Integration of photosensitizers (PSs) within nanoscale delivery systems offers great potential for overcoming some of the “Achiles’ heels” of photodynamic therapy (PDT). Herein, we have encapsulated ...a mitochondria-targeted coumarin PS into amphoteric polyurethane–polyurea hybrid nanocapsules (NCs) with the aim of developing novel nanoPDT agents. The synthesis of coumarin-loaded NCs involved the nanoemulsification of a suitable prepolymer in the presence of a PS without needing external surfactants, and the resulting small nanoparticles showed improved photostability compared with the free compound. Nanoencapsulation reduced dark cytotoxicity of the coumarin PS and significantly improved in vitro photoactivity with red light toward cancer cells, which resulted in higher phototherapeutic indexes compared to free PS. Importantly, this nanoformulation impaired tumoral growth of clinically relevant three-dimensional multicellular tumor spheroids. Mitochondrial photodamage along with reactive oxygen species (ROS) photogeneration was found to trigger autophagy and apoptotic cell death of cancer cells.
Consanguineous couples have an increased risk of severe diseases in offspring due to autosomal recessive disorders. Exome sequencing (ES) offers the possibility of extensive preconception carrier ...screening (PCS) in consanguineous couples who may be at risk of rare genetic disorders.
We retrospectively analysed ES data from 65 probands affected with rare genetic disorders born from consanguineous couples. We explored diagnostic yield and carrier status for recessive disorders.
The overall diagnostic yield in a singleton approach was 53.8%, mostly recessive variants. In a hypothetical exome-based PCS, only 11.7% of these causative rare variants would have been missed in the filtering process. Carrier screening for recessive conditions allowed the identification of at least one additional pathogenic or likely pathogenic variant in 85.7% of the probands, being the majority with a gene carrier frequency <1 in 200. In addition, considering only clinically actionable conditions, we estimated that 12.3% of our close consanguineous couples may be at risk for an additional recessive disease.
Our results demonstrate that ES outperforms panel-based screening in a PCS context in consanguineous couples and could potentially increase their reproductive autonomy and facilitate informed decision-making.
Clinical exome sequencing has the potential to identify pathogenic variants unrelated to the purpose of the study (secondary findings, SFs). Data describing actual choices of SFs in participants in a ...clinical setting and factors influencing their decision are virtually non-existant in Europe. In this work, we report the acceptance rate of SFs, calculate their prevalence and study factors associated with the decision in a cohort of patients affected with a rare genetic disorder in a Spanish Hospital. Finally, we re-examine the presence of previously non reported family history in positive cases. We retrospectively reviewed informed consent choices and SF results from 824 unrelated probands affected with rare genetic disorders who underwent whole-genome or exome sequencing. Ninety percent of families (740/824) affected with rare disorders wished to be informed of SFs. Declining SFs was associated with a prenatal setting (30% vs. 8.7%, p = 0.025), consanguinity (19% vs. 8.7%, p = 0.013), male gender (10.6% vs. 1.5%, p = 0.00865) and the proband being a minor (10.6% vs. 1.5%, p = 0.014). Overall, 27 pathogenic or likely pathogenic variants were identified in 27 individuals, with an SF prevalence of 3.6%. Disclosure of SFs increased the percentage of positive family histories and resulted in early diagnosis or changes in the management of 10 individuals from five families. We show that the acceptance of SFs in Spain is high and the disclosure of SFs leads to a clinically meaningful change in the medical management of individuals.
Cornelia de Lange syndrome (CdLS) is a multisystemic genetic disorder characterized by distinctive facial features, growth retardation, and intellectual disability, as well as various systemic ...conditions. It is caused by genetic variants in genes related to the cohesin complex. Single-nucleotide variations are the best-known genetic cause of CdLS; however, copy number variants (CNVs) clearly underlie a substantial proportion of cases of the syndrome. The NIPBL gene was thought to be the locus within which clinically relevant CNVs contributed to CdLS. However, in the last few years, pathogenic CNVs have been identified in other genes such as HDAC8, RAD21, and SMC1A. Here, we studied an affected girl presenting with a classic CdLS phenotype heterozygous for a de novo ~32 kbp intragenic duplication affecting exon 10 of HDAC8. Molecular analyses revealed an alteration in the physiological splicing that included a 96 bp insertion between exons 9 and 10 of the main transcript of HDAC8. The aberrant transcript was predicted to generate a truncated protein whose accessibility to the active center was restricted, showing reduced ease of substrate entry into the mutated enzyme. Lastly, we conclude that the duplication is responsible for the patient’s phenotype, highlighting the contribution of CNVs as a molecular cause underlying CdLS.
BACKGROUND AND AIM:Patients with chronic hepatitis C (CHC) frequently associated comorbidities and concomitant medication. Sustained virological response (SVR12) has been related to an increase in ...cholesterol serum levels and in peripheral vascular resistance. Our aim was to evaluate the impact of SVR12 on the use of concomitant medication and serum lipid profile.
METHODS:Prospective study including patients treated with direct-acting antivirals who had achieved the SVR12. Clinical data and concomitant drugs were analysed at baseline and at least 1 year after SVR12. Differences from baseline to follow-up in the concomitant medication were evaluated by Stuart–Maxwell test and lipid profile by Wilcoxon signed-rank test. Patients were categorized according to the increase/decrease in the number of drugs included in each class (Anatomical Therapeutic Chemical classification system).
RESULTS:Two hundred twenty-six patients with SVR12 were included, 73.5% were receiving concomitant drugs (49.6% with antihypertensive effect, 30.5% antacids, 16.4% anti-diabetic drugs, and 7.1% lipid-lowering agents). One year after SVR12, total cholesterol serum levels increased from 161 to 179 mg/dl (P < 0.001) and, after a median time of 25.7 months, the use of lipid-lowering drugs increased from 7.8 to 11.5% (P = 0.009). In addition, we observed a trend to use more antihypertensive drugs in older patients (P = 0.06), especially in those with cirrhosis. Anxiolytics decreased after SVR12 from 13.7 to 10.6% (P = 0.035).
CONCLUSION:CHC cure is associated with a significant increase in cholesterol serum levels and the use of lipid-lowering agents, as well as the use of drugs with antihypertensive effect in older patients.
The evaluation system for the subject of Athletics at the "Manuel Fajardo" University of Physical Culture and Sports Sciences requires a change in its procedure, based on the use of indicators that ...show the transformations that have comprehensively occurred in the students' learning, mainly in practical classes, according to the new professional training model proposed by the Ministry of Higher Education (MES). The objective was to analyze the results obtained with the application of the indicators for the comprehensive evaluation of student learning in the practical classes of the Athletics subject, an instrument valued through expert criteria and that offers a structure composed of dimensions of knowledge (cognitive, procedural and axiological), indicators, parameters, measurement criteria that allow not only the comprehensive evaluation of student learning but also enable evaluation by each dimension. Theoretical and empirical methods were used, mainly synthetic analysis, experiment, expert judgment and structured observation, as well as descriptive and inferential statistical processing techniques. The analysis of the results of the learning evaluation in the practical classes with a productive orientation in the Athletics subject of the D-15 group was carried out qualitatively and quantitatively and the applied indicators were taken into account, which made it possible to demonstrate the improvement of the students in the learning variable in all its dimensions and in a comprehensive manner, which guarantees that through co-evaluation they reach logical criteria about their knowledge.
O sistema de avaliação da disciplina de Atletismo da Universidade de Cultura Física e Ciências do Desporto “Manuel Fajardo” exige uma mudança no seu procedimento, baseada na utilização de indicadores que evidenciem as transformações ocorridas na aprendizagem dos alunos. nas aulas práticas, de acordo com o novo modelo de formação profissional proposto pelo Ministério do Ensino Superior). O objetivo foi analisar os resultados obtidos com a aplicação dos indicadores para avaliação abrangente da aprendizagem dos alunos nas aulas práticas da disciplina de Atletismo. Foram utilizados métodos teóricos e empíricos, fundamentalmente a análise sintética, experimento, critério de observação pericial e estruturada. , bem como técnicas de processamento estatístico descritivo e inferencial. A análise dos resultados da avaliação da aprendizagem nas aulas práticas com orientação produtiva na disciplina de Atletismo do grupo D-15 foi realizada de forma qualitativa e quantitativa e foram tidos em conta os indicadores aplicados, o que permitiu demonstrar a melhoria dos alunos na variável de aprendizagem em todas as suas dimensões e de forma abrangente, o que garante que através da coavaliação eles atinjam critérios lógicos sobre seus conhecimentos.
El sistema de evaluación de la asignatura de Atletismo en la Universidad de Ciencias de la Cultura Física y el Deporte "Manuel Fajardo" precisa de un cambio en su proceder, a partir del uso de indicadores que evidencien las transformaciones ocurridas en el aprendizaje de los estudiantes de forma integral, principalmente en las clases prácticas, según el nuevo modelo de formación del profesional propuesto por el Ministerio de Educación Superior). El objetivo consistió en analizar los resultados que se obtienen con la aplicación de los indicadores para la evaluación integral del aprendizaje de los estudiantes en las clases prácticas de la asignatura Atletismo- Se emplearon métodos teóricos y empíricos, fundamentalmente el analítico sintético, experimento, criterio de experto y la observación estructurada, así como técnicas de procesamiento estadístico descriptivas e inferenciales. El análisis de los resultados de la evaluación del aprendizaje en las clases prácticas con orientación productiva en la asignatura Atletismo del grupo D-15 se realizó cualitativa y cuantitativamente y se tuvieron en cuenta los indicadores aplicados, lo que permitió evidenciar la mejoría de los estudiantes en la variable aprendizaje en todas sus dimensiones y de manera integral, lo que garantiza que a través de la coevaluación lleguen a criterios lógicos sobre su conocimiento.
Cornelia de Lange syndrome (CdLS) is a multisystemic genetic disorder characterized by distinctive facial features, growth retardation, and intellectual disability, as well as various systemic ...conditions. It is caused by genetic variants in genes related to the cohesin complex. Single-nucleotide variations are the best-known genetic cause of CdLS; however, copy number variants (CNVs) clearly underlie a substantial proportion of cases of the syndrome. The NIPBL gene was thought to be the locus within which clinically relevant CNVs contributed to CdLS. However, in the last few years, pathogenic CNVs have been identified in other genes such as HDAC8, RAD21, and SMC1A. Here, we studied an affected girl presenting with a classic CdLS phenotype heterozygous for a de novo ~32 kbp intragenic duplication affecting exon 10 of HDAC8. Molecular analyses revealed an alteration in the physiological splicing that included a 96 bp insertion between exons 9 and 10 of the main transcript of HDAC8. The aberrant transcript was predicted to generate a truncated protein whose accessibility to the active center was restricted, showing reduced ease of substrate entry into the mutated enzyme. Lastly, we conclude that the duplication is responsible for the patient’s phenotype, highlighting the contribution of CNVs as a molecular cause underlying CdLS.
Rare diseases (RDs) as a whole affect a huge number of individuals although each specific condition comprises a low number of individuals. As a consequence, funds allocated to expand research to all ...conditions are often limited. Several initiatives have emerged to invest more resources for research in RDs, but patients express unmet needs regarding educational initiatives, awareness support, and psychosocial resources. We developed an educational training program in the format of weekly sessions covering basic medical scientific knowledge and psychosocial aspects of RDs. The aim of this initiative was to assess its overall impact regarding knowledge, psychological issues, and participant satisfaction. Items were evaluated through surveys before and after the sessions. Here, we report the experience and impact of two editions of this initiative with a total of 37 participants. Our results show improvements in knowledge and better management of the psychological impact. Moreover, participants were able to exchange experiences and concerns, most of which were shared even though the RDs were different. Overall, the program was evaluated by the participants as a highly beneficial experience and all of them were interested in attending advanced editions.
From the results of a research aimed at improving the quality of life of families with a child with intellectual disability, the purpose of this paper is to provide a methodology for the ...implementation of the family-centered model in early childhood intervention centers in our country. Quantitative and qualitative analyses of the collected data allow us to systematize the steps or stages that would be necessary to provide professionals and families in early intervention centers with useful tools to empower the families and to enhance the children’s development. This article represents another step further from the proposals made by other researchers in other countries with different traditions and culture in the field of early intervention, and intends to reflect the characteristics of our country in terms of the history and the path of early intervention in recent decades.
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