Suivi de l’opération d’enrobage pour le développement d’une forme posologique facile à avaler pour des fins pédiatriques : étude du procédé et développement d’outils pour un suivi en temps réel

Malgré les mesures récentes des organismes de réglementation, il y a encore des lacunes dans la mise en œuvre de formulations adaptées à l'âge à l’intention de la population pédiatrique. Les différences au sein de cette population, conjuguées à la non-adhésion thérapeutique due au mauvais goût des médicaments, présentent de grands défis pour la formulation de médicaments pris par voie orale. Des formulations orales solides souples, comme les microsphères, ont été proposées comme solutions de rechange aux formulations déjà commercialisées, comme les comprimés ou les formes posologiques orales liquides. Les microsphères sont des systèmes matriciels dans lesquels le principe actif (PA) est dispersé. Le PA est donc subdivisé en plusieurs petites unités posologiques. De plus, les microsphères peuvent être enrobées afin de masquer le goût. La stratégie consiste à appliquer une barrière protectrice à la microsphère qui empêchera la libération du médicament dans la cavité buccale, tout en maintenant une libération immédiate dès que le produit médicamenteux atteint le site d’absorption, pour ainsi obtenir un profil neutre sur le plan du goût sans affecter la biodisponibilité du PA. Les lits d’air fluidisé avec : Wurster sont utilisés depuis plusieurs années dans l’industrie pharmaceutique pour enrober les petites particules, car ils produisent des particules uniformément enrobés. La nécessité d’acquérir une meilleure compréhension des procédés conventionnels utilisés dans l’industrie pharmaceutique est connue. Les organismes de réglementation favorisent l’utilisation des principes de qualité par la conception, ainsi que des nouvelles technologies, comme les outils de la technologie d’analyse des procédés (PAT), dans le but d’élaborer une stratégie pour transformer un procédé de fabrication qui se rapproche davantage d’une forme d’art en procédé basé sur des données scientifiques. La présente thèse porte spécifiquement sur cette question et plus particulièrement sur une meilleure compréhension de la relation entre la formulation de la solution d’enrobage et le procédé d’enrobage pour la dissolution du PA. Dans le cadre de ces travaux, un plan d’expérience D-optimal couplé à la mise en œuvre de trois outils PAT en ligne a permis d’identifier les paramètres critiques du procédé et les attributs critiques du matériau (formulation de la solution d’enrobage) qui influencent la libération in-vitro du PA au pH buccal. Le niveau de l’enrobage, le niveau de plastifiant, le débit, la température du lit et le durcissement sont les paramètres critiques identifiés pour une formation complète du film. La criticité de la morphologie de l’enrobage sur la dissolution dans la salive simulée est également démontrée. La performance en ligne de la spectroscopie Raman, de la spectroscopie proche infrarouge et de la mesure de la réflectance du faisceau focalisé, ainsi que les données du procédé et les attributs des matières premières sont évalués et comparés pour faire le suivi du procédé d’enrobage des microsphères. En recourant à une analyse multiblock partial least squares, il est démontré que la spectroscopie Raman a une performance supérieure pour assurer le suivi du procédé et obtenir ainsi un enrobage constant pour la membrane barrière à couche mince, essentielle à l'observance du patient.Abstract: Despite recent incentives provided by regulatory agencies there is still a gap in the implementation of age-appropriate formulations for the pediatric population. The differences within this population, coupled with the non-compliance due to poor taste, present great challenges for oral drug formulation. Flexible solid oral formulations, such as microspheres, have been proposed as alternatives to existing marketed formulations such as tablets or liquid oral dosage forms. Microspheres are matrix systems where the Active Pharmaceutical Ingredient (API) is dispersed. The API is thus subdivided into a plurality of small dosage units. Additionally, microspheres can be coated as a strategy to achieve taste masking. It consists in applying a protective barrier to the microsphere that will prevent the release of drug in the oral cavity, while maintaining an immediate release once the drug product reaches the absorption site, thereby achieving a taste neutral profile without adversely affect the bioavailabity of the API. To coat small particles Wurster fluid bed coaters have been used for many years in the pharmaceutical industry, as they produce uniformly coated particles. There is a recognized need to better understand conventional processes used within the pharmaceutical industry. The regulatory agencies have encouraged the employment of quality by design principles, together with new technologies, such as Process Analytical Technology (PAT) tools, with the aim of developing a strategy to transform, what is generally considered an art form, into sound science based processes. This thesis specifically concerns this issue by focusing on better understanding the relation between both coating formulation and coating process to dissolution of the API. In this work, a D-optimal design coupled with the implementation of three in-line PAT tools helped identify the critical process parameters and critical material attributes (coating formulation) influencing in-vitro API release at mouth pH. Coating level, plasticizer level, spray rate and product bed temperature and curing are the identified critical parameters for a complete film formation. The criticality of coating morphology on the dissolution in simulated saliva is also demonstrated. The in-line performance of Raman spectroscopy, near infrared spectroscopy and focused beam reflectance measurement, together with process data and raw material attribute is evaluated and compared to monitor the microsphere coating process. By resorting to multiblock partial least squares it is shown that Raman has superior performance to ensure consistent coating performance for thin film barrier membrane, essential to patient compliance

“It won’t work here”: Lessons for just nature-based stream restoration in the context of urban informality

Nature-Based Solutions (NBS) have been advocated for their potential to contribute to the making of sustainable and just cities. However, a growing body of research shows that NBS cannot inherently provide just outcomes and might instead (re)produce environmental injustices. This research explores NBS for stream/river restoration in ‘informal’ areas, showing how riparian margins have become spaces of conflict. It draws lessons from two linear parks integrated into neighbourhood regeneration strategies in São Paulo. Data were collected from household surveys and focus group discussions to examine local populations’ values towards stream restoration. They provide understandings of residents’ perceptions towards multiple health and safety risks and concerns over contested responsibilities, notably revealing that local preferences for stream burial have been shaped by persisting waste dumping issues. An environmental justice lens helps highlight the limited integration of plural social and cultural values into project plans. This further helps draw lessons on ways to address local conflicts and integrate multiple socio-environmental values into NBS planning, with support from policy tools that allow stronger community engagement. Findings also support the identification of justice pathways for NBS in informal settings. The analysis of material and interpretative human-environment relationships provides evidence of opportunities for NBS to be integrated into everyday uses of local space and pre-existing environmental caring practices. For this, communities need to have stronger influence over decisions affecting them. The research thereby demonstrates that NBS will only become a mechanism for ecological recovery with city-wide benefits if marginalised groups are better included in their planning

Trypanosoma brucei triggers a broad immune response in the adipose tissue

Copyright: © 2021 Machado et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Adipose tissue is one of the major reservoirs of Trypanosoma brucei parasites, the causative agent of sleeping sickness, a fatal disease in humans. In mice, the gonadal adipose tissue (AT) typically harbors 2-5 million parasites, while most solid organs show 10 to 100-fold fewer parasites. In this study, we tested whether the AT environment responds immunologically to the presence of the parasite. Transcriptome analysis of T. brucei infected adipose tissue revealed that most upregulated host genes are involved in inflammation and immune cell functions. Histochemistry and flow cytometry confirmed an increasingly higher number of infiltrated macrophages, neutrophils and CD4+ and CD8+ T lymphocytes upon infection. A large proportion of these lymphocytes effectively produce the type 1 effector cytokines, IFN-γ and TNF-α. Additionally, the adipose tissue showed accumulation of antigen-specific IgM and IgG antibodies as infection progressed. Mice lacking T and/or B cells (Rag2-/-, Jht-/-), or the signature cytokine (Ifng-/-) displayed a higher parasite load both in circulation and in the AT, demonstrating the key role of the adaptive immune system in both compartments. Interestingly, infections of C3-/- mice showed that while complement system is dispensable to control parasite load in the blood, it is necessary in the AT and other solid tissues. We conclude that T. brucei infection triggers a broad and robust immune response in the AT, which requires the complement system to locally reduce parasite burden.This work was supported by the European Research Council (FatTryp, ref. 771714) awarded to LMF, by Fundação para a Ciência e Tecnologia (CEECIND/03322/2018) awarded to LMF, (PTDC/MED-IMU/30948/2017 and CEECIND/00697/2018) awarded to KS, (PD/BD/128286/2017) awarded to HM, (SFRH/BPD/89833/2012) awarded to ST, (IMM/BI/83-2017 through PTDC/BIM-MET/4471/2014) awarded to TB-R and by the National Institutes of Health (NIGMS K99GM132557) awarded to FR-F. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio

APLICAÇÃO DAS GEOTECNOLOGIAS NA PRODUÇÃO DE EXERCÍCIOS VOLTADOS PARA O ENSINO DE GEOGRAFIA: UM ESTUDO DE CASO PARA A ILHA DO GOVERNADOR – RJ

Este trabalho tem como objetivo a utilização do Google Earth para a produção de materiais didáticos voltados para o ensino de Geografia, sobretudo de temas de Geomorfologia e espaço geográfico, para estudantes do ensino fundamental 2, que vivem na Ilha do Governador, município do Rio de Janeiro. O uso de imagens extraídas do Google Earth, em diferentes escalas, permite aos alunos uma interpretação mais completa de suas vizinhanças, além de possibilitar a integração espacial de diferentes componentes espaciais com a Baia de Guanabara. É interessante notar que a utilização desta ferramenta facilita a visualização oblíqua e vertical do espaço, e ainda em perspectiva 2D e 3D, bem como a abordagem de temas geográficos de uma forma dinâmica e interdisciplinar. A escolha dos temas foi baseada no estudo dos Parâmetros Curriculares Nacionais (PCN), e também sobre os conteúdos considerados importantes para os alunos das escolas de Ilha do Governador. As atividades foram construídas em folhas A4 a um baixo custo, e aplicadas para introduzir os temas a serem discutidos nas aulas de geografia, tornando possível ainda a revisão do conhecimento prévio dos alunos, além de contribuir no desenvolvimento de habilidades voltadas para análise de dados espaciais

Schistosoma mansoni SmKI-1 or Its C-Terminal Fragment Induces Partial Protection Against S. mansoni Infection in Mice

Current schistosomiasis control strategies are mainly based on chemotherapy, but the development of a vaccine against this parasitic disease would contribute to a long-lasting decrease in disease spectrum and transmission. When it comes to vaccine candidates, several genes encoding Schistosoma mansoni proteins expressed at the mammalian host–parasite interface have been tested. Among the most promising molecules are the proteins present on the tegument and digestive tract of the parasite. In this study, we evaluate the potential of SmKI-1, the first Kunitz-type protease inhibitor functionally characterized in S. mansoni, as a vaccine candidate. Bioinformatic analysis points to the C-terminal fragment as the main region of the molecule responsible for the development of a potential protective immune response induced by SmKI-1. Therefore, for the vaccine formulations, we produced the recombinant (r) SmKI-1 and two different fragments, its Kunitz (KI) domain and its C-terminal tail. First, we demonstrate that mice immunized with recombinant SmKI-1 (rSmKI-1) or its fragments, formulated with Freund’s adjuvant, induced the production of IgG-specific antibodies. Further, all vaccine formulations tested here also induced a Th1-type of immune response, as suggested by the production of IFN-γ and TNF-α by protein-stimulated cultured splenocytes. However, the protective effect conferred by vaccination was only observed in groups which received rSmKI-1 or C-terminal domain vaccines. Mice administered with rSmKI-1 demonstrated reduction of 47% in worm burden, 36% in egg number in mouse livers, and 33% in area of liver granulomas. Additionally, mice injected with C-terminal domain showed reduction of 28% in worm burden, 38% in egg number in liver, and 25% in area of liver granulomas. In contrast, KI domain immunization was unable to reduce worm burden and ameliorate liver pathology after challenge infection. Taken together, our data demonstrated that SmKI-1 is a potential candidate for use in a vaccine to control schistosomiasis, and its C-terminal tail seems to be the main region of the molecule responsible for protection conferred by this antigen

Role of MurT C-Terminal Domain in the Amidation of Staphylococcus aureus Peptidoglycan

Fundacao para a Ciencia e a Tecnologia (FCT) through grants PTDC/FIS-NAN/ 0117/2014 and PTDC/BIA-MIC/31645/2017. project UID/Multi/04378/2019 (Unidade de Ciencias Biomoleculares Aplicadas-UCIBIO), funded by FCT/MCTES; project LISBOA-01-0145-FEDER-007660 (Microbiologia Molecular, Estrutural e Celular), funded by FEDER through COMPETE2020-Programa Operacional Competitividade e Internacionalizacao (POCI); national funds through FCT; by project ONEIDA (LISBOA-01-0145-FEDER-016417), cofunded by FEEI (Fundos Europeus Estruturais e de Investimento) from the Programa Operacional Regional Lisboa 2020; and by national funds from FCT. Funding was also provided by European Society of Clinical Microbiology and Infectious Diseases research grant 2015, awarded to R.G.S. B.V.G., T.A.F., and I.R.G. were supported by fellowships SFRH/BD/131623/2017 respectively. J.S.D. acknowledges the National NMR Network (PTNMR) and Infrastructure Project ROTEIRO/0031/2013-PINFRA/22161/2016 (cofinanced by FEDER through COMPETE 2020, POCI, PORL, and FCT through PIDDAC).Glutamate amidation, a secondary modification of the peptidoglycan, was first identified in Staphylococcus aureus. It is catalyzed by the protein products of the murT and gatD genes, which are conserved and colocalized in the genomes of most sequenced Gram-positive bacterial species. The MurT-GatD complex is required for cell viability, full resistance to β-lactam antibiotics, and resistance to human lysozyme and is recognized as an attractive target for new antimicrobials. Great effort has been invested in the study of this step, culminating recently in three independent reports addressing the structural elucidation of the MurT-GatD complex. In this work, we demonstrate through the use of nonstructural approaches the critical and multiple roles of the C-terminal domain of MurT, annotated as DUF1727, in the MurT-GatD enzymatic complex. This domain provides the physical link between the two enzymatic activities and is essential for the amidation reaction. Copurification of recombinant MurT and GatD proteins and bacterial two-hybrid assays support the observation that the MurT-GatD interaction occurs through this domain. Most importantly, we provide in vivo evidence of the effect of substitutions at specific residues in DUF1727 on cell wall peptidoglycan amidation and on the phenotypes of oxacillin resistance and bacterial growth.publishersversionpublishe

Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have led to the identification of a number of common variants associated with modest risk. Several risk variants map within the vicinity of TGFβ/BMP signaling pathway genes, including rs4939827 within an intron of SMAD7 at 18q21.1. A previous study implicated a novel SNP (novel 1 or rs58920878) as a functional variant within an enhancer element in SMAD7 intron 4. In this study, we show that four SNPs including novel 1 (rs6507874, rs6507875, rs8085824, and rs58920878) in linkage disequilibrium (LD) with the index SNP rs4939827 demonstrate allele-specific enhancer effects in a large, multi-component enhancer of SMAD7. All four SNPs demonstrate allele-specific protein binding to nuclear extracts of CRC cell lines. Furthermore, some of the risk-associated alleles correlate with increased expression of SMAD7 in normal colon tissues. Finally, we show that the enhancer is responsive to BMP4 stimulation. Taken together, we propose that the associated CRC risk at 18q21.1 is due to four functional variants that regulate SMAD7 expression and potentially perturb a BMP negative feedback loop in TGFβ/BMP signaling pathways

A multivalent chimeric vaccine composed of Schistosoma mansoni SmTSP-2 and Sm29 was able to induce protection against infection in mice

Schistosoma mansoni is a blood fluke parasite responsible for schistosomiasis. The best long-term strategy to control schistosomiasis is through immunization combined with drug treatment. In this study, we cloned, expressed and purified SmTSP-2 fused to the N- and C-terminal halves of Sm29 and tested these chimeras as vaccine candidates using an adjuvant approved to be used in humans. The results demonstrated that vaccination with SmTSP-2 fused to N- or C-terminus of Sm29-induced reduction in worm burden and liver pathology when compared to control animals. Additionally, we detected high levels of mouse-specific IgG, IgG1 and IgG2a against both chimeras and significant amounts of IFN-γ and TNF-α and no IL-4. Finally, studies with sera from patients resistant to infection and living in schistosomiasis endemic areas revealed high levels of specific IgG to both chimeras when compared to healthy individuals. In conclusion, SmTSP-2/Sm29 chimeras tested here induced partial protection against infection and might be a potential vaccine candidate

Economic Impact of the COVID-19 Pandemic among Dentists in One of the Poorest Brazilian States: A Cross-Sectional Study

Objective: To analyze the impact of the COVID-19 pandemic on dentists’ income and to identify associated factors in one of the poorest Brazilian states. Material and Methods: A cross-sectional study including dentists who volunteered to answer an electronic questionnaire in Maranhão. Hierarchical multinomial logistic regression analyses were performed, estimating crude and adjusted odds ratios (OR) and respective 95% confidence intervals (95%CI) (alpha=5%). Results: The COVID-19 pandemic impacted the professionals´ income negatively [55.44% (50.26-60.52%)] and also positively [6.9% (4.55-9.94%)]. The negative impact on income was greater among male dentists (OR=2.54; 95%CI: 1.16-5.53), over 30 years of age (OR=3.03; 95%CI: 1.34-6.87), with family income below two minimum wages (OR=4.63; 95%CI: 1.50-14.30), who worked in the continent instead of in the capital island (OR=2.21; 95%CI: 1.14-4.29) and in the private sector (OR=31.43; 95%CI: 11.59-85.22). Moreover, those who had been tested for COVID-19, with a negative result, had a 21.3-fold greater chance of having an increased household income when compared to those who had not been tested. Conclusion: The COVID-19 pandemic negatively impacted the dentists’ income in Maranhão, especially the older, males, with lower incomes, and who worked in the private sector, living far from the capital. The SUS played an important role in the social protection of dentists during the COVID-19 pandemic, mitigating the economic impacts on the public sector working class

Depressed mothers and infants are more relaxed during breastfeeding versus bottlefeeding interactions: brief report

Depressed and non-depressed mothers and their 3-month-old infants were videotaped during breastfeeding and bottlefeeding interactions. The videotapes were subsequently coded for a number of feeding interaction behaviors as well as being rated on the Interaction Rating Scales. No differences were noted between the depressed and non-depressed mothers. Several breastfeeding versus bottlefeeding group effects were observed. The breastfeeding mothers showed less burping and less intrusive behavior during the nipple-in periods as well as during the nipple-out periods. In addition, the breastfeeding mothers and their infants received better ratings on the Interaction Rating Scales. These data suggest that the depressed mothers and their infants not unlike the non-depressed mothers and their infants were benefited by breastfeeding