Fluoxetine effects assessment on the life cycle of aquatic invertebrates

International audienceFluoxetine is a serotonin re-uptake inhibitor, generally used as an antidepressant. It is suspected to provoke substantial effects in the aquatic environment. This study reports the effects of fluoxetine on the life cycle of four invertebrate species, Daphnia magna, Hyalella azteca and the snail Potamopyrgus antipodarum exposed to fluoxetine spiked-water and the midge Chironomus riparius exposed to fluoxetine-spiked sediments. For D. magna, a multi-generational study was performed with exposition of newborns from exposed organisms. Effects of fluoxetine could be found at low measured concentrations (around 10 micro g l(-1)), especially for parthenogenetic reproduction of D. magna and P. antipodarum. For daphnids, newborns length was impacted by fluoxetine and the second generation of exposed individuals showed much more pronounced effects than the first one, with a NOEC of 8.9 micro g l(-1). For P. antipodarum, significant decrease of reproduction was found for concentrations around 10 micro g l(-1). In contrast, we found no effect on the reproduction of H. azteca but a significant effect on growth, which resulted in a NOEC of 33 micro g l(-1), expressed in nominal concentration. No effect on C. riparius could be found for measured concentrations up to 59.5 mg kg(-1). General mechanistic energy-based models showed poor relevance for data analysis, which suggests that fluoxetine targets specific mechanisms of reproduction

A multi-scale modeling framework for individualized, spatiotemporal prediction of drug effects and toxicological risk

International audienceIn this study, we focus on a novel multi-scale modeling approach for spatiotemporal prediction of the distribution of substances and resulting hepatotoxicity by combining cellular models, a 2D liver model, and whole body model. As a case study, we focused on predicting human hepatotoxicity upon treatment with acetaminophen based on in vitro toxicity data and potential inter-individual variability in gene expression and enzyme activities. By aggregating mechanistic, genome-based in silico cells to a novel 2D liver model and eventually to a whole body model, we predicted pharmacokinetic properties, metabolism, and the onset of hepatotoxicity in an in silico patient. Depending on the concentration of acetaminophen in the liver and the accumulation of toxic metabolites, cell integrity in the liver as a function of space and time as well as changes in the elimination rate of substances were estimated. We show that the variations in elimination rates also influence the distribution of acetaminophen and its metabolites in the whole body. Our results are in agreement with experimental results. What is more, the integrated model also predicted variations in drug toxicity depending on alterations of metabolic enzyme activities. Variations in enzyme activity, in turn, reflect genetic characteristics or diseases of individuals. In conclusion, this framework presents an important basis for efficiently integrating inter-individual variability data into models, paving the way for personalized or stratified predictions of drug toxicity and efficacy

Incidence of hypohidration in athletes and sedentary male adults with intellectual disability

El presente estudio descriptivo de tipo transversal se diseñó para determinar el nivel de hidratación de deportistas con discapacidad intelectual y su comparación con adultos sedentarios con la misma discapacidad. Participaron 22 deportistas federados que realizan el mismo programa de entrenamiento además de 22 adultos sedentarios ajustados en sexo, edad y cociente de inteligencia. Los parámetros ensayados fueron la densidad urinaria determinada mediante refractómetro así como la ingesta diaria de líquido adlibitum. Este protocolo fue aprobado por un Comité de Ética Institucional. Tan solo 6 deportistas (21,6%) presentaron valores de euhidratación frente a 9 (40,9%) de los participantes sedentarios incluidos en el grupo control. Las únicas diferencias significativas respecto a la ingesta de líquidos se estableció precisamente entre deportistas y sedentarios con euhidratación. Se concluye que los deportistas con discapacidad intelectual se encuentran en riesgo de deshidratación que podría explicarse, al menos en parte, por una insuficiente ingesta hídricaThe current study was designed to determine hydration status of well-trained, male athletes with ID. A secondary purpose was to compare these results with hydration status of sedentary young adults with ID. A total of 22 athletes with ID volunteered for this cross-sectional, descriptive study. The control group included 22, age, sex and IQ-matched sedentary adults with ID. Main outcome measurements were urine specific gravity (USG) and daily fluid intake for three consecutive days. With regard to athletes with ID, it was found that 5 participants (21,7%) stayed significantly hypohydrated, 12 athletes (52,2%) appeared hypohydrated and 6 participants (26,1%) stayed euhydrated. In fact, a significantly lower percentage of athletes was euhydrated when compared to sedentary matched adults with ID (26,1vs.40,9%;χ2=5,67;p<001). In conclusion, athletes with ID are at increased risk of dehydration that may be explained, at least in part, given that ad-libitum fluid consumption was insufficien

Evolution of a TRIM5-CypA splice isoform in old world monkeys

The TRIM family proteins share a conserved arrangement of three adjacent domains, an N-terminal RING domain, followed by one or two B-boxes and a coiled-coil, which constitutes the tripartite-motif for which the family is named. However, the C-termini of TRIM proteins vary, and include at least nine evolutionarily distinct, unrelated protein domains. Antiviral restriction factor TRIM5alpha has a C-terminal B30.2/SPRY domain, which is the major determinant of viral target specificity. Here, we describe the evolution of a cyclophilin-A encoding exon downstream of the TRIM5 locus of Asian macaques. Alternative splicing gives rise to chimeric transcripts encoding the TRIM motif fused to a C-terminal CypA domain (TRIM5-CypA). We detected TRIM5-CypA chimeric transcripts in primary lymphocytes from two macaque species. These were derived in part from a CypA pseudogene in the TRIM5 locus, which is distinct from the previously described CypA insertion in TRIM5 of owl monkeys. The CypA insertion is linked to a mutation in the 3\u27 splice site upstream of exon 7, which may prevent or reduce expression of the alpha-isoform. All pig-tailed macaques (M. nemestrina) screened were homozygous for the CypA insertion. In contrast, the CypA-containing allele was present in 17% (17/101) of rhesus macaques (M. mulatta). The block to HIV-1 infection in lymphocytes from animals bearing the TRIM5-CypA allele was weaker than that in cells from wild type animals. HIV-1 infectivity remained significantly lower than SIV infectivity, but was not rescued by treatment with cyclosporine A. Thus, unlike owl monkey TRIMCyp, expression of the macaque TRIM5-CypA isoform does not result in increased restriction of HIV-1. Despite its distinct evolutionary origin, Macaca TRIM5-CypA has a similar domain arrangement and shares approximately 80% amino-acid identity with the TRIMCyp protein of owl monkeys. The independent appearance of TRIM5-CypA chimeras in two primate lineages constitutes a remarkable example of convergent evolution. Based on the presence of the CypA insertion in separate macaque lineages, and its absence from sooty mangabeys, we estimate that the Macaca TRIM5-CypA variant appeared 5-10 million years ago in a common ancestor of the Asian macaques. Whether the formation of novel genes through alternative splicing has played a wider role in the evolution of the TRIM family remains to be investigated

Evolution of a TRIM5-CypA Splice Isoform in Old World Monkeys

The TRIM family proteins share a conserved arrangement of three adjacent domains, an N-terminal RING domain, followed by one or two B-boxes and a coiled-coil, which constitutes the tripartite-motif for which the family is named. However, the C-termini of TRIM proteins vary, and include at least nine evolutionarily distinct, unrelated protein domains. Antiviral restriction factor TRIM5α has a C-terminal B30.2/SPRY domain, which is the major determinant of viral target specificity. Here, we describe the evolution of a cyclophilin-A encoding exon downstream of the TRIM5 locus of Asian macaques. Alternative splicing gives rise to chimeric transcripts encoding the TRIM motif fused to a C-terminal CypA domain (TRIM5-CypA). We detected TRIM5-CypA chimeric transcripts in primary lymphocytes from two macaque species. These were derived in part from a CypA pseudogene in the TRIM5 locus, which is distinct from the previously described CypA insertion in TRIM5 of owl monkeys. The CypA insertion is linked to a mutation in the 3′ splice site upstream of exon 7, which may prevent or reduce expression of the α-isoform. All pig-tailed macaques (M. nemestrina) screened were homozygous for the CypA insertion. In contrast, the CypA-containing allele was present in 17% (17/101) of rhesus macaques (M. mulatta). The block to HIV-1 infection in lymphocytes from animals bearing the TRIM5-CypA allele was weaker than that in cells from wild type animals. HIV-1 infectivity remained significantly lower than SIV infectivity, but was not rescued by treatment with cyclosporine A. Thus, unlike owl monkey TRIMCyp, expression of the macaque TRIM5-CypA isoform does not result in increased restriction of HIV-1. Despite its distinct evolutionary origin, Macaca TRIM5-CypA has a similar domain arrangement and shares ∼80% amino-acid identity with the TRIMCyp protein of owl monkeys. The independent appearance of TRIM5-CypA chimeras in two primate lineages constitutes a remarkable example of convergent evolution. Based on the presence of the CypA insertion in separate macaque lineages, and its absence from sooty mangabeys, we estimate that the Macaca TRIM5-CypA variant appeared 5–10 million years ago in a common ancestor of the Asian macaques. Whether the formation of novel genes through alternative splicing has played a wider role in the evolution of the TRIM family remains to be investigated

Current practices and challenges in adaptation of clinical guidelines : A qualitative study based on semistructured interviews

Funding YS is funded by China Scholarship Council (No 201707040103).Altres ajuts: CSC/201707040103Objective This study aims to better understand the current practice of clinical guideline adaptation and identify challenges raised in this process, given that published adapted clinical guidelines are generally of low quality, poorly reported and not based on published frameworks. Design A qualitative study based on semistructured interviews. We conducted a framework analysis for the adaptation process, and thematic analysis for participants' views and experiences about adaptation process. Setting Nine guideline development organisations from seven countries. Participants Guideline developers who have adapted clinical guidelines within the last 3 years. We identified potential participants through published adapted clinical guidelines, recommendations from experts, and a review of the Guideline International Network Conference attendees' list. Results We conducted ten interviews and identified nine adaptation methodologies. The reasons for adapting clinical guidelines include developing de novo clinical guidelines, implementing source clinical guidelines, and harmonising and updating existing clinical guidelines. We identified the following core steps of the adaptation process (1) selection of scope and source guideline(s), (2) assessment of source materials (guidelines, recommendations and evidence level), (3) decision-making process and (4) external review and follow-up process. Challenges on the adaptation of clinical guidelines include limitations from source clinical guidelines (poor quality or reporting), limitations from adaptation settings (lacking resources or skills), adaptation process intensity and complexity, and implementation barriers. We also described how participants address the complexities and implementation issues of the adaptation process. Conclusions Adaptation processes have been increasingly used to develop clinical guidelines, with the emergence of different purposes. The identification of core steps and assessment levels could help guideline adaptation developers streamline their processes. More methodological research is needed to develop rigorous international standards for adapting clinical guidelines

Indications and outcome of repeat penetrating keratoplasty in India

BACKGROUND: Repeat penetrating keratoplasty is quite often required as there is high chance of failure of the primary graft particularly in the developing world. We planned a study to analyze the indications and outcome of repeat penetrating keratoplasty in a tertiary care centre in India. METHODS: A retrospective analysis of all the patients who underwent repeat penetrating keratoplasty, between January 1999 and December 2001 was performed. The parameters evaluated were indication for the primary penetrating keratoplasty, causes of failure of the previous graft, and final visual outcome and clarity of the repeat corneal grafts. RESULTS: Of fifty-three eyes of 50 patients with repeat penetrating keratoplasty (three patients underwent bilateral corneal regrafts), 37 eyes had undergone one regraft each, 14 eyes two regrafts and two eyes had three regrafts. The follow-up of the patients ranged from one to three years. The most common primary etiologic diagnosis was vascularized corneal scars (66%), of which the scars related to infection were most common (68.5%). Twenty-eight regrafts (52.8%) remained clear at a mean follow-up of 1.54 ± 0.68 years, of which 25 were single regrafts (89.3%). The commonest cause of failure of regraft was infection to the corneal graft (recurrence of herpetic infection in 9 eyes and perforated graft ulcers in 3 eyes). Three (18.6%) of the 16 eyes with multiple corneal regrafts achieved a BCVA of 6/60. Overall, only five eyes (all with single regraft) achieved a BCVA of 6/18 or better at the end of follow-up. CONCLUSION: Graft infection is the leading cause of failure of repeat keratoplasty in this part of the world. Prognosis for visual recovery and graft survival is worse in eyes undergoing multiple regrafts

Biodegradação de matéria orgânica em lama sedimentada - definição de parâmetros na lagoa de piratininga, RJ: Biodegradation of organic matter in the sedimented mud - parameters definition at the piratininga lagoon, RJ

Entre março e julho/22, duas tecnologias complementares, EM® e Pulmão™, foram testadas para estudar a biorremediação na camada de lama da Lagoa de Piratininga, Niterói, RJ. Dados ortométricos, matéria orgânica, carbono orgânico, nitrogênio Kjeldahl total, fósforo e biopolímeros foram quantificados na superfície do sedimento. As concentrações crescentes de nitrogênio Kjeldahl indicaram aportes de esgoto doméstico ao sistema. O fósforo orgânico predominou sobre o total, pois foi consumido no processo de biorremediação. Ocorreram mudanças quali- quantitativas na composição da matéria orgânica lábil, com consumo de lipídio, molécula recalcitrante, e produção de proteínas e carboidratos. Os dados altimétricos indicaram maior tendência de consumo da lama na área que reuniu as tecnologias EM1®+Pulmão™, onde o aporte sedimentar foi praticamente anulado. Houve uma diminuição da espessura da lama, refletindo no aumento sutil de profundidade superficial da camada sedimentar. Estas modificações nas áreas experimentais indicam que o processo de restauração ambiental está ocorrendo