Treatment of advanced soft-tissue sarcomas using a combined strategy of high-dose ifosfamide, high-dose doxorubicin and salvage therapies.

Having determined in a phase I study the maximum tolerated dose of high-dose ifosfamide combined with high-dose doxorubicin, we now report the long-term results of a phase II trial in advanced soft-tissue sarcomas. Forty-six patients with locally advanced or metastatic soft-tissue sarcomas were included, with age <60 years and all except one in good performance status (0 or 1). The chemotherapy treatment consisted of ifosfamide 10 g m(-2) (continuous infusion for 5 days), doxorubicin 30 mg m(-2) day(-1) x 3 (total dose 90 mg m(-2)), mesna and granulocyte-colony stimulating factor. Cycles were repeated every 21 days. A median of 4 (1-6) cycles per patient was administered. Twenty-two patients responded to therapy, including three complete responders and 19 partial responders for an overall response rate of 48% (95% CI: 33-63%). The response rate was not different between localised and metastatic diseases or between histological types, but was higher in grade 3 tumours. Median overall survival was 19 months. Salvage therapies (surgery and/or radiotherapy) were performed in 43% of patients and found to be the most significant predictor for favourable survival (exploratory multivariate analysis). Haematological toxicity was severe, including grade > or =3 neutropenia in 59%, thrombopenia in 39% and anaemia in 27% of cycles. Three patients experienced grade 3 neurotoxicity and one patient died of septic shock. This high-dose regimen is toxic but nonetheless feasible in multicentre settings in non elderly patients with good performance status. A high response rate was obtained. Prolonged survival was mainly a function of salvage therapies.

On Strategy-proofness and symmetric single-peakedness

We characterize the class of strategy-proof social choice functions on the domain of symmetric single-peaked preferences. This class is strictly larger than the set of generalized median voter schemes (the class of strategy-proof and tops-only social choice functions on the domain of single-peaked preferences characterized by Moulin (1980)) since, under the domain of symmetric single-peaked preferences, generalized median voter schemes can be disturbed by discontinuity points and remain strategy-proof on the smaller domain. Our result identifies the specific nature of these discontinuities which allow to design non-onto social choice functions to deal with feasibility constraints.

Life cycle and influence of age and feeding on the first mating of Triatoma mazzottii (Hemiptera: Reduviidae)

A cohort of 100 eggs of Triatoma mazzottii Usinger was studied to obtain information on its life cycle. Egg incubation took 24 days; mean duration of 1st, 2nd, 3rd, 4th, and 5th instar nymphs was 27, 36, 39, 46 and 64 days respectively; mean time from egg to adult was 236 days. The total duration of the nymphal stages was 212 days. The total nymph mortality in cohort was 16.3% and the embryonic egg mortality was 14.0%. The grater mortality occured in the 2nd instar. The average number of eggs/female/week was 9.8 during 15 weeks of observation. Of the total eggs laid (2,514), only 58.7% hatched. The total of insects that achieved the adult stage (72), 38 were females (52.8%), and 34 were males (47.2%). The influence of age and feeding on the first mating of T. mazzottii were also studied. It was found that the first mating depended on the male's age and it was on the average 30 days after the last imaginal molt. The female could be mating since 2nd days after the imaginal life. The nutritional status did not play an important role in the capacity of the insect for the first mating.

Reduced peroxisomal citrate synthase activity increases substrate availability for polyhydroxyalkanoate biosynthesis in plant peroxisomes.

Polyhydroxyalkanoates (PHAs) are bacterial carbon storage polymers used as renewable, biodegradable plastics. PHA production in plants may be a way to reduce industrial PHA production costs. We recently demonstrated a promising level of peroxisomal PHA production in the high biomass crop species sugarcane. However, further production strategies are needed to boost PHA accumulation closer to commercial targets. Through exogenous fatty acid feeding of Arabidopsis thaliana plants that contain peroxisome-targeted PhaA, PhaB and PhaC enzymes from Cupriavidus necator, we show here that the availability of substrates derived from the β-oxidation cycle limits peroxisomal polyhydroxybutyrate (PHB) biosynthesis. Knockdown of peroxisomal citrate synthase activity using artificial microRNA increased PHB production levels approximately threefold. This work demonstrates that reduction of peroxisomal citrate synthase activity may be a valid metabolic engineering strategy for increasing PHA production in other plant species.

Targeting mitochondria in the infection strategy of the hepatitis C virus.

Hepatitis C virus (HCV) infection induces a state of oxidative stress more pronounced than that observed in many other inflammatory diseases. Here, we propose a temporal sequence of events in the HCV-infected cell whereby the primary alteration consists of a release of Ca(2+) from the endoplasmic reticulum, followed by uptake into mitochondria. This ensues successive mitochondrial dysfunction leading to the generation of reactive oxygen species and a progressive metabolic adaptive response. Evidence is provided for a positive feed-back mechanism between alterations of calcium and redox homeostasis. This likely involves deregulation of the mitochondrial permeability transition and induces progressive dysfunction of cellular bioenergetics. Pathogenetic implications of the model and new opportunities for therapeutic intervention are discussed. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.

Strategy-proof social choice

This paper surveys the literature on strategy-proofness from a historical perspective. While I discuss the connections with other works on incentives in mechanism design, the main emphasis is on social choice models. This article has been prepared for the Handbook of Social Choice and Welfare, Volume 2, Edited by K. Arrow, A. Sen and K. Suzumura

Aprender investigando. Una experiencia formativa en el ámbito de la enfermería = Research teaching processes used as a methodological strategy in the education of healthcare professionals

Este trabajo tiene como propósito presentar y valorar, desde la perspectiva del alumnado participante, un proyecto de investigación-formación puesto en marcha durante el curso 2003-2004 en la elaboración del trabajo de tesina, fin de carrera, en la Escuela de Enfermería de Vitoria, dentro del programa de Licenciatura Europea de Enfermería. Constituye el punto de partida de un proyecto a largo plazo, iniciado con la intención de desarrollar principios teóricos y procedimientos prácticos que nos permitan sistematizar procesos formativos que, centrados en la investigación, articulen la teoría y la práctica e integren una perspectiva comunicativa y cooperativa.

Development of a vaccine strategy against human and bovine schistosomiasis: background and update

Schistosomiasis is a chronic and debilitating parasitic disease that affects over 200 million people throughout the world and causes about 500,000 deaths annually. Two specific characteristics of schistosome infection are of primordial importance to the development of a vaccine: schistosomes do not multiply within the tissues of their definitive hosts (unlike protozoan parasites) and a partial non-sterilizing immunity can have a marked effect on the incidence of pathology and on disease transmission. Since viable eggs are the cause of disease pathology, a reduction in worm fecundity whether or not accompanied by a reduction in parasite burden is a sufficient goal for vaccine induced immunity. We originally showed that IgE antibodies played in experimental models a pivotal role for the development of protective immunity. These laboratory findings have been now confirmed in human populations. Following the molecular cloning and expression of a protein 28 kDa protein of Schistosoma mansoni and its identification as a glutathion S-transferase, immunization experiments have been undertaken in several animal species (rats, mice, baboons). Together with a significant reduction in parasite burden, vaccination with Sm28 GST was recently shown to reduce significantly parasite fecundity and egg viability leading to a decrease in liver pathology. Whereas IgE antibodies were shown to be correlated with protection against infection, IgA antibodies have been identified as one of the factors affecting egg laying and viability. In human populations, a close association was found between IgA antibody production to Sm28 GST and the decrease of egg output. The use of appropriate monoclonal antibody probes has allowed the demonstration that the inhibition of parasite fecundity following immunization was related to the inhibition of enzymatic activity of the molecule. Epitope mapping of Sm28 GST has indicated the prominent role of the N and C terminal domains. Immunization with the corresponding synthetic peptides was followed by a decrease of 70% of parasite fecundity and egg viability. As a preliminary step towards phase I human trials, vaccination experiments have been performed in cattle, a natural model for Schistosoma bovis. Vaccination of calves with the S. bovis GST has led to a reduction of ever 80% of egg output and tissue egg count. Significant levels of protection were also observed in goats after immunization with the recombinant S. bovis GST. Increasing evidence of the participation of IgA antibodies in protective immunity has prompted us toward the development of mucosal immunization. Preliminary results indicate that significant levels of protection can be achieved following oral immunization with live attenuated vectors or liposomes. These studies seem to represent a promising approach towards the future development of a vaccine strategy against one of major human parasitic diseases.

Lessons of peace in Aceh: administrative decentralization and political freedom as a strategy of pacification in Aceh

This working paper shows the evolution of the Aceh conflict until its peaceful resolution in 2005. The key factors in the success of this peace process have been the confluence of several factors related to the internal and external dynamics of the country, including the new political leadership, the decreasing role of the military power, the international support and the meeting of the objectives of both groups, and so on. The end of the conflict in Aceh shows that the administrative decentralization and the promotion of the political participation of the main actors involved have made possible the development of a solid alternative to the arms strategy of conflict resolution used for years in Indonesia.

The influence of sugars and amino acids on the blood-feeding behaviour, oviposition and longevity of laboratory colony of Lutzomyia longipalpis (Lutz & Neiva, 1912) (Diptera: Psychodidae, Phlebotominae)

Schneider's Drosophila medium, a complex amino acid rich medium was tested alone and with seven different sugars for some aspects of the biology of Lutzomyia longipalpis. Statistically significant results were obtained when sucrose was used alone, indicating that among the sugars tested, this is still the most suitable and practical one for the maintenance of L. longipalpis colonies. However, the addition of Schneider's medium to a pool of different sugars, was suggested to be related with the acceptance of the first and second blood meals and to longevity, these being, obviously, quite relevant aspects when tansmission experiments are contemplated.

Feeding and defaecation patterns in Triatoma sordida

Triatoma sordida is a peridomestic Triatominae that could play an important role in the transmission of Trypanosoma cruzi, although its vectorial competence is not well known. The aim of this work was to evaluate two aspects of the vectorial competence: the feeding behaviour and defaecation patterns, and to compare them with T. infestans. The feeding and defaecation patterns were studied in adults and fifth instar nymphs of T. sordida fed ad libitum on a restrained pigeon. The results showed how the blood meal size controls excretion behaviour. Blood intake and time to first defaecation showed a significant negative correlation. Adults and nymphs frequently defaecated during the blood meal, reaching the maximum frequency within the first 10 minutes.

Artificial Feeding of Amblyomma cajennense (Fabricius, 1787) (Acari: Ixodidae) through Silicone Membrane

An artificial feeding system was used where citrated bovine blood was offerred to male and female Amblyomma cajennense. Vestiges of blood, sweat, hair and exfoliated skin were used as phago-stimulants placed on the surface of the silicone membrane. The ticks were collected, as engorged nymphs, from naturally infested equines, with the ecdysis occurring in the laboratory. Four hundred ticks were used, 50% being female, at three to four weeks post-ecdysis. Vestiges of blood on the silicone membrane were the most efficient phago-stimulant and the association of vestiges of blood and sweat residue smears yielded better results compared to the other phago-stimulants used

Group strategy-proof social choice functions with binary ranges and arbitrary domains: characterization results

We define different concepts of group strategy-proofness for social choice functions. We discuss the connections between the defined concepts under different assumptions on their domains of definition. We characterize the social choice functions that satisfy each one of them and whose ranges consist of two alternatives, in terms of two types of basic properties.