Selecting optimal hyperspectral bands to discriminate nitrogen status in durum wheat: a comparison of statistical approaches.

Hyperspectral data can provide prediction of physical and chemical vegetation properties, but data handling, analysis, and interpretation still limit their use. In this study, different methods for selecting variables were compared for the analysis of on-the-ground hyperspectral signatures of wheat grown under a wide range of nitrogen supplies. Spectral signatures were recorded at the end of stem elongation, booting, and heading stages in 100 georeferenced locations, using a 512-channel portable spectroradiometer operating in the 325-1075-nm range. The following procedures were compared: (i) a heuristic combined approach including lambda-lambda R(2) (LL R(2)) model, principal component analysis (PCA), and stepwise discriminant analysis (SDA); (ii) variable importance for projection (VIP) statistics derived from partial least square (PLS) regression (PLS-VIP); and (iii) multiple linear regression (MLR) analysis through maximum R-square improvement (MAXR) and stepwise algorithms. The discriminating capability of selected wavelengths was evaluated by canonical discriminant analysis. Leaf-nitrogen concentration was quantified on samples collected at the same locations and dates and used as response variable in regressive methods. The different methods resulted in differences in the number and position of the selected wavebands. Bands extracted through regressive methods were mostly related to response variable, as shown by the importance of the visible region for PLS and stepwise. Band selection techniques can be extremely useful not only to improve the power of predictive models but also for data interpretation or sensor design.

Experimental Chagas disease in Balb/c mice previously vaccinated with T. rangeli. II. The innate immune response shows immunological memory: reality or fiction?

Trypanosoma cruzi is a real challenge to the host's immune system, because it requires strong humoral and cellular immune response to remove circulating trypomastigote forms, and to prevent the replication of amastigote forms in tissues, involving many regulator and effector components. This protozoan is responsible for Chagas disease, a major public health problem in Latinamerica. We have developed a model of vaccination with Trypanosoma rangeli, a parasite closely related to T. cruzi, but nonpathogenic to humans, which reduces the infectiousness in three different species of animals, mice, dogs and guinea pigs, against challenge with T. cruzi. In a previous work, we demonstrated that mice vaccinated with T. rangeli showed important soluble mediators that stimulate phagocytic activity versus only infected groups. The aim of this work was to study the innate immune response in mice vaccinated or not with T. rangeli. Different population cells and some soluble mediators (cytokines) in peritoneal fluid and plasma in mice vaccinated-infected and only infected with T. cruzi were studied. In the first hours of challenge vaccinated mice showed an increase of macrophages, NK, granulocytes, and regulation of IL6, IFNγ, TNFα and IL10, with an increase of IL12, with respect to only infected mice. Furthermore an increase was observed of Li T, Li B responsible for adaptative response. Finally the findings showed that the innate immune response plays an important role in vaccinated mice for the early elimination of the parasites, complementary with the adaptative immune response, suggesting that vaccination with T. rangeli modulates the innate response, which develops some kind of immunological memory, recognizing shared antigens with T. cruzi. These results could contribute to the knowledge of new mechanisms which would have an important role in the immune response to Chagas disease.

Improving residual feed intake of mule progeny of Muscovy ducks: genetic parameters and responses to selection with emphasis on carcass composition and fatty liver quality.

In France, about 95% of the fatty liver production comes from mule ducks, an infertile hybrid cross between female common ducks (Anas platyrhynchos) and Muscovy drakes (Cairina moschata). As a hybrid, genetic improvement of the performance of mule ducks is achieved by selection of the parental populations. Feed represents two-thirds of the total costs of duck production; thus, the breeders' main concern is to improve the birds' feed efficiency without impairing their capacity to be overfed after the growing period. To obtain insight into this economically important trait, we designed a divergent selection experiment for Muscovy sires on the basis of the residual feed intake (RFI) of their male mule progeny. Residual feed intake represents the fraction of feed intake that cannot be explained by maintenance and production requirements. Data comprised records from generations 0 to 2 with 227 Muscovy sires of 2,016 mule ducks. Growth and fat deposition were measured individually for all mule ducks. Half-sib mule ducks were placed together in 1 small pen, and the feed consumption was recorded for each pen; all half-sibs therefore had the same feed intake estimates. Heritability of RFI was high (0.83 ± 0.42), and after 2 generations of selection, the differences between lines in terms of RFI (contrast of 9.13 g/d, representing 0.76 phenotypic standard deviation; P < 0.0001) and feed conversion ratio (contrast of 0.08, representing 0.28 phenotypic standard deviation; P = 0.0003) were marked. In regard to carcass traits, the low-RFI line (high-efficiency animals) had heavier legs (476 vs. 463 g; P < 0.0001) and magret muscles (268 vs. 262 g; P = 0.001) than the high-RFI line (low-efficiency animals). No differences were observed for either the liver weight or the melting rate between the 2 lines (P > 0.46). Selection on RFI thus improves the feed efficiency of animals without impairing their capacity to produce fatty liver.

Detailed analysis of the individual feeding behavior of male and female mule ducks.

The feeding behavior of 19 mule ducks (males and females) bred in a group was studied during their growth phase (between 3 and 8 wk of age) using the recording system for waterfowl feeding behavior developed in our lab. The basic feeding behavior data obtained allowed us to confirm on the one hand the reliability of our tool and, on the other hand, to compute food intake traits per day (ADFI, number of visits, and time spent feeding per day), per visit (feed intake per visit, visit duration, and visit feeding rate), and per meal (meal size, meal duration, and meal feeding rate). Daily feed intake increased with age (130 to 248 g/d) while the time spent feeding decreased from 14 to 5.5 min/d. Because the duration of visits remained stable (average 45 s), this reflected a decrease in the number of visits per day. At the same time the feed intake per visit and the feeding rate per visit increased sharply with age. The same trend was observed at the meal level for both the feed intake and the feeding rate. Feed intake did not differ between males and females, but the time spent feeding was significantly greater for females than for males (10.8 and 8.9 min per day and 53 and 37 s per visit for females and males, respectively), leading to significantly greater feeding rate for males (30 g/min) than for females (24 g/min). Grouping visits in meal events minimized the differences between genders as the meals tended to comprise fewer visits for females. Under the hypothesis of a genetic link between feeding behavior during growth and force-feeding ability of ducks, genetic selection of these behavioral traits could be included in breeding programs to improve the force-feeding capacity of mule ducks.

Vaccination with Trypanosoma rangeli induces resistance of guinea pigs to virulent Trypanosoma cruzi.

Chagas' disease, endemic in Latin America, is spread in natural environments through animal reservoirs, including marsupials, mice and guinea pigs. Farms breeding guinea pigs for food are located in some Latin-American countries with consequent risk of digestive infection. The aim of this work was to study the effect of vaccination with Trypanosoma rangeli in guinea pigs challenged with Trypanosoma cruzi. Animals were vaccinated with fixated epimastigotes of T. rangeli, emulsified with saponin. Controls received only PBS. Before being challenged with T. cruzi, parasitemia, survival rates and histological studies were performed. The vaccinated guinea pigs revealed significantly lower parasitemia than controls (p<0.0001-0.01) and a discrete lymphomonocytic infiltrate in cardiac and skeletal muscles was present. In the chronic phase, the histological view was normal. In contrast, control group revealed amastigote nests and typical histopathological alterations compatible with chagasic myocarditis, endocarditis and pericarditis. These results, together with previous works in our laboratory, show that T. rangeli induces immunoprotection in three species of animals: mice, guinea pigs and dogs. The development of vaccines for use in animals, like domestic dogs and guinea pigs in captivity, opens up new opportunities for preventive tools, and could reduce the risk of infection with T. cruzi in the community.

Experimental Chagas disease. Innate immune response in Balb/c mice previously vaccinated with Trypanosoma rangeli. I. The macrophage shows immunological memory: Reality or fiction?

Chagas' disease, caused by Trypanosoma cruzi, is a major vector borne health problem in Latin America and an emerging or re-emerging infectious disease in several countries. Immune response to T. cruzi infection is highly complex and involves many components, both regulators and effectors. Although different parasites have been shown to activate different mechanisms of innate immunity, T. cruzi is often able to survive and replicate in its host because they are well adapted to resisting host defences. An experimental model for vaccinating mice with Trypanosoma rangeli, a parasite closely related to T. cruzi, but nonpathogenic to humans, has been designed in our laboratory, showing protection against challenge with T. cruzi infection. The aim of this work was to analyze some mechanisms of the early innate immune response in T. rangeli vaccinated mice challenged with T. cruzi. For this purpose, some interactions were studied between T. cruzi and peritoneal macrophages of mice vaccinated with T. rangeli, infected or not with T. cruzi and the levels of some molecules or soluble mediators which could modify these interactions. The results in vaccinated animals showed a strong innate immune response, where the adherent cells of the vaccinated mice revealed important phagocytic activity, and some soluble mediator (Respiratory Burst: significantly increase, p ≤ 0.03; NO: the levels of vaccinated animals were lower than those of the control group; Arginasa: significantly increase, p ≤ 0.04). The results showed an important role in the early elimination of the parasites and their close relation with the absence of histological lesions that these animals present with regard to the only infected mice. This behaviour reveals that the macrophages act with some type of memory, recognizing the antigens to which they have previously been exposed, in mice were vaccinated with T. rangeli, which shares epitopes with T. cruzi.

Feed efficiency in the laying duck: appropriate measurements and genetic parameters.

The objective of this study was to characterize residual feed intake (RFI) in common laying ducks by a) adjusting position and duration of the measurement period and b) estimating genetic parameters of RFI. The feed intake (FI), BW, and egg mass laid (EML) were recorded for 64 I444 common ducks at the beginning (-35 wk of age) and the middle (41-48 wk of age) of the laying curve. Much feed wastage was observed at the beginning of the laying curve and led to biased FI data. However, when laying was well-established, weekly and fortnightly FI measurements were well correlated phenotypically (Rp from 0.84 to 0.92 and from 0.91 to 0.94, respectively for weekly and fortnightly FI) with the measurements over the whole 2-mo period. Regarding egg mass laid, phenotypic correlations between the one-week measurements and the measurements over the whole 2-mo period were more variable than those for FI, ranging from 0.74 to 0.94, and similar to whatever was the period of measurement. The RFI was investigated in a second experiment based on 384 common female ducks, for which FI, EML, BW, and BW gain were recorded at 39 wk of age. The RFI was determined by multiple regression of FI on metabolic BW and EML. Heritability values of FI and RFI were 0.34 and 0.24, respectively. In addition, if the heritability values obtained for BW (0.65) and BW gain (0.09) were consistent with studies in chickens, the very low EML estimates (0.06) were unexpected. The RFI was strongly genetically linked to FI (Rg = +0.89) but appeared to be independent from BW. Selection based on RFI should therefore reduce the FI of animals without clearly modifying the other components. Moreover, the correlated responses on reproductive traits seem favorable because lower RFI values increase the number of eggs produced per year as well as the hatchability and fertility rates.

Genetic structure of Eurasian and North American mallard ducks based on mtDNA data.

To elucidate the origin and genetic structure of the domesticated duck in Eurasia and North America, we sequenced 114 duck D-loop sequences and retrieved 489 D-loop sequences from GenBank. In total, 603 ducks including 50 duck breeds/populations from eight countries (China, France, Russia, India, Kazakhstan, Mongolia, Thailand and USA) were used in this study. One hundred and thirty-four haplotypes and 81 variable sites were detected. H49 was the predominant haplotype, which was considered to be the same dominant haplotype found in the previous studies, and was found in 309 birds. The smallest values for both genetic differentiation index (F(ST), 0.04156) and the number of the net nucleotide substitutions between two populations (D(A), 0.00018) were observed between Eurasian domestic ducks and Eurasian mallards. No geography, breed or population clusters were observed in the Eurasian domestic ducks and mallards. Five haplotypes were shared by USA mallards and Eurasian domestic duck/Eurasian mallards. Only one haplotype (H49) was shared by Eurasian domestic ducks and China spot-billed ducks. By combining phylogenetic analyses, haplotype network profile, genetic distances and shared haplotypes, we can draw two major conclusions: (i) Eurasian and North American mallards show a clear geographic distribution pattern; (ii) Eurasian domestic ducks are derived from the Eurasian mallards, not from the spot-billed ducks.

Microsatellite mapping of quantitative trait loci affecting meat quality, stress hormones and production traits in Duroc × Large White F2 pigs.

An F2 cross between Duroc and Large White pigs was carried out in order to detect quantitative trait loci (QTL) for 11 meat quality traits (L*, a* and b* Minolta coordinates and water-holding capacity (WHC) of two ham muscles, ultimate pH of two ham and one loin muscles), 13 production traits (birth weight, average daily gain during post-weaning and fattening periods, carcass fat depths at three locations, estimated lean meat content, carcass length and weights of five carcass cuts) and three stress hormone-level traits (cortisol, adrenaline and noradrenaline). Animals from the three generations of the experimental design (including 456 F2 pigs) were genotyped for 91 microsatellite markers covering all the autosomes. A total of 56 QTL were detected: 49 reached the chromosome-wide level (suggestive QTL with a maximal probability of 0.05) and seven were significant at the genome-wide level (with a probability varying from 6 × 10(-4) to 3 × 10(-3)). Twenty suggestive QTL were identified for ultimate pH, colour measurements and WHC on chromosome (SSC) 5, 6, 7, 8, 9, 11, 13, 14, 15 and 17. For production traits, 33 QTL were detected on all autosomes except SSC6, 8 and 9. Seven of these QTL, located on SSC2, 3, 10, 13, 16 and 17, exceeded the genome-wide significance threshold. Finally, three QTL were identified for levels of stress hormones: a QTL for cortisol level on SSC7 in the cortisol-binding globulin gene region, a QTL for adrenaline level on SSC10 and a QTL for noradrenaline level on SSC13. Among all the detected QTL, seven are described for the first time: a QTL for ultimate pH measurement on SSC5, two QTL affecting birth weight on SSC2 and 10, two QTL for growth rate on SSC15 (during fattening) and 17 (during post-weaning) and two QTL affecting the adrenaline and noradrenaline levels. For each QTL, only one to five of the six F1 sires were found to be heterozygous. It means that all QTL are segregating in at least one of the founder populations used in this study. These results suggest that both meat quality and production traits can be improved in purebred Duroc and Large White pigs through marker-assisted selection. It is of particular interest for meat quality traits, which are difficult to include in classical selection programmes.

Genetic parameters of product quality and hepatic metabolism in fattened mule ducks.

Genetic parameters of traits related to hepatic lipid metabolism, carcass composition, and product quality of overfed mule ducks were estimated on both parental lines of this hybrid: the common duck line for the maternal side and the Muscovy line for the paternal side. The originality of the statistical model was to include simultaneously the additive genetic effect of the common ducks and that of the Muscovy ducks, revealing a greater genetic determinism in common than in Muscovy. Plasma metabolic indicators (glucose, triglyceride, and cholesterol contents) were heritable, in particular at the end of the overfeeding period, and heritabilities increased with the overfeeding stage. Carcass composition traits were highly heritable in the common line, with values ranging from 0.15 for liver weight, 0.21 for carcass weight, and 0.25 for abdominal fat weight to 0.32 for breast muscle weight. Heritabilities of technological outputs were greater for the fatty liver (0.19 and 0.08, respectively, on common and Muscovy sides for liver melting rate) than for the pectoralis major muscle (between 0.02 and 0.05 on both parental sides for cooking losses). Fortunately, the processing industry is mainly facing problems in liver quality, such as too high of a melting rate, than in meat quality. The meat quality appraisal criteria (such as texture and cooking losses), usually dependent on pH and the rate of decline of pH, were also very lowly heritable. This study demonstrated that genetic determinism of meat quality and ability of overfeeding is not similar in the common population and in the Muscovy population; traits related to fattening, muscle development, and BW have heritability values from 2 to 4 times greater on the common line than on the Muscovy line, which is relevant for considering different selection strategies.

Mediadores solubles liberados por la infección con Trypanosoma cruzi podrían desencadenar mecanismos de fisiopatogenia en la enfermedad de Chagas experimental / Soluble mediators in Trypanosoma cruzi infection could trigger mechanisms of pathogenesis in Chagas disease

El Trypanosoma cruzi, agente etiológico de la enfermedad de Chagas, afecta a cerca de 2.500.000 personas en nuestro país y 18 millones en América latina. Este parásito presenta en el hospedador dos estadios de importancia médica: la forma amastigote, intracelular, que se replica activamente, y la forma extracelular, el tripomastigote, que es infectante. Por ello, para controlar la infección se requiere una potente respuesta inmune humoral y celular, y es importante el resultado de la interacción hospedador­parásito en etapas tempranas de la infección. El 30% de los infectados desarrolla algún grado de patología, cardíaca o digestiva, a lo largo de los años. Algunos autores lo atribuyen a la acción directa del parásito, otros, a reacciones autoinmunes inducidas por el T. cruzi. El objetivo del presente trabajo fue estudiar en líquido peritoneal (sitio de infección), en un modelo experimental murino, algunos mediadores de respuesta innata en las primeras horas post infección con T. cruzi y la respuesta adaptativa al final de la fase aguda. Los resultados revelaron aumento del estallido respiratorio y síntesis de IL-6 desde las primeras horas. La concentración de óxido nítrico aumentó con la evolución de la infección mientras que la activación de arginasa se mantuvo controlada y fue importante la producción de inmunoglobulinas específicas. Los mecanismos estudiados estarían involucrados no sólo en la eliminación del T. cruzi, sino también en la fisiopatogenia de la infección. Estos hallazgos estimulan la continuación de estudios orientados a avanzar en el conocimiento de eventos inmunológicos tempranos para el desarrollo de nuevas terapéuticas profilácticas en el hombre.(AU)

Trypanosoma cruzi, ethiologic agent of Chagas disease, affects about 2.500.000 people in our country and 18 millon in Latin America. The parasite presents two stages of medical importance in the host, the amastigote, intracellular replicating form and the extracellular trypomastigote, the infective form. That is why the control of infection requires a strong humoral and cellular immune response, hence, it is very important the outcome of host-parasite interaction in the early stages of infection. 30% of infected people, develop some degree of pathology, cardiac or digestive in the chronic period of infection, attribute this to the direct action of the parasite, or to autoimmune reactions induced by Trypanosoma cruzi. The aim of this work was to study at local level, in a murine experimental model some mediators in the early infections with T. cruzi and the adaptive response at the end of the acute phase. The results revealed increased respiratory burst and synthesis of IL-6 since the first hours. Nitric oxide concentration increased with the progression of the infection, while the activation of arginase remained regulated and it was important the specific immunoglobulin production. These mediators would be involved in mechanisms of resistence to T. cruzi, but also in the pathogenia of the infection. These findings stimulate to go further in the knowledge of immunological early events directed to the development to therapeutic approaches in Chagas disease(AU)

Estimation of genetic parameters and genome scan for 15 semen characteristics traits of Holstein bulls.

A QTL detection experiment was performed in French dairy cattle to search for QTL related to male fertility. Ten families, involving a total of 515 bulls, were phenotyped for ejaculated volume and sperm concentration, number of spermatozoa, motility, velocity, percentage of motile spermatozoa after thawing and abnormal spermatozoa. A set of 148 microsatellite markers were used to realize a genome scan. First, genetic parameters were estimated for all traits. Semen production traits were found to have moderate heritabilities (from 0.15 to 0.30) while some of the semen quality traits such as motility had high heritabilities (close to 0.60). Genetic correlations among traits showed negative relationships between volume and concentration and between volume and most quality traits such as motility or abnormal sperm while correlations between concentration and these traits were rather favourable. Percentages of abnormal sperm were negatively related to quality traits, especially with motility and velocity of spermatozoa. Three QTL related to abnormal sperm frequencies were significant at p < 0.01. In total, 11 QTL (p < 0.05) were detected. However, the number of QTL detected was within the range of expected false positives. Because of the lack of power to find QTL in this design further analyses are required to confirm these QTL.

Cusp anomalous dimension in maximally supersymmetric Yang-Mills theory at strong coupling.

We construct an analytical solution to the integral equation which is believed to describe logarithmic growth of the anomalous dimensions of high-spin operators in planar N=4 super Yang-Mills theory and use it to determine the strong coupling expansion of the cusp anomalous dimension.

Evaluating energy efficiency of site-specific tillage in maize in NE Italy.

This paper examine the efficiency of energy use of three conservation tillage practices (SST - sub-soil tillage; MT - minimum tillage; and NT - no tillage) performed within two management zones, previously identified in a field according to the stability of yield variability. Experiments were carried out in 2003 in NE Italy, on a farm near Rovigo, on a 8-ha field with clay soil, in maize (Zea mays, L.). The purpose of the paper is (i) to investigate the energy variability due to these tillage practices performed spatially within two management zones and (ii) to analyze the long-term energetic efficiency for each tillage practice. The energy balance was highest for SST with respect to MT and NT, due to labor and fuel consumption rates. The energy balance was influenced by the spatial pattern of yield, with appreciable differences between practices in terms of both the conversion index of energy for tillage (9.0, 12.6 and 22.8GJha(-1) for SST, MT and NT, respectively) and the energy use efficiency for tillage (8.0, 11.6, 21.8GJha(-1) for SST, MT and NT, respectively). Based on the simulated data and the calibration results, SALUS model proved to be a good tool for analyzing long-term effects of tillage practices on yield. The NT treatment showed the best efficiency over years, due to the low inputs in comparison with the output level.

Intensive olive orchards on sloping land: good water and pest management are essential.

There is intensive cultivation of olives on sloping land in Jaen-Granada (Spain), Basilicata (Italy) and Western Crete (Greece). The intensive olive groves here are characterised by a tree density of about 250treesha(-1), yearly fertilisation and pruning, several chemical sprays for pest control, soil tillage once to thrice per year and irrigation up to 2700m3ha(-1)yr(-1). Intensive management results in high yields of 3600-6500kgha(-1) but also higher labour costs of 1154-1590euroha(-1)yr(-1), varying per area. The major environmental concerns in this system are related to chemical residues in the fruit, the extinction of useful insects, the depletion of groundwater resources, the pollution of soil and water and the erosion of soil. This paper describes the impact of intensive orchard management on natural resources and gives recommendations for soil and water conservation, reduction of chemicals use and biodiversity enhancement. The specific recommendations for the relevant stakeholders--farmers, technicians, agricultural services and policy makers--are based on the experimental evaluation of different agricultural practices and a socio-economic analysis of local and global production and markets.

Enfermedad de Chagas congenita en Córdoba, Argentina: aspectos epidemiológicos, clínicos, diagnósticos y terapéuticos. Experiencia de 30 años de seguimiento / Congenital Chagas disease in Córdoba, Argentina: epidemiological, clinical, diagnostic, and therapeutic aspects. Experience of 30 years of follow up

Chagas'disease has a great epidemiological relevance. Most of infected children are asymptomatics, with low mortality rate. The most frequent clinical findings are hepatomegaly and splenomegaly Parasitological methods: fresh smears, microStrout and Hemoculture, sequentially performed, detect the parasite in almost 100% of infected children. The gold standard for immunodiagnosis are serological curves, due to the interference of maternal IgG. Infected children maintain their antibody levels , whereas non infected became negatives. IgM test show false positive and false negative results. In children acutely infected during the first year of life and in cases of congenital infection, we observed high serum levels of soluble receptors of TNFalpha, IL-2 and sCD8, with significantly post treatment decrease. In a prospective 30 years research, we observed high therapeutic efficacy when children were treated before 3 years of life with benznidazol or nifurtimox, with good clinical evolution, together with parasitological and serological negativization.

Genomic stability in Arabidopsis thaliana transgenic plants obtained by floral dip.

The occurrence of DNA modification is an undesired phenomenon accompanying plant cell transformation. The event has been correlated with the stress imposed by the presently utilised transformation procedures, all depending on plant differentiation from in vitro cell culture, but other causes have not been excluded. In this work, transgenic Arabidopsis thaliana plants have been produced by an approach that does not require cell dedifferentiation, being based on in planta Agrobacterium-mediated gene transfer by flower infiltration, which is followed by recovery and selection of transgenic progeny. Genomic DNA changes in transgenic and control plants have been investigated by AFLP and RAMP analysis. Results show no statistically relevant genomic modifications in transgenic plants, as compared with control untreated plants. Variations were observed in callus-derived A. thaliana plants, thus supporting the conclusion that somaclonal variation is essentially correlated with the stress imposed by the in vitro cell culture, rather than with the integration of a foreign gene.

Pharmacokinetic comparison of 120-hour infusion versus hyperfractionated oral administration of idarubicin.

The aim of this study was to compare the pharmacokinetics of idarubicin (IDA) and its active metabolite idarubicinol (IDOL) after chronic oral and continuous intravenous (i.v.) IDA administration in order to establish the oral doses needed to reach the i.v. equiactive plasma drug exposure. The pharmacokinetic profile of IDA and IDOL was investigated in 23 patients receiving 12 mg/m2 IDA by 120-h i.v. infusion (2.4 mg/m2/day) combined with cyclophosphamide, etoposide and prednisone in comparison to 28 patients receiving oral IDA doses ranging from 2 to 10 mg/day for 21 days in a phase I study. We found that IDA AUC24h/dose/m2 was 4.7-fold greater during i.v. than oral administration, whereas IDOL AUC24h/dose/m2 was only about 2-fold higher after i.v. administration. The metabolic ratio between IDOL AUC24h and IDA AUC24h in plasma was about 3-fold higher after oral administration. Based on these results we were able to estimate that equiactive plasma drug exposure was reached with an approximately 2.5-fold greater oral dose/m2 of IDA than the corresponding i.v. dose.

Acute Trypanosoma cruzi infection: IL-12, IL-18, TNF, sTNFR and NO in T. rangeli-vaccinated mice.

We have developed an experimental model of vaccination against the infection with the protozoa Trypanosoma cruzi, the agent of Chagas disease in Latin America. Vaccination was performed with Trypanosoma rangeli, a non-pathogenic protozoa sharing many antigens with T. cruzi. It strongly protected BALB/c mice, sharply reducing parasitaemia and mortality rate of the acute T. cruzi infection. The aim of the present work was to complete our previous study on the production of IFN-gamma and IL-10 in this vaccination model by investigating the production of IL-12p35 and p40, IL-18, TNF, TNF soluble receptors (sTNFR), and nitric oxide (NO), factors known to play a key role in the outcome of T. cruzi infection. We show that the protection obtained against the acute T. cruzi infection was surprisingly associated with reduced circulating levels of IL-18 and NO, whereas the release of IL-12p40 was enhanced in comparison to non-vaccinated infected animals. IL-12p35 remained undetectable in infected animals, vaccinated or not. The balance between sTNFR and TNF suggested a decrease of TNF bioactivity in vaccinated mice. These results show that the protection induced by the vaccination with T. rangeli against a challenging infection with T. cruzi is not associated with the strong type 1 immune response usually involved in the control of intracellular pathogens, particularly questioning the protective role of NO during the acute phase of T. cruzi infection.

Population pharmacokinetics and pharmacodynamics of oral etoposide.

AIMS: To study the population pharmacokinetics and pharmacodynamics of oral etoposide in patients with solid tumours. METHODS: A prospective, open label, cross-over, bioavailability study was performed in 50 adult patients with miscellaneous, advanced stage solid tumours, who were receiving oral (100 mg capsules) etoposide for 14 days and i.v. (50 mg) etoposide on day 1 or day 7 in randomised order during the first cycle treatment. Total and unbound etoposide concentration were assayed by h.p.l.c. Population PK parameters estimation was done by using the P-Pharm software (Simed). Haematological toxicity and tumour response were the main pharmacodynamic endpoints. RESULTS: Mean clearance was 1.14 l h(-1) (CV 25%). Creatinine clearance was the only covariable to significantly reduce clearance variability (residual CV 18%). (CL = 0.74 + 0.0057 CLCR; r(2) = 0.32). Mean bioavailability was 45% (CV 22%) and mean protein binding 91.5% (CV 5%). Exposure to free, pharmacologically active etoposide (free AUC p.o.) was highly variable (mean value 2.8 mg l(-1) h; CV 64%; range 0.4-9.5). It decreased with increased creatinine clearance and increased with age which accounted for 9% of the CV. Mean free AUC p.o. was the best predictor of neutropenia. Free AUC50 (exposure producing a 50% reduction in absolute neutrophil count) was 1.80 mg l(-1) h. In patients with lung cancer, the free AUC p.o. was higher in the two patients with responsive tumour (5.9 mg l(-1) h) than in patients with stable (2.1 mg l-1 h) or progressive disease (2.3 mg l-1 h) (P = 0.01). CONCLUSIONS: Exposure to free etoposide during prolonged oral treatment is highly variable and is the main determinant of pharmacodynamic effects. The population PK model based on creatinine clearance is poorly predictive of exposure. Therapeutic drug monitoring would be necessary for dose individualization or to study the relationship between exposure and antitumour effect.