Further insights into the allan-herndon-dudley syndrome: Clinical and functional characterization of a novel MCT8 mutation

Background. Mutations in the thyroid hormone (TH) transporter MCT8 have been identified as the cause for Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and altered TH serum levels. Here we report a novel MCT8 mutation identified in 4 generations of one family, and its functional characterization. Methods. Proband and family members were screened for 60 genes involved in X-linked cognitive impairment and the MCT8 mutation was confirmed. Functional consequences of MCT8 mutations were studied by analysis of [125I]TH transport in fibroblasts and transiently transfected JEG3 and COS1 cells, and by subcellular localization of the transporter. Results. The proband and a male cousin demonstrated clinical findings characteristic of AHDS. Serum analysis showed high T3, low rT3, and normal T4 and TSH levels in the proband. A MCT8 mutation (c.869C>T; p.S290F) was identified in the proband, his cousin, and several female carriers. Functional analysis of the S290F mutant showed decreased TH transport, metabolism and protein expression in the three cell types, whereas the S290A mutation had no effect. Interestingly, both uptake and efflux of T3 and T4 was impaired in fibroblasts of the proband, compared to his healthy brother. However, no effect of the S290F mutation was observed on TH efflux from COS1 and JEG3 cells. Immunocytochemistry showed plasma membrane localization of wild-type MCT8 and the S290A and S290F mutants in JEG3 cells. Conclusions. We describe a novel MCT8 mutation (S290F) in 4 generations of a family with Allan-Herndon-Dudley Syndrome. Functional analysis demonstrates loss-of-function of the MCT8 transporter. Furthermore, our results indicate that the function of the S290F mutant is dependent on cell context. Comparison of the S290F and S290A mutants indicates that it is not the loss of Ser but its substitution with Phe, which leads to S290F dysfunction

A Toxicological Study of HangAmDan-B in Mice

AbstractThe aim of the study was to define the toxicity of HangAmDan-B (HAD-B) in mice over the short and long term. HAD-B was studied in 1-week single and 5-week repeated oral dose toxicity tests on male Imprinting Control Region mice. Doses used in 1 week single oral dose toxicity tests were 0, 0.2, 1, 5, and 25 g/kg/day and those of repeated toxicity test were 0, 0.04, 0.2, 1, and 2 g/kg/day. Blood and urine samples were assayed and their morphology observed. Numerical data were compared using Mann-Whitney U test and analysis of variance. Significantly decreased red blood cell levels in mice from S2-HAD-B, S3-HAD-B, S4-HAD-B, and S5-HAD-B groups were observed in single oral dose toxicity tests. Hemoglobin, hematocrit, and mean cell hemoglobin values in mice from the S4-HAD-B and S5-HAD-B groups were also significantly decreased. No mortalities or significant differences in all factors were observed during the dosing period of the repeated dose toxicity test. Administering 2 g/kg/day of HAD-B in mice over a 5-week period showed no significant hematological changes. However, risk of anemia with more than 5 g/kg/ day administration of HAD-B was found. In general, HAD-B appears to be safe and nontoxic, and a no observed adverse effect level in mice was established at 2 g/kg/ day. This data serves as satisfactory preclinical evidence for the safety of HAD-B should a future clinical trial for HAD-B be launched. Further studies are required to confirm these safety results and to carry out a safety trial in humans

Moment redistribution in continuous FRP reinforced concrete beams

yesThe main purpose of this paper is to assess moment redistribution in continuous concrete beams reinforced with fibre reinforced polymer (FRP) bars. A numerical technique based on equilibrium of forces and full compatibility of strains has been developed to evaluate the moment–curvature relationships and moment capacities of FRP and steel reinforced concrete sections. Moment redistribution has then been assessed by comparing elastic and experimental moments at failure, and moment capacity at critical sections of continuous FRP reinforced concrete beams reported on the literature. The curvature of under reinforced FRP sections was large at FRP rupture but failure was sudden, that would not allow any moment redistribution. On the other hand, FRP over reinforced sections experienced higher curvature at failure than steel over reinforced sections owing to the lower FRP modulus of elasticity. Although the experimental and elastic bending moment distributions at failure are significantly different for many beams tested elsewhere, in particular CFRP reinforced concrete beams, the experimental bending moment over the middle support at failure was far lower than the corresponding moment capacity owing to the de-bonding of FRP bars from concrete in the middle support region. Furthermore, the hogging moment redistribution over the middle support is always larger than that at mid-span by around 66%. It was also shown that the load capacity prediction of continuous FRP reinforced concrete beams using the de-bonding moment at the middle support section was the closest to the experimental failure load

The Effects of Achievement Motivation and Perceived Teacher Involvement in Academic Tasks on the Academic Achievement and Psychological Well-being of Rural Students in the Interior Sabah Division, Malaysia

This study examines the effects of achievement motivation and perceived teacher involvement on academic achievement and psychological well-being of rural students in the Interior Sabah Division (Beaufort, Keningau, Kuala Penyu, Membakut, Pensiangan, Sipitang, Tambunan & Tenom). We predicted that achievement motivation contributes to both academic achievement and psychological well-being. We also predicted teachers’ involvement in students’ academic work also contributes to both dependent variables. A total of 1586 students participated in this study from 21 rural schools in the Interior Division Sabah. A questionnaire, divided into four sections, was used to measure all the variables. Section A measured the demographic variables, such as the academic achievement, academic level, age, gender and location; Section B; measured achievement motivation; Section C measured the perception of teacher involvement in students’academic work and Section D measured psychological well-being. Hierarchical regression analyses were used to analyze the data. The study found that achievement motivation contributed 4% to the variance in academic achievement and 16% on psychological well-being. In regards to teachers’ involvement in academic studies, it contributed 6% to students’ psychological well-being but not in academic achievement. These significant findings may create awareness and bring the matter to the attention of the Ministry of Education, the schools and Parent-Teacher Association. From this study, it is our hope that the Educational Institution may provide more achievement motivational programs to enhance rural students’ psychological well-being and academic achievement

A novel nonsense CDK5RAP2 mutation in a Somali child with primary microcephaly and sensorineural hearing loss

Primary microcephaly is a genetically heterogeneous condition characterized by reduced head circumference (-3 SDS or more) and mild-to-moderate learning disability. Here, we describe clinical and molecular investigations of a microcephalic child with sensorineural hearing loss. Although consanguinity was unreported initially, detection of 13.7 Mb of copy neutral loss of heterozygosity (cnLOH) on chromosome 9 implicated the CDK5RAP2 gene. Targeted sequencing identified a homozygous E234X mutation, only the third mutation to be described in CDK5RAP2, the first in an individual of non-Pakistani descent. Sensorineural hearing loss is not generally considered to be consistent with autosomal recessive microcephaly and therefore it seems likely that the deafness in this individual is caused by the co-occurrence of a further gene mutation, independent of CDK5RAP2. Nevertheless, further detailed clinical descriptions of rare CDK5RAP2 patients, including hearing assessments will be needed to resolve fully the phenotypic range associated with mutations in this gene. This study also highlights the utility of SNP-array testing to guide disease gene identification where an autosomal recessive condition is plausible