Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: regional experience and high incidence of carnitine deficiency

Background Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common inherited defect in the mitochondrial fatty acid oxidation pathway, resulting in significant morbidity and mortality in undiagnosed patients. Newborn screening (NBS) has considerably improved MCADD outcome, but the risk of complication remains in some patients. The aim of this study was to evaluate the relationship between genotype, biochemical parameters and clinical data at diagnosis and during follow-up, in order to optimize monitoring of these patients. Methods We carried out a multicenter study in southwest Europe, of MCADD patients detected by NBS. Evaluated NBS data included free carnitine (C0) and the acylcarnitines C8, C10, C10:1 together with C8/C2 and C8/C10 ratios, clinical presentation parameters and genotype, in 45 patients. Follow-up data included C0 levels, duration of carnitine supplementation and occurrence of metabolic crises. Results C8/C2 ratio and C8 were the most accurate biomarkers of MCADD in NBS. We found a high number of patients homozygous for the prevalent c.985A > G mutation (75%). Moreover, in these patients C8, C8/C10 and C8/C2 were higher than in patients with other genotypes, while median value of C0 was significantly lower (23 μmol/L vs 36 μmol/L). The average follow-up period was 43 months. To keep carnitine levels within the normal range, carnitine supplementation was required in 82% of patients, and for a longer period in patients homozygotes for the c.985A>G mutation than in patients with other genotypes (average 31 vs 18 months). Even with treatment, median C0 levels remained lower in homozygous patients than in those with other genotypes (14 μmol/L vs 22 μmol/L). Two patients died and another three suffered a metabolic crisis, all of whom were homozygous for the c.985 A>G mutation. Conclusions Our data show a direct association between homozygosity for c.985A>G and lower carnitine values at diagnosis, and a higher dose of carnitine supplementation for maintenance within the normal range. This study contributes to a better understanding of the relationship between genotype and phenotype in newborn patients with MCADD detected through screening which could be useful in improving follow-up strategies and clinical outcome

Multifunctional silver-coated transparent TiO2 thin films for photocatalytic and antimicrobial applications

Transparent TiO2 thin films coated with Ag NPs were synthesized using two industrially applicable techniques, pulsed laser ablation (PLAL) and spray pyrolysis without using high vacuum. These transparent thin films were deposited on glass in order to generate glass materials with photocatalytic and antimicrobial properties and a minimum loss of transparency. The structural, morphological and optical properties of the thin films were examined using Grazing incidence X-ray diffraction (GIXRD), Raman spectroscopy, Scanning electron microscopy (SEM) and ultraviolet–visible spectroscopy. Transmission electron microscopy (TEM) was used to identify the NPs on the TiO2 surface. The transmittance value for the thin films was greater than 80%.The thin films thus synthesized were then assessed to determine their photocatalytic capacity by monitoring the degradation of Rhodamine B (RhB) under UV light irradiation. Ag NPs on the TiO2 surface ensures an improvement in the photocatalytic properties, with a 99% degradation of RhB in 210 min under UV light. In addition, these transparent thin films showed high antimicrobial activity on Gram-negative bacteria when irradiated by UV light for 4 h, killing 93% of these bacteria.Funding for open access charge: CRUE-Universitat Jaume

Genetic and Non-genetic Predictors of LINE-1 Methylation in Leukocyte DNA.

Background: Altered DNA methylation has been associated with various diseases. Objective: We evaluated the association between levels of methylation in leukocyte DNA at long interspersed nuclear element 1 (LINE-1) and genetic and non-genetic characteristics of 892 control participants from the Spanish Bladder Cancer/EPICURO study. Methods: We determined LINE-1 methylation levels by pyrosequencing. Individual data included demographics, smoking status, nutrient intake, toenail concentrations of 12 trace elements, xenobiotic metabolism gene variants, and 515 polymorphisms among 24 genes in the one-carbon metabolism pathway. To assess the association between LINE-1 methylation levels (percentage of methylated cytosines) and potential determinants, we estimated beta coefficients (βs) by robust linear regression. Results: Women had lower levels of LINE-1 methylation than men (β = –0.7, p = 0.02). Persons who smoked blond tobacco showed lower methylation than nonsmokers (β = –0.7, p = 0.03). Arsenic toenail concentration was inversely associated with LINE-1 methylation (β = –3.6, p = 0.003). By contrast, iron (β = 0.002, p = 0.009) and nickel (β = 0.02, p = 0.004) were positively associated with LINE-1 methylation. Single nucleotide polymorphisms (SNPs) in DNMT3A (rs7581217-per allele, β = 0.3, p = 0.002), TCN2 (rs9606756-GG, β = 1.9, p = 0.008; rs4820887-AA, β = 4.0, p = 4.8 × 10–7; rs9621049-TT, β = 4.2, p = 4.7 × 10–9), AS3MT (rs7085104-GG, β = 0.7, p = 0.001), SLC19A1 (rs914238, TC vs. TT: β = 0.5 and CC vs. TT: β = –0.3, global p = 0.0007) and MTHFS (rs1380642, CT vs. CC: β = 0.3 and TT vs. CC; β = –0.8, global p = 0.05) were associated with LINE-1 methylation. Conclusions: We identified several characteristics, environmental factors, and common genetic variants that predicted DNA methylation among study participants.This work was partially supported by the Association for International Cancer Research (AICR; grant 09-0780, and a doctoral scholarship awarded to S.M.T.); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, MINECO, Spain (grants 00/0745, PI051436, PI061614, PI09-02102, and G03/174); Red Temática de Investigación Cooperativa en Cáncer (grant RD06/0020-RTICC); the U.S. National Institutes of Health (grant RO1-CA089715); a postdoctoral fellowship awarded to A.F.S.A. from the Fundación Científica de la AECC; Fundació Marató TV3; and The Johns Hopkins University Vredenburg Scholarship awarded to A.L.C

Sobre proyectos de espacios públicos de calidad: estrategias urbanas comparadas

La ciudad compacta, policéntrica y con espacios públicos de calidad constituye un modelo urbano implícito en los Objetivos de Desarrollo Sostenible (ODS). La Nueva Agenda Urbana promueve la calidad del espacio público como bien común, y por ello es pertinente reconsiderar los parámetros de calidad e investigar su potencial de desarrollo. Este artículo se fundamenta en una reflexión teórica y metodológica sobre la calidad de los espacios públicos, teniendo en cuenta las aportaciones de la tradición urbanística. Con esta perspectiva se han analizado una selección de proyectos de espacio público en el ámbito europeo, lo que ha permitido identificar una serie de parámetros que, posteriormente, se aplican a nueve ejemplos representativos en Madrid, Barcelona y Zaragoza. El objetivo es efectuar evaluaciones sobre la calidad de los espacios públicos y determinar en qué medida están en relación con las condiciones de seguridad, accesibilidad e inclusividad que estos ofrecen. The polycentric, compact city with quality public spaces constitutes an implicit urban model in the Sustainable Development Goals (SDGs). The New Urban Agenda promotes the quality of public space as a common good. Therefore, it is pertinent to reconsider the quality parameters and investigate its development potential. This article is based on a theoretical and methodological reflection on the quality of public spaces, taking into account the contributions of the urban tradition. With this perspective, a selection of public space projects in the European sphere has been analyzed. This has made it possible to identify a series of parameters that are subsequently applied to nine representative examples in Madrid, Barcelona and Zaragoza. The objective is to carry out evaluations on the quality of public spaces and determine to what extent they are in relation to the conditions of security, accessibility and inclusivity that they offer

Oral chondroitin sulfate and prebiotics for the treatment of canine Inflammatory Bowel Disease: a randomized, controlled clinical trial

BACKGROUND Canine inflammatory bowel disease (IBD) is a chronic enteropathy of unknown etiology, although microbiome dysbiosis, genetic susceptibility, and dietary and/or environmental factors are hypothesized to be involved in its pathogenesis. Since some of the current therapies are associated with severe side effects, novel therapeutic modalities are needed. A new oral supplement for long-term management of canine IBD containing chondroitin sulfate (CS) and prebiotics (resistant starch, β-glucans and mannaoligosaccharides) was developed to target intestinal inflammation and oxidative stress, and restore normobiosis, without exhibiting any side effects. This double-blinded, randomized, placebo-controlled trial in dogs with IBD aims to evaluate the effects of 180 days administration of this supplement together with a hydrolyzed diet on clinical signs, intestinal histology, gut microbiota, and serum biomarkers of inflammation and oxidative stress. RESULTS Twenty-seven client-owned biopsy-confirmed IBD dogs were included in the study, switched to the same hydrolyzed diet and classified into one of two groups: supplement and placebo. Initially, there were no significant differences between groups (p > 0.05) for any of the studied parameters. Final data analysis (supplement: n = 9; placebo: n = 10) showed a significant decrease in canine IBD activity index (CIBDAI) score in both groups after treatment (p < 0.001). After treatment, a significant decrease (1.53-fold; p < 0.01) in histologic score was seen only in the supplement group. When groups were compared, the supplement group showed significantly higher serum cholesterol (p < 0.05) and paraoxonase-1 (PON1) levels after 60 days of treatment (p < 0.01), and the placebo group showed significantly reduced serum total antioxidant capacity (TAC) levels after 120 days (p < 0.05). No significant differences were found between groups at any time point for CIBDAI, WSAVA histologic score and fecal microbiota evaluated by PCR-restriction fragment length polymorphism (PCR-RFLP). No side effects were reported in any group. CONCLUSIONS The combined administration of the supplement with hydrolyzed diet over 180 days was safe and induced improvements in selected serum biomarkers, possibly suggesting a reduction in disease activity. This study was likely underpowered, therefore larger studies are warranted in order to demonstrate a supplemental effect to dietary treatment of this supplement on intestinal histology and CIBDAI

Survival of patients receiving a liver transplant for hepatocellular carcinoma, and risk of tumor recurrence

Objective: the goal of this research has been to evaluate the survival, in long and short term, of the patient receiving liver transplant for hepatocellular carcinoma (HCC), the risk of posttransplant tumor relapse and factors related to this complication. Design: retrospective study of a consecutive series of patients having had liver transplant for HCC. Patients and methodology: transplant patients for HCC from 1989 to November 2003. Patients were selected due to general limitations of nodule size and quantity, which were subsequently published as Milan criteria. Also, criteria agreed in the Conference of Barcelona were followed in the pre-transplant diagnosis. Results: the survival of this 81 patients group was of the 80, 61 and 52% for 1, 5 and 10 years respectively. In the 32% of the cases the HCC was an incidental finding in the explant. In the 12.3%, the tumor relapse was verified. The multivariate research identified the size of the nodule (OR = 1,7944) (IC 95% = 1,1332-2,8413) and the vascular invasion (OR = 6,6346) (IC 95% = 1,4624-30,1003) as risk factors of relapse. Conclusions: the liver transplant in selected patients with HCC has good results in medium and long term. The risk of post-transplant tumor relapse becomes notably reduced and is associated with the size of the nodule and the microscopic vascular invasion

H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells

In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone post-translational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells (MSCs) obtained from individuals aged 2 to 92 yr identified 18,735 hypermethylated and 45,407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on nongenetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type, and chromatin context involved and that, depending on the locus, the changes can be modulated by genetic and/or external factors

Effects of parity order and reproductive management on the efficiency of rabbit productive systems.

The aim of this work was to study the effect of parity order and reproductive management systems on rabbit production performance. A total of 73 rabbit does (I group) were submitted to a 35-day intensive rhythm [artificial insemination (AI) on day 4 post-partum (pp) and weaning at 25 days of lactation], and 108 rabbit does (SI group) were submitted to a 42-day semi-intensive rhythm (AI on day 11 pp and weaning at 35 days of lactation) during 9 months. Primiparous does had the lowest live body weight at parturition (P < 0.0001) and at 21 days of lactation (P < 0.0001). They also had lower milk production (P < 0.0001) than does with later parities. I group animals needed a higher number of AI than SI group to become pregnant (1.70 ± 0.03 vs. 1.39 ± 0.03; P < 0.0001: especially after the third). Prolificacy was not affected by the management system. Parturition interval (PI) was longer than expected in both groups [56.0 ± 1.4 and 50.9 ± 1.38 days in I and SI groups, respectively (P < 0.05)]. Mean productivity, estimated as number of weaned rabbits per female and year, was 12 kits higher in rabbit does of the SI group (P < 0.05). From the third parturition onward, an increase in live body weight of kits at different ages was observed. At 21 (P < 0.05) and 25 days of age (P < 0.01), kits from the I group rabbit does weighed more than those from the SI group; however, the latter showed a higher weight at 35 (P < 0.05) and 60 days of age (P < 0.05). Rabbit does with two or three parturitions had higher litter size at 21 and 25 days of age (P < 0.0001 and P < 0.001, respectively). Kit mortality between 21 and 25 days of age and between 35 and 60 days of age was not affected by treatments but was higher in the I group between 25 and 35 days (18.2 vs. 5.03% in the I and SI groups, respectively; P < 0.0001) and as age of does increased (P < 0.05). In light of these results, we could conclude that long term doe reproductive performance is negatively affected and litter viability decreased when using intensive compared to a semi-intensive reproductive management