Functional and pharmacological evaluation of novel GLA variants in Fabry disease identifies six (two de novo) causative mutations and two amenable variants to the chaperone DGJ

Abstract Background Allelic heterogeneity is an important feature of the GLA gene for which almost 900 known genetic variants have been discovered so far. Pathogenetic GLA variants cause alpha-galactosidase A (α-Gal A) enzyme deficiency leading to the X-linked lysosomal storage disorder Fabry disease (FD). Benign GLA intronic and exonic variants ( e.g. pseudodeficient p.Asp313Tyr) have also been described. Some GLA missense variants, previously deemed to be pathogenetic ( e.g. p.Glu66Gln and p.Arg118Cys), they have been reclassified as benign after re-evaluation by functional and population studies. Hence, the functional role of novel GLA variants should be investigated to assess their clinical relevance. Results We identified six GLA variants in 4 males and 2 females who exhibited symptoms of FD: c.159C>G p.(Asn53Lys), c.400T>C p.(Tyr134His), c.680G>C (p.Arg227Pro), c.815A>T p.(Asn272Ile), c.907A>T p.(Ile303Phe) and c.1163_1165delTCC (p.Leu388del). We evaluated their impact on the α-Gal A protein by bioinformatic analysis and homology modelling, by analysis of the GLA mRNA, and by site-directed mutagenesis and in vitro expression studies. We also measured their responsiveness to the pharmacological chaperone DGJ. Conclusions The six detected GLA variants cause deficient α-Gal A activity and impairment or loss of the protein wild-type structure. We found p.Asn53Lys and p.Ile303Phe variants to be susceptible to DGJ

Effects of Prenatal Yoga on Labor Pain, Maternal and Newborn Outcomes: An Integrative Literature Review

Background: Labor pain management in the U.S. is commonly accomplished with the use of pharmacological pain management. However, pharmacological pain management of labor pain is associated with several adverse effects. New studies suggest that labor pain can be managed using a nonpharmacologic approach. Complementary and Alternative Medicine (CAM) is an alternative method used during pregnancy and childbirth associated with innumerable benefits for mothers and the newborn, including the management of pain during labor. Objectives: The purpose of this integrative literature review is to analyze the effects and benefits that prenatal yoga, a form of Complementary and Alternative Medicine, has on pregnancy, labor pain, in addition to mothers and newborn outcomes. Method: An integrative literature review guided by Kolcaba was conducted using PubMed and Cumulative Index to Nursing and Health Literature (CINAHL). A search was performed using these terms: labor pain, pain management, Complementary and Alternative Medicine (CAM), and prenatal yoga Results: Six studies met the inclusion and exclusion criteria. The results revealed that yoga practice during pregnancy is effective in improving the quality of life of pregnant women by reducing stress and anxiety during pregnancy. Prenatal yoga and yoga breathing exercise can be supportive in managing stress during labor and delivery as well as promoting comfort and reducing pain. Prenatal yoga improves maternal and newborn outcomes and may have a role in reducing the incidence of preterm labor. Conclusion: Prenatal yoga can have a positive impact on the management of pain during labor as well as on the wellness of mother and newborn. Studies on this topic are insufficient and more research focusing on the benefits of yoga practice during pregnancy should be conducted

Micronucleus cytome assay in exfoliated buccal cells of children for the evaluation of early biological effects of air pollution exposure. The MAPEC_LIFE project.

Introduction Air pollution is a global problem. In 2013, air pollution and particulate matter were classified as carcinogenic to human by the IARC. Children are a high-risk group in terms of the health effects of air pollution and early exposure during childhood can increase the risk of developing chronic diseases in adulthood. The MAPEC_LIFE (Monitoring Air Pollution Effects on Children for supporting public health policy) is a project founded by EU Life+ Programme (LIFE12 ENV/IT/000614) which intends to evaluate the associations between air pollution and early biological effects in children and to propose a model for estimating the global risk of early biological effects due to air pollutants and other factors in children. This work aims to investigate micronuclei frequency in child cells in association with air pollutant levels and other factors, as lifestyle. Methods The micronucleus test was performed in buccal cells of 6–8-year-old children from 5 Italian towns with different air pollution levels. Data on air quality during the study period were obtained from the Regional Agency for Environmental Protection. Details of children diseases, socio-economic status, exposures to other pollutants and lifestyle were collected using a questionnaire administered to children’s parents. Results During the winter campaign, 1315 children were recruited and their buccal cells sampled. As about air quality, the levels of main pollutants were, as expected, higher in the North of Italy, with a PM10 mean values of 62 and 40 μg/m3 in Torino and Brescia, respectively, than in the other towns (Pisa, Perugia, Lecce). In contrast, micronucleus frequency in buccal cells of children was higher in Brescia (0.06/100 cells) than in any other towns (from 0.03 to 0.04/100 cells). Conclusions The results suggested that, in addition to air pollution exposure, some other factors related to lifestyle or further exposures may influence micronucleus frequency and cellular response to air pollutants

Socio-economic and environmental factors associated with overweight and obesity in children aged 6–8 years living in five Italian cities (The MAPEC_LIFE cohort)

The prevalence of obesity among Italian children has reached such alarming levels as to require detailed studies of the causes of the phenomenon. A cross-sectional study was carried out in order to assess the weight status of 1164 Italian children aged 6–8 years (the Monitoring Air Pollution Effects on Children for Supporting Public Health Policy (MAPEC_LIFE) cohort) and to identify any associations between selected socio-economic and environmental factors and overweight/obesity. The data were obtained by means of a questionnaire given to parents, and any associations were examined by binomial logistic regression analyses. Overweight was found to be positively associated with male gender, parents of non-Italian origin, and parents who smoke, and negatively associated with the parents’ level of education and employment. In addition, the frequency of overweight varied in relation to the geographical area of residence, with a greater prevalence of overweight children in the cities of central-southern Italy. This study highlights the need to implement appropriate obesity prevention programs in Italy, which should include educational measures concerning lifestyle for parents from the earliest stages of their child’s life

Functional and pharmacological evaluation of novel GLA variants in Fabry disease identifies six (two de novo ) causative mutations and two amenable variants to the chaperone DGJ

Abstract Background Allelic heterogeneity is an important feature of the GLA gene for which almost 900 known genetic variants have been discovered so far. Pathogenetic GLA variants cause alpha-galactosidase A (α-Gal A) enzyme deficiency leading to the X-linked lysosomal storage disorder Fabry disease (FD). Benign GLA intronic and exonic variants ( e.g. pseudodeficient p.Asp313Tyr) have also been described. Some GLA missense variants, previously deemed to be pathogenetic ( e.g. p.Glu66Gln and p.Arg118Cys), they have been reclassified as benign after re-evaluation by functional and population studies. Hence, the functional role of novel GLA variants should be investigated to assess their clinical relevance. Results We identified six GLA variants in 4 males and 2 females who exhibited symptoms of FD: c.159C>G p.(Asn53Lys), c.400T>C p.(Tyr134His), c.680G>C (p.Arg227Pro), c.815A>T p.(Asn272Ile), c.907A>T p.(Ile303Phe) and c.1163_1165delTCC (p.Leu388del). We evaluated their impact on the α-Gal A protein by bioinformatic analysis and homology modelling, by analysis of the GLA mRNA, and by site-directed mutagenesis and in vitro expression studies. We also measured their responsiveness to the pharmacological chaperone DGJ. Conclusions The six detected GLA variants cause deficient α-Gal A activity and impairment or loss of the protein wild-type structure. We found p.Asn53Lys and p.Ile303Phe variants to be susceptible to DGJ