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1.
Ecotoxicol Environ Saf ; 184: 109565, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31514078

RESUMO

To address the concern about the environmental impact of engineered nanoparticles frequently used in the recently marketed personal care and hygiene products (PCPs), we conducted a toxicity assessment and determined the EC50 values of the nanosized inorganic UV filter TiO2 (nano-TiO2), as well as those of the organic UV filter oxybenzone (BP3) and three parabens (methyl, propyl, and benzylparaben) present in most PCPs formulation. The bioassays were carried out through standardized toxicity bioassays on two environmentally relevant aquatic species i.e. Daphnia magna and Phaeodactylum tricornutum. For nano-TiO2 48 h EC50 on D. magna was 3.09 mgL-1 and for parabens ranged from 32.52 to 1.35 mgL-1. The two most toxic compounds on D. magna, nano-TiO2 and benzylparaben (BzP), were further tested with the algae. For nano-TiO2 72 h EC50 value was 2.27 mgL-1 and for BzP it was 10.61 mgL-1. In addition, D. magna was exposed to selected binary mixtures of the target compounds i.e. nano-TiO2+BP3, nano-TiO2+BzP and BP3+BzP On the endpoint of 48 h, a synergistic action was observed for nano-TiO2+BP3 and nano-TiO2+BzP, but an antagonistic effect occurred in the mixture BP3+BzP. These findings suggest that nano-TiO2 can increase the toxicity of the mixture when combined with other compounds.

2.
Acta Derm Venereol ; 99(10): 894-898, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31120544

RESUMO

Autosomal recessive congenital ichthyosis (ARCI) is a group of rare non-syndrome diseases that affect cornification. PNPLA1 is one of the 12 related genes identified so far. Mutation screening of this gene has resulted in the identification of 13 individuals, from 10 families, who carried 7 different PNPLA1 mutations. These mutations included 2 missense, 2 frame-shift and 3 nonsense, 3 of them being novel. One of the identified variants, c.417_418delinsTC, was highly prevalent, as it was found in 6 out of 10 (60%) of our ARCI families with PNPLA1 mutations. Clinical manifestations varied significantly among patients, but altered sweating; erythema, palmar hyperlinearity and small whitish scales in flexor-extensor and facial areas were common symptoms. Haplotype analyses of c.417_418delinsTC carriers confirmed the existence of a common ancestor. This study expands the spectrum of the PNPLA1 disease, which causes variants and demonstrates that the c.417_418delinsTC mutation has founder effects in the Spanish population.

3.
Radiother Oncol ; 138: 59-67, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31146072

RESUMO

PURPOSE: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. METHODS: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated. RESULTS: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician- (47,025 forms) and patient- (54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n = 4409) and PAXgene tubes (n = 3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade ≥2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). CONCLUSION: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers. PATIENT SUMMARY: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short- and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity.

4.
J Natl Cancer Inst ; 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31095341

RESUMO

BACKGROUND: 10-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. METHODS: We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3,871) in men with European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. Grouped relative risk models tested associations with ∼6 million genotyped/imputed variants (time to first ≥grade 2 toxicity event). Variants with two-sided Pmeta<5x10-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided. RESULTS: Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism (SNP) rs17055178 with rectal bleeding (Pmeta=6.2x10-10), rs10969913 with decreased urinary stream (Pmeta=2.9x10-10) and rs11122573 with hematuria (Pmeta=1.8x10-8). Fine scale mapping of these three regions identified another independent signal (rs147121532) associated with hematuria (Pconditional=4.7x10-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts. CONCLUSIONS: This study increases understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multi-national radiogenomics studies in larger cohorts are worthwhile.

5.
Hum Mutat ; 40(10): 1781-1796, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31112363

RESUMO

BRCA1 and BRCA2 (BRCA1/2) pathogenic sequence variants (PSVs) confer elevated risks of multiple cancers. However, most BRCA1/2 PSVs reports focus on European ancestry individuals. Knowledge of the PSV distribution in African descent individuals is poorly understood. We undertook a systematic review of the published literature and publicly available databases reporting BRCA1/2 PSVs also accessed the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) database to identify African or African descent individuals. Using these data, we inferred which of the BRCA PSVs were likely to be of African continental origin. Of the 43,817 BRCA1/2 PSV carriers in the CIMBA database, 469 (1%) were of African descent. Additional African descent individuals were identified in public databases (n = 291) and the literature (n = 601). We identified 164 unique BRCA1 and 173 unique BRCA2 PSVs in individuals of African ancestry. Of these, 83 BRCA1 and 91 BRCA2 PSVs are of likely or possible African origin. We observed numerous differences in the distribution of PSV type and function in African origin versus non-African origin PSVs. Research in populations of African ancestry with BRCA1/2 PSVs is needed to provide the information needed for clinical management and decision-making in African descent individuals worldwide.

6.
Rev. cuba. estomatol ; 56(1): e1815, ene.-mar. 2019. tab, graf
Artigo em Espanhol | LILACS | ID: biblio-1003869

RESUMO

Introducción: La caries dental infantil constituye un problema de salud pública en el Ecuador. Los niños de 3 a 5 años que padecen caries dental decidua, sufren complicaciones como dolor al comer y dormir, alteración del estado de ánimo, inasistencia escolar; en general, un impacto negativo en su calidad de vida. Los padres cumplen un rol clave en el cuidado de la salud bucal de sus hijos, el cual es determinado muchas veces por su nivel educativo. Objetivo: Determinar el impacto que la salud bucal tiene en la calidad de vida de preescolares, evaluado por sus padres o responsables y relacionado con su nivel de educación. Métodos: Se realizó un estudio descriptivo y transversal. Se evaluaron a 382 padres y/o representantes de preescolares niños y niñas entre 3 a 5 años pertenecientes a cuatro provincias del Ecuador seleccionadas a conveniencia del investigador; quienes previa aceptación de participación y firma de consentimiento informado respondieron la encuesta ECOHIS (Early Childhood Oral Health Impact Scale) versión en español, que valora la relación entre salud bucal y calidad de vida en preescolares. Los datos recolectados fueron tabulados en tablas de Excel y analizados mediante software libre R.V3.4.1 empleando intervalos de verosimilitud al 14,7 por ciento equivalente al 95 por ciento de confianza para proporciones, y prueba estadística de chi cuadrado. Resultados: Los valores de significancia fueron: al relacionar con el dolor referido por los niños (p=0,152), las dificultades al beber (p= 0,003), consumir alimentos (p= 0,03), al sonreír (p= 0,002), al hablar (p= 0,09) y la repercusión económica asociada a problemas de salud bucal (p= 0,003). Conclusiones: Existe asociación entre el nivel de educación de los padres y su percepción sobre la influencia que tiene la salud bucal en la calidad de vida de sus hijos(AU)


Introduction: Childhood dental caries is a public health problem in Ecuador. Children aged 3-5 years with deciduous dental caries experience unpleasant symptoms such as pain while eating or sleeping, mood changes and school absenteeism, all of which has a negative impact on their quality of life. The key role played by parents in the oral care of their children is often determined by their educational level. Objective: Determine the impact of oral health on the quality of life of preschoolers aged under 5 years as evaluated by their parents or guardians and in relation to their educational level. Methods: A descriptive cross-sectional study was conducted of 382 parents and/or guardians of preschool children aged 3-5 years from four Ecuadorian provinces selected by convenience sampling, who gave their informed consent and answered the ECOHIS (Early Childhood Oral Health Impact Scale) survey, Spanish version, which assesses the relationship between oral health and quality of life among preschoolers. The surveys were identified with codes. The data collected were transferred onto Excel tables and analyzed with the free software R.V3.4.1 using likelihood ratios at 14.7 percent equivalent to 95 percent confidence intervals for proportions, as well as the chi-square statistical test. Results: The following significance levels were obtained: for pain as reported by children (p=0.152), for difficulty when drinking (p= 0.003), eating (p= 0.03), smiling (p= 0.002), speaking (p= 0.09), and for economic impact associated to oral health problems (p= 0.003). Conclusions: An association was found between the educational level of parents and their perception of the influence of oral health upon the quality of life of their children(AU)


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Qualidade de Vida , Inquéritos de Saúde Bucal/estatística & dados numéricos , Poder Familiar , Cárie Dentária/complicações , Epidemiologia Descritiva , Estudos Transversais
8.
Mol Genet Genomic Med ; 7(5): e608, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30916489

RESUMO

BACKGROUND: Autosomal recessive congenital ichthyoses (ARCI) have been associated with different phenotypes including: harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lamellar ichthyosis (LI). While pathogenic variants in all ARCI genes are associated with LI and CIE phenotypes, the unique gene associated with HI is ABCA12. In HI, the most severe ARCI form, pathogenic variants in both ABCA12 gene alleles usually have a severe impact on protein function. The presence of at least one non-truncating variant frequently causes a less severe congenital ichthyosis phenotype (LI and CIE). METHODS: We report the case of a 4-year-old Ecuadorian boy with a severe skin disease. Genetic diagnosis was performed by NGS. In silico predictions were performed using Alamut software v2.11. A review of the literature was carried out to identify all patients carrying ABCA12 splice-site and missense variants, and to explore their genotype-phenotype correlations. RESULTS: Genetic testing revealed a nonsense substitution, p.(Arg2204*), and a new missense variant, p.(Val1927Leu), in the ABCA12 gene. After performing in silico analysis and a comprehensive review of the literature, we conclude that p.(Val1927Leu) affects a well conserved residue which could either disturb the protein function or alter the splicing process, both alternatives could explain the severe phenotype of our patient. CONCLUSION: This case expands the spectrum of ABCA12 reported disease-causing variants which is important to unravel genotype-phenotype correlations and highlights the importance of missense variants in the development of HI.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Ictiose Lamelar/genética , Mutação com Perda de Função , Fenótipo , Pré-Escolar , Códon sem Sentido , Humanos , Ictiose Lamelar/patologia , Masculino , Mutação de Sentido Incorreto , Sítios de Splice de RNA
9.
Aesthetic Plast Surg ; 43(3): 571-581, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30725197

RESUMO

BACKGROUND: Numerous methods have been designed to reduce breasts size and weight. The goal today is to not only to reduce size but also to create a pleasing shape. Breast reduction techniques do not obtain the desired upper pole fullness, and commonly recurrent ptosis develops. To improve and maintain breast shape in the late postoperative period, we combine breast reduction with implants. METHODS: Three hundred and sixty-six patients who underwent combined breast reduction or mastopexy with implants from January 2014 to November 2017 at IM Clinic were retrospectively reviewed. We present the indications, surgical technique, and outcomes of these patients to determine the safety and efficacy of our technique. RESULTS: No major complications were noted in an average of 2 years of follow-up (range 2 months to 4 years). Minor complications occurred in 61 patients, of whom 46 required revision surgery (12.6%). The most common tissue-related complications were dog ears (7.6%) and poor scarring (4.9%). The most common implant-related complication was capsular contracture (0.8%). CONCLUSIONS: Breast reduction with implants is a reliable option to provide additional volume to the upper pole of the breast to improve long-term breast shape and avoid ptosis recurrence. Our study indicates that the procedure is safe and has complication and revision rates comparable to traditional breast reduction or augmentation mastopexy techniques. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

11.
Prog Biomater ; 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30725401

RESUMO

In vitro effect of 1% theobromine addition on the physical and chemical properties of conventional glass ionomer (GIC) cement was investigated. Conventional GIC (GIC-C) and 1% theobromine added to GIC (GIC-THEO) specimens were compared regarding the microhardness (n = 10), sorption (n = 5), solubility (n = 5), color change (n = 10), fluoride release in saliva (n = 10) and the amount of biofilm deposition (n = 20). Compared against conventional GIC, adding 1% theobromine increased microhardness (p < 0.05), while its sorption, solubility, color and fluoride release to saliva (p > 0.05) remained unchanged. On the other hand, Streptococcus mutans biofilm amount deposited on its surface decreased statistically when theobromine was added to GIC (p < 0.05). Based on the results, it could be concluded that 1% theobromine addition to GIC can be a good strategy as it keeps some of its properties and improves microhardness and biofilm deposits strengthening its role in the preventive approach of dentistry.

12.
Rev Esp Cardiol (Engl Ed) ; 72(2): 166, 2019 Feb.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30704726
15.
Eur J Hum Genet ; 27(4): 556-562, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30626930

RESUMO

The present work describes the value of genetic analysis as a confirmatory measure following the detection of suspected inborn errors of metabolism in the Spanish newborn mass spectrometry screening program. One hundred and forty-one consecutive DNA samples were analyzed by next-generation sequencing using a customized exome sequencing panel. When required, the Illumina extended clinical exome panel was used, as was Sanger sequencing or transcriptional profiling. Biochemical tests were used to confirm the results of the genetic analysis. Using the customized panel, the metabolic disease suspected in 83 newborns (59%) was confirmed. In three further cases, two monoallelic variants were detected for two genes involved in the same biochemical pathway. In the remainder, either a single variant or no variant was identified. Given the persistent absence of biochemical alterations, carrier status was assigned in 39 cases. False positives were recorded for 11. In five cases in which the biochemical pattern was persistently altered, further genetic analysis allowed the detection of two variants affecting the function of BCAT2, ACSF3, and DNAJC12, as well as a second, deep intronic variant in ETFDH or PTS. The present results suggest that genetic analysis using extended next-generation sequencing panels can be used as a confirmatory test for suspected inborn errors of metabolism detected in newborn screening programs. Biochemical tests can be very helpful when a diagnosis is unclear. In summary, simultaneous genomic and metabolomic analyses can increase the number of inborn errors of metabolism that can be confirmed following suggestive newborn screening results.

17.
J Inherit Metab Dis ; 42(3): 407-413, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30671984

RESUMO

PURPOSE: We report a patient with a human cationic amino acid transporter 2 (CAT-2) defect discovered due to a suspected arginase 1 deficiency observed in newborn screening (NBS). METHODS: A NBS sample was analyzed using tandem mass spectrometry. Screen results were confirmed by plasma and urine amino acid quantification. Molecular diagnosis was done using clinical exome sequencing. Dimethylated arginines were determined by HPLC and nitrate/nitrite levels by a colorimetric assay. The metabolomic profile was analyzed using 1D nuclear magnetic resonance spectroscopy. RESULTS: A Spanish boy of nonconsanguineous parents had high arginine levels in a NBS blood sample. Plasma and urinary cationic amino acids were high. Arginase enzyme activity in erythrocytes was normal and no pathogenic mutations were identified in the ARG1 gene. Massive parallel sequencing detected two loss-of-function mutations in the SLC7A2 gene. Currently, the child receives a protein-controlled diet of 1.2 g/kg/day with protein-and amino-acid free infant formula, 30 g/day, and is asymptomatic. CONCLUSION: We identified a novel defect in human CAT-2 due to biallelic pathogenic variants in the SLC7A2 gene. The characteristic biochemical profile includes high plasma and urine arginine, ornithine, and lysine levels. NBS centers should know of this disorder since it can be detected in arginase 1 deficiency screening.

18.
Int J Cancer ; 145(2): 401-414, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30623411

RESUMO

A subset of genetic variants found through screening of patients with hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome impact RNA splicing. Through target enrichment of the transcriptome, it is possible to perform deep-sequencing and to identify the different and even rare mRNA isoforms. A targeted RNA-seq approach was used to analyse the naturally-occurring splicing events for a panel of 8 breast and/or ovarian cancer susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, PTEN, STK11, CDH1, TP53), 3 Lynch syndrome genes (MLH1, MSH2, MSH6) and the fanconi anaemia SLX4 gene, in which monoallelic mutations were found in non-BRCA families. For BRCA1, BRCA2, RAD51C and RAD51D the results were validated by capillary electrophoresis and were compared to a non-targeted RNA-seq approach. We also compared splicing events from lymphoblastoid cell-lines with those from breast and ovarian fimbriae tissues. The potential of targeted RNA-seq to detect pathogenic changes in RNA-splicing was validated by the inclusion of samples with previously well characterized BRCA1/2 genetic variants. In our study, we update the catalogue of normal splicing events for BRCA1/2, provide an extensive catalogue of normal RAD51C and RAD51D alternative splicing, and list splicing events found for eight other genes. Additionally, we show that our approach allowed the identification of aberrant splicing events due to the presence of BRCA1/2 genetic variants and distinguished between complete and partial splicing events. In conclusion, targeted-RNA-seq can be very useful to classify variants based on their putative pathogenic impact on splicing.

19.
Clin Genet ; 95(5): 615-626, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30653653

RESUMO

The congenital disorders of glycosylation (CDG) are defects in glycoprotein and glycolipid glycan synthesis and attachment. They affect multiple organ/systems, but non-specific symptoms render the diagnosis of the different CDG very challenging. Phosphomannomutase 2 (PMM2)-CDG is the most common CDG, but advances in genetic analysis have shown others to occur more commonly than previously thought. The present work reports the clinical and mutational spectrum of 25 non-PMM2 CDG patients. The most common clinical symptoms were hypotonia (80%), motor or psychomotor disability (80%) and craniofacial dysmorphism (76%). Based on their serum transferrin isoform profile, 18 were classified as CDG-I and 7 as CDG-II. Pathogenic variations were found in 16 genes (ALG1, ALG6, ATP6V0A2, B4GALT1, CCDC115, COG7, DOLK, DPAGT1, DPM1, GFPT1, MPI, PGM1, RFT1, SLC35A2, SRD5A3, and SSR4). Overall, 27 variants were identified, 12 of which are novel. The results highlight the importance of combining genetic and biochemical analyses for the early diagnosis of this heterogeneous group of disorders.

20.
Rev Esp Cardiol (Engl Ed) ; 72(1): 77, 2019 Jan.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30580788
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