A novel c.-22T>C mutation in GALK1 promoter is associated with elevated galactokinase phenotype

<p>Abstract</p> <p>Background</p> <p>Many genetic variations of <it>GALK1 </it>have been identified in the patients with galactokinase (GALK1) deficiency. However, the molecular characteristics of <it>GALK1 </it>in individuals with elevated GALK1 activity are relatively unknown.</p> <p>Methods</p> <p>We investigated the relationship between elevated GALK1 activity and the molecular <it>GALK1 </it>gene variations, and the molecular mechanism underlying elevated GALK1 activity. PCR products from 63 subjects, without any attenuation of galactose degradation enzymes, were sequenced to screen for nucleotide alterations in the <it>GALK1 </it>promoter.</p> <p>Results</p> <p>Three nucleotide substitutions were identified: c.-179A>G, c.-27A>C, and c.-22T>C. With respect to the c.-22T>C mutation, GALK1 activity in 13 subjects with the T/C or C/C genotype was significantly higher than those in 50 subjects with the T/T genotype (p < 0.001). The dual luciferase reporter assay in Hep3B cells showed that the luciferase activity with the <it>GALK1 </it>promoter with the c.-22C mutant allele increased approximately 2.5-fold, compared to that with the c.-22T. A specific DNA-protein complex was observed in an electrophoretic mobility shift assay, with slightly higher affinity to c.-22C than to c.-22T.</p> <p>Conclusion</p> <p>The c.-22T>C mutation, which was observed frequently in individuals with elevated GALK1 activity, increased the expression of a reporter gene through enhanced binding of a currently unidentified nuclear protein. These results suggest that the elevated GALK1 activity resulted from enhanced gene expression, due to nucleotide variation within <it>GALK1 </it>promoter.</p

Genetics of Microenvironmental Sensitivity of Body Weight in Rainbow Trout (Oncorhynchus mykiss) Selected for Improved Growth

Microenvironmental sensitivity of a genotype refers to the ability to buffer against non-specific environmental factors, and it can be quantified by the amount of residual variation in a trait expressed by the genotype’s offspring within a (macro)environment. Due to the high degree of polymorphism in behavioral, growth and life-history traits, both farmed and wild salmonids are highly susceptible to microenvironmental variation, yet the heritable basis of this characteristic remains unknown. We estimated the genetic (co)variance of body weight and its residual variation in 2-year-old rainbow trout (Oncorhynchus mykiss) using a multigenerational data of 45,900 individuals from the Finnish national breeding programme. We also tested whether or not microenvironmental sensitivity has been changed as a correlated genetic response when genetic improvement for growth has been practiced over five generations. The animal model analysis revealed the presence of genetic heterogeneity both in body weight and its residual variation. Heritability of residual variation was remarkably lower (0.02) than that for body weight (0.35). However, genetic coefficient of variation was notable in both body weight (14%) and its residual variation (37%), suggesting a substantial potential for selection responses in both traits. Furthermore, a significant negative genetic correlation (−0.16) was found between body weight and its residual variation, i.e., rapidly growing genotypes are also more tolerant to perturbations in microenvironment. The genetic trends showed that fish growth was successfully increased by selective breeding (an average of 6% per generation), whereas no genetic change occurred in residual variation during the same period. The results imply that genetic improvement for body weight does not cause a concomitant increase in microenvironmental sensitivity. For commercial production, however, there may be high potential to simultaneously improve weight gain and increase its uniformity if both criteria are included in a selection index

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study

Peer reviewe

Meditation or Medication? Mindfulness training versus medication in the treatment of childhood ADHD: a randomized controlled trial

Background Attention-Deficit-Hyperactivity-Disorder (ADHD) is, with a prevalence of 5 %, a highly common childhood disorder, and has severe impact on the lives of youngsters and their families. Medication is often the treatment of choice, as it currently is most effective. However, medication has only short-term effects, treatment adherence is often low and most importantly; medication has serious side effects. Therefore, there is a need for other interventions for youngsters with ADHD. Mindfulness training is emerging as a potentially effective training for children and adolescents with ADHD. The aim of this study is to compare the (cost) effectiveness of mindfulness training to the (cost) effectiveness of methylphenidate in children with ADHD on measures of attention and hyperactivity/impulsivity. Methods/design A multicenter randomized controlled trial with 2 follow-up measurements will be used to measure the effects of mindfulness training versus the effects of methylphenidate. Participants will be youngsters (aged 9 to 18) of both sexes diagnosed with ADHD, referred to urban and rural mental healthcare centers. We aim to include 120 families. The mindfulness training, using the MYmind protocol, will be conducted in small groups, and consists of 8 weekly 1.5-h sessions. Youngsters learn to focus and enhance their attention, awareness, and self-control by doing mindfulness exercises. Parents will follow a parallel mindful parenting training in which they learn to be fully present in the here and now with their child in a non-judgmental way, to take care of themselves, and to respond rather than react to difficult behavior of their child. Short-acting methylphenidate will be administered individually and monitored by a child psychiatrist. Assessments will take place at pre-test, post-test, and at follow-up 1 and 2 (respectively 4 and 10 months after the start of treatment). Informants are parents, children, teachers, and researchers. Discussion This study will inform mental health care professionals and health insurance companies about the clinical and cost effectiveness of mindfulness training for children and adolescents with ADHD and their parents compared to the effectiveness of methylphenidate. Limitations and several types of bias that are anticipated for this study are discussed