Expedient organocatalytic syntheses of 4-substituted pyrazolidines and isoxazolidines

The efficient organocatalytic synthesis of heterocyclic systems of biological relevance is a subject of growing interest. We have found that the pyrrolidine/benzoic acid-catalyzed reaction of α-substituted propenals such as methacrolein, 2-benzylpropenal and 2-(n-hexyl)propenal with activated hydrazines takes place in very good yields (83%-99.6%) under very mild conditions to afford 4-substituted pyrazolidin-3-ols (as diastereomer mixtures); subsequent oxidation with PCC affords the corresponding-4-substituted-3-pyrazolidinones in essentially quantitative yields. In a similar way, 4-substituted isoxazolidinones are obtained with N-Cbz-hydroxylamine as a reagent. The use of chiral diarylprolinol trimethylsilyl ethers as catalysts allows the synthesis of several of these compounds in optically active form, in some cases with excellent enantioselectivity (up to 96:4 er). A preliminary evaluation of the biological activity shows that some of these compounds exhibit interesting antibacterial and antifungal activities

La différence épidémiologique des hémorragies digestives hautes entre les hommes et les femmes

Introduction: Des différences épidémiologiques, étiologique voire pronostique des hémorragies digestives hautes (HDH) entre les deux sexes opposés ont été cité par différentes études. Méthodes: Nous avons essayé de déceler ces différences à travers une analyse rétrospective nichée sur une étude prospective sur les hémorragies digestives hautes ayant inclus 945 patients.Résultats: Six cents trente-sept patients étaient des hommes (67,4% Vs 32,6%). Un antécédent d’HDH était trouvé chez 24,2% des cas sans différence significative entre les deux sexes. L’âge de survenue de l’hémorragie était plus élevé chez les femmes que chez les hommes : 51,5 ans ± 18,8 Vs 47,8 ans ± 18,3 (p : 0,003). Les étiologies de l’HDH étaient différentes entre les deux sexes. Alors que l’hémorragie liée à l’HTP était la première cause chez la femme (38 % Vs 23,5 % chezl’homme, p<0,0001), c’est la pathologie ulcéreuse qui venait en premier chez l’homme (62 % Vs 36,7 % chez la femme, p <0,0001). Un besointransfusionnel était noté chez 42,4 % des patients de sexe masculin contre 35,4 % des patientes avec un p = 0,03. Le taux de récidive et de décès global étaient de 7,5 % et de 5,7 % des cas respectivement, sans différence significative entre les deux sexes.Conclusion: L’étude trouve un profil épidémiologique, clinique et étiologique différent selon le sexe des patients.Key words: Hémorragie digestive haute, épidémiologie, sexe masculin, sexe féminin, endoscopie, ulcère gastroduodénal, hypertension portal

Targeting Splicing in the Treatment of Human Disease

The tightly regulated process of precursor messenger RNA (pre-mRNA) alternative splicing (AS) is a key mechanism in the regulation of gene expression. Defects in this regulatory process affect cellular functions and are the cause of many human diseases. Recent advances in our understanding of splicing regulation have led to the development of new tools for manipulating splicing for therapeutic purposes. Several tools, including antisense oligonucleotides and trans-splicing, have been developed to target and alter splicing to correct misregulated gene expression or to modulate transcript isoform levels. At present, deregulated AS is recognized as an important area for therapeutic intervention. Here, we summarize the major hallmarks of the splicing process, the clinical implications that arise from alterations in this process, and the current tools that can be used to deliver, target, and correct deficiencies of this key pre-mRNA processing event. Keywords: alternative splicing, precursor messenger RNA, therapy, genetic diseas

Brushing RemInder 4 Good oral HealTh (BRIGHT) trial: does an SMS behaviour change programme with a classroom-based session improve the oral health of young people living in deprived areas? A study protocol of a randomised controlled trial

Background: Almost one-half of 12–15 year olds living in deprived areas of the UK have dental caries (tooth decay) with few oral health promotion programmes aimed at children of this age. Mobile phone-based interventions such as short messaging service (SMS) interventions have been found effective at changing certain behaviours and improving health outcomes. This protocol describes the BRIGHT Trial, investigating the clinical and cost-effectiveness of a behaviour change intervention—classroom-based session (CBS) embedded in the curriculum and a series of SMS delivered to participants twice daily to remind them to brush their teeth, compared to usual curriculum and no SMS—to reduce the prevalence of dental caries in young people from deprived areas. Objectives: To investigate the clinical and cost-effectiveness of a complex intervention to improve the oral health of young people living in deprived areas. Methods/design: This is a school-based, assessor-blinded, two-arm cluster-randomised controlled trial with an internal pilot trial. Overall, the trial will involve approximately 5040 11–13 year olds in 42 schools with a 3-year follow-up. The trial will take place in secondary schools in England, Scotland and Wales. The primary outcome is the presence of carious lesions in permanent teeth at 3 years. Secondary outcomes are: number of carious teeth, frequency of twice-daily toothbrushing, plaque levels, gingivitis, child health-related quality of life and oral health-related quality of life. A cost-utility analysis will be conducted. Discussion: The findings of the trial have implications for embedding oral health interventions into school curricula guidance produced by national bodies, including departments for education and dental public health and guideline-development organisations. Trial registration: ISRCTN registry, ISRCTN12139369. Registered on 10 May 2017

Development of a secondary school-based digital behaviour change intervention to improve tooth brushing

Background Dental caries in adolescents remains a significant public health problem with few oral health promotion interventions aimed at reducing dental caries in secondary school-aged students. Previous oral health and mobile health (mHealth) research has suggested the need for the development of a school-based behaviour change intervention incorporating a digital component. This study aimed to describe the development process of a behaviour change intervention to improve the oral health of students aged 11–16 years attending secondary schools in the UK. Methods A six-step process was used to develop the complex intervention informed by behaviour change theory and involving students, young people, parents and teachers in the process. The steps were: (1) identifying the target behaviours, namely tooth brushing with a fluoride toothpaste (2) identifying the theoretical basis and developing the causal model (3) reviewing the relevant literature and developing the logic model (4) designing the intervention with young people, parents and school staff (5) specifying the intervention content and (6) translating this content into features of the intervention and piloting. Results The resultant intervention included a quality-assured classroom-based session (CBS) (guided by a lesson plan and teaching resources), delivered by school teachers which was embedded within the school curriculum. This CBS was followed by a series of (Short Message Service) SMS texts delivered twice daily to student’s mobile telephones with the content, duration and timing of the messages informed by involvement of students and young people. Conclusions An intervention to improve the oral health of secondary school students through improved tooth brushing was rigorously developed based on behaviour change theory and work with young people, parents and school staff. Further research is needed to evaluate the outcomes and processes involved following the delivery of this intervention

Cholesteryl oleate-loaded cationic solid lipid nanoparticles as carriers for efficient gene-silencing therapy

Background: Cationic solid lipid nanoparticles (SLNs) have been given considerable attention for therapeutic nucleic acid delivery owing to their advantages over viral and other nanoparticle delivery systems. However, poor delivery efficiency and complex formulations hinder the clinical translation of SLNs. Aim: The aim of this study was to formulate and characterize SLNs incorporating the cholesterol derivative cholesteryl oleate to produce SLN-nucleic acid complexes with reduced cytotoxicity and more efficient cellular uptake. Methods: Five cholesteryl oleate-containing formulations were prepared. Laser diffraction and laser Doppler microelectrophoresis were used to evaluate particle size and zeta potential, respectively. Nanoparticle morphology was analyzed using electron microscopy. Cytotoxicity and cellular uptake of lipoplexes were evaluated using flow cytometry and fluorescence microscopy. The gene inhibition capacity of the lipoplexes was assessed using siRNAs to block constitutive luciferase expression. Results: We obtained nanoparticles with a mean diameter of approximately 150-200 nm in size and zeta potential values of 25-40 mV. SLN formulations with intermediate concentrations of cholesteryl oleate exhibited good stability and spherical structures with no aggregation. No cell toxicity of any reference SLN was observed. Finally, cellular uptake experiments with DNAand RNA-SLNs were performed to select one reference with superior transient transfection efficiency that significantly decreased gene activity upon siRNA complexation. Conclusion: The results indicate that cholesteryl oleate-loaded SLNs are a safe and effective platform for nonviral nucleic acid delivery

Improved synthesis and characterization of cholesteryl oleate-loaded cationic solid lipid nanoparticles with high transfection efficiency for gene therapy applications

The development of new nanoparticle formulations that are capable of high transfection efficiency without toxicity is essential to provide new tools for gene therapy. However, the issues of complex, poorly reproducible manufacturing methods, and low efficiencies during in vivo testing have prevented translation to the clinic. We have previously reported the use of cholesteryl oleate as a novel excipient for solid lipid nanoparticles (SLNs) for the development of highly efficient and nontoxic nucleic acid delivery carriers. Here, we performed an extensive characterization of this novel formulation to make the scale up under Good Manufacturing Practice (GMP) possible. We also describe the complete physicochemical and biological characterization of cholesteryl oleate-loaded SLNs to ensure the reproducibility of this formula and the preservation of its characteristics before and after the lyophilization process. We defined the best manufacturing method and studied the influence of some parameters on the obtained nanoparticles using the Quality by Design (ICH Q8) guideline to obtain cholesteryl oleate-loaded SLNs that remain stable during storage and guarantee in vitro nucleic acid delivery efficacy. Our results indicate that this improved formulation is suitable for gene therapy with the possibility of scale-up the manufacturing of nanoparticles under GMP conditions

Cross-tolerance to abiotic stresses in halophytes: Application for phytoremediation of organic pollutants

International audienceHalopytes are plants able to tolerate high salt concentrations but no clear definition was retained for them. In literature, there are more studies that showed salt-enhanced tolerance to other abiotic stresses compared to investigations that found enhanced salt tolerance by other abiotic stresses in halophytes. The phenomenon by which a plant resistance to a stress induces resistance to another is referred to as cross-tolerance. In this work, we reviewed cross-tolerance in halophytes at the physiological, biochemical, and molecular levels. A special attention was accorded to the cross-tolerance between salinity and organic pollutants that could allow halophytes a higher potential of xenobiotic phytoremediation in comparison with glycophytes