inhibitors (TIMP-1 and TIMP-2, respectively), as well as their MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios, between patients with controlled RHTN (CRHTN, n=41) and uncontrolled RHTN (UCRHTN, n=35). In addition, the association of those parameters with clinical characteristics, office blood pressure (BP) and arterial stiffness (determined by pulse wave velocity) was evaluate in those subgroups.Methods:This study included 76 individuals diagnosed with RHTN and submitted to physical examination, electrocardiogram, and laboratory tests to assess biochemical parameters.Results:Similar values of MMP-9, MMP-2, TIMP-1, TIMP-2, and MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios were found in the UCRHTN and CRHTN subgroups (P>0.05). A significant correlation was found between diastolic BP (DBP) and MMP-9/TIMP-1 ratio (r=0.37; P=0.02) and DPB and MMP-2 (r=-0.40; P=0.02) in the UCRHTN subgroup. On the other hand, no correlation was observed in the CRHTN subgroup. Logistic regression models demonstrated that MMP-9, MMP-2, TIMP-1, TIMP-2 and their ratios were not associated with the lack of BP control.Conclusion:These findings suggest that neither MMP-2 nor MMP-9 affect BP control in RHTN subjects.

Venture capital meets contract theory: risky claims or formal control?

This paper develops a theory of the joint allocation of formal control and cash-flow rights in venture capital deals. We argue that when the need for investor support calls for very high-powered outside claims, entrepreneurs should optimally retain formal control in order to avoid excessive interference. Hence, we predict that risky claims should be be negatively correlated to control rights, both along the life of a start-up and across deals. This challenges the idea that risky claims should a ways be associated to more formal control, and is in line with contractual terms increasingly used in venture capital, in corporate venturing and in partnership deals between biotech start-ups and large drug companies. The paper provides a theoretical explanation to some puzzling evidence documented in Gompers (1997) and Kaplan and Stromberg (2000), namely the inclusion in venture capital contracts of contingencies that trigger both a reduction in VC control and the conversion! of her preferred stocks into common stocks.

Nuclear Weapons as Symbols. The Role of Norms in Nuclear Policy Making

Throughout history, nuclear weapons have been considered to be the ultimate weapons. This understanding largely detached them from the portfolio of conventional military means and assigned them a symbolic meaning that influenced the identity and norms creation of nations. In most countries today, the development of nuclear weapons is considered morally prohibitive, incompatible with a country’s identity and international outlook. In some states, however, these negative norms are overridden by a positive set of norms, causing nuclear weapons to become either symbols of invulnerability to perceived threats or the regalia of major power status. Main purpose of this paper is to explore on the conditions that cause most states to develop a moral aversion to nuclear weapons, yet effectively lead to their glorification in others. Many studies on the normative understanding of nuclear weapons consider the existence of a negative normative predisposition, often referred to as ‘nuclear taboo’, as a major factor in preventing their acquisition and use. Other studies acknowledge the existence of a nuclear taboo inhibiting the use of nuclear weapons, but point to the existence of the opposing effect of norms, frequently referred to as the ‘nuclear myth’, when it comes to the acquisition of nuclear weapons. This myth emerges when certain symbolic meanings are attached to nuclear weapons, such as a state’s identity, self-image, and its desired position in the international system. With 180 odd countries in the world abstaining from the acquisition of nuclear weapons and 8 countries in possession of them (with two further countries assumed to have pursued their acquisition), one might consider the dominance of the nuclear taboo over the nuclear myth to be the rule. The core question is thus why and how this relationship reversed in the case of defectors.

Malignant transformation of a rat fibroma by the treatment with an anti-fibrosing drug: CY-168F (Plastenan)

Fifteen albino (Sprague Dawley) rats with subcutaneous transplanted fibromas was used in the present study. The tumour was formed by typical fibroblasts in a dense collagen matrix and was provenient from a fibroma that appeared spontaneously in an albino rat of the same strain. Ultrastructurally collagen disclosed normal periodicity and the fibroblasts showed irregular notched nuclei with irregular distribution of chromatin, that suggests transitional aspects to fibrosarcoma. The 15 animals, from different passage groups, were divided into: 8 animals submitted to treatment with the drug acexamic acid (CY-168F) - N acetyl-amino-6-hexanoic acid (plastenan) and 7 untreated control animals. Three of the treated animals showed a malignant transformation to fibrosarcoma. transitional histological features from typical fibroma to highly indifferentiated fibrosarcoma could be detected in come animal subjected to repeated biopsies. Ultrastructural study disclosed nuclear alterations and hyperactive ergastoplasm and collagen containing inclusions into the cytoplasm of fibroblasts. In the group of 7 untreated naimals, no malignant transformation could be detected histologically. Two aspects deserve attention: the malignant potential of a typical fibroma and the apparent effect of an antifibrosing drug in inducing malignization of this tumour.

Economic impact of alternative policy measures implemented on the energy activities of the Catalan production system: an input-output analysis

The aim of the paper is to analyse the economic impact of alternative policies implemented on the energy activities of the Catalan production system. Specifically, we analyse the effects of a tax on intermediate energy uses, a reduction in the final production of energy, and a reduction in intermediate energy uses. The methodology involves two versions of the input-output price model: a competitive price formulation and a mark-up price formulation. The input-output price framework will make it possible to evaluate how the alternative measures modify production prices, consumption prices, private welfare, and intermediate energy uses. The empirical application is for the Catalan economy and uses economic data for the year 2001.

Aptitude au volant: comment ne pas perdre les pédales [Driving ability: how not to lose control?].

Any primary care doctor should be able to decide on the fitness to drive of a given patient. The issue of an older driver, patients addicted to alcohol or drugs, under current psychotropic drug treatment, or diabetic, is discussed in the light of legal provisions and current recommendations. This article also discusses aspects associated with neurological, cardiac and orthopedic issues.

Salvia divinorum: an hallucinogenic mint which might become a new recreational drug in Switzerland.

Salvia divinorum Epling & Jativa is an hallucinogenic mint traditionally used for curing and divination by the Mazatec Indians of Oaxaca, Mexico. Young people from Mexican cities were reported to smoke dried leaves of S. divinorum as a marijuana substitute. Recently, two S. divinorum specimens were seized in a large-scale illicit in-door and out-door hemp plantation. Salvinorin A also called divinorin A, a trans-neoclerodane diterpene, was identified in several organic solvent extracts by gas chromatography-mass spectrometry. The botanical identity of the plant was confirmed by comparing it to an authentic herbarium specimen. More plants were then discovered in Swiss horticulturists greenhouses. All these data taken together suggest that many attempts exist in Switzerland to use S. divinorum as a recreational drug. This phenomenon may be enhanced because neither the magic mint, nor its active compound are banned substances listed in the Swiss narcotic law.

Optimal feedback control rules sensitive to controlled endogenous risk-aversion

The objective of this paper is to correct and improve the results obtained by Van der Ploeg (1984a, 1984b) and utilized in the theoretical literature related to feedback stochastic optimal control sensitive to constant exogenous risk-aversion (see, Jacobson, 1973, Karp, 1987 and Whittle, 1981, 1989, 1990, among others) or to the classic context of risk-neutral decision-makers (see, Chow, 1973, 1976a, 1976b, 1977, 1978, 1981, 1993). More realistic and attractive, this new approach is placed in the context of a time-varying endogenous risk-aversion which is under the control of the decision-maker. It has strong qualitative implications on the agent's optimal policy during the entire planning horizon.

Linking Global Youth Tobacco Survey (GYTS) data to the WHO Framework Convention on Tobacco Control (FCTC): the case for the Seychelles

Tobacco control has been recognized as a main public health concern in Seychelles for the past two decades. Tobacco advertising, sponsoring and promotion has been banned for years, tobacco products are submitted to high taxes, high-profile awareness programs are organized regularly, and several other control measures have been implemented. The Republic of Seychelles was the first country to ratify the WHO Framework Convention on Tobacco Control (FCTC) in the African region. Three population-based surveys have been conducted in adults in Seychelles and results showed a substantial decrease in the prevalence of smoking among adults between 1989 and 2004. A first survey in adolescents was conducted in Seychelles in 2002 (the Global Youth Tobacco Survey, GYTS) in a representative sample of 1321 girls and boys aged 13-15 years. The results show that approximately half of students had tried smoking and a quarter of both boys and girls had smoked at least one cigarette during the past 30 days. Although "current smoking" is defined differently in adolescents (>or=1 cigarette during the past 30 days) and in adults (>or=1 cigarette per day), which precludes direct comparison, the high smoking prevalence in youth in Seychelles likely predicts an increasing prevalence of tobacco use in the next adult generation, particularly in women. GYTS 2002 also provides important data on a wide range of specific individual and societal factors influencing tobacco use. Hence, GYTS can be a powerful tool for monitoring the situation of tobacco use in adolescents, for highlighting the need for new policy and programs, and for evaluating the impact of current and future programs.

When the Line is Crossed... : Paths to Control and Sanction Behaviour Necessitating a State Reaction

The article presents a special form of a European comparative synopsis. For this case examples have been chosen ranging from administrative or minor (criminal) offences to increasingly serious offences and offenders. In this way it can be comparatively demonstrated how the criminal justice systems studied handle specific cases and whether they do so in a similar or different way.

Five-year evolution of drug prescribing in a university adult intensive care unit

Introduction: Drug prescription is difficult in ICUs as prescribers are many, drugs expensive and decisions complex. In our ICU, specialist clinicians (SC) are entitled to prescribe a list of specific drugs, negotiated with intensive care physicians (ICP). The objective of this investigation was to assess the 5-year evolution of quantity and costs of drug prescription in our adult ICU and identify the relative costs generated by ICP or SC. Methods: Quantities and costs of drugs delivered on a quarterly basis to the adult ICU of our hospital between 2004 and 2008 were extracted from the pharmacy database by ATC code, an international five-level classification system. Within each ATC first level, drugs with either high level of consumption, high costs or large variations in quantities and costs were singled out and split by type of prescriber, ICP or SC. Cost figures used were drug purchase prices by the hospital pharmacy. Results: Over the 5-year period, both quantities and costs of drugs increased, following a nonsteady, nonparallel pattern. Four ATC codes accounted for 80% of both quantities and costs, with ATC code B (blood and haematopoietic organs) amounting to 63% in quantities and 41% in costs, followed by ATC code J (systemic anti-infective, 20% of the costs), ATC code N (nervous system, 11% of the costs) and ATC code C (cardiovascular system, 8% of the costs). Prescription by SC amounted to 1% in drug quantities, but 19% in drug costs. The rate of increase in quantities and costs was seven times larger for ICP than for SC (Figure 1 overleaf ). Some peak values in costs and quantities were related to a very limited number of patients. Conclusions: A 5-year increase in quantities and costs of drug prescription in an ICU is a matter of concern. Rather unexpectedly, total costs and cost increases were generated mainly by ICP. A careful follow-up is necessary to try influencing this evolution through an institutional policy co-opted by all professional categories involved in the process.