A novel mutation in the last exon of ATRX in a patient with α-thalassemia myelodysplastic syndrome

Abstract:  We describe a patient with acquired alpha-thalassemia myelodysplastic syndrome (ATMDS). A previously healthy 66-year-old man presented with hemoglobin of 9.3 g/dL, mean corpuscular volume 59 fL, and a bone marrow aspirate with increased erythroid precursors and hypolobulated megakaryocytes. Hemoglobin H inclusions were seen in most red cells after 1% brilliant cresyl blue supravital stain of the peripheral blood. At the molecular level, we identified of a novel mutation in the most 3' exon of the ATRX gene ( C GA→ T GA substitution in codon 2407) resulting in a premature termination codon (p.R2407X). This case provides further evidence for a link between ATRX mutations and ATMDS, and suggests a possible role for the conserved Q-box element in ATRX function.     

Comparison of failure characteristics of a range of cancellous bone-bone cement composites

Over the past decade, orthopedic surgery has embraced an increase in the depth of cement penetration into the adjacent cancellous bone structure. The resultant interdigitation transforms this zone into a thick layer of continuous interpenetrating composite material. The failure behavior of the composite formed with a number of potential bone cements with different bonding ability was investigated. The cancellous bone-cement composites exhibit considerable resistance to crack extension, and in situ optical observation indicates that the contribution of the cancellous bone is analogous to that of a typical fiber bridging process. The critical stress intensity factor and the work of fracture have been used to quantify the failure characteristics of the cancellous bone-cement composites. The nature of the crack propagation through these cement-bone composites was also captured via optical microscopy, and scanning electron microscopic images were taken of the failure surfaces. The R-curve behavior, or crack extension characteristic, of the cancellous bone-cement composite was also determined. The interesting outcome is that the cancellous bone-PMMA (poly-methylmethacrylate) composite, despite the absence of chemical bonding with bone, required the highest energy to fracture. In addition, the dimensional stability of the cement has a great effect on the interface.     

PAF-acether in chronic arthritis

Platelet activating factor (PAF-acether) is a potent pro-inflammatory mediator. The possible involvement of this molecule in the pathogenesis of chronic erosive arthritis has been investigated using an animal model, antigen-induced arthritis in the rabbit, which closely resembles rheumatoid arthritis. The arthritic joint fluids from rabbits with antigen-induced arthritis contained low levels of PAF-acether in the acute stages of the disease. However, PAF-acether was not detectable in the chronic stages of the lesion. The biologically inactive precursor/metabolite of PAF-acether, lyso-PAF-acether, was detectable in both control and arthritic joint washes. However, the levels of lyso-PAF-acether in the arthritic joint fluids were significantly elevated above those of control in the acute stages of the disease, but not in the chronic stages. Intra-articular injection of PAF-acether at doses up to 100 times the levels detected in the acute stages of this model did not induce joint swelling or leucocyte accumulation in normal rabbits. This study suggests that PAF-acether may contribute to the acute phase of antigeninduced arthritis but is less likely to be involved in the chronic processes.     

Sequence comparison of human and yeast telomeres identifies structurally distinct subtelomeric domains

We have sequenced and compared DNA from the ends of three human chromosomes: 4p, 16p and 22q. In all cases the pro-terminal regions are subdivided by degenerate (TTAGGG)n repeats into distal and proximal sub- domains with entirely different patterns of homology to other chromosome ends. The distal regions contain numerous, short (<2 kb) segments of interrupted homology to many other human telomeric regions. The proximal regions show much longer (approximately 10-40 kb) uninterrupted homology to a few chromosome ends. A comparison of all yeast subtelomeric regions indicates that they too are subdivided by degenerate TTAGGG repeats into distal and proximal sub-domains with similarly different patterns of identity to other non-homologous chromosome ends. Sequence comparisons indicate that the distal and proximal sub-domains do not interact with each other and that they interact quite differently with the corresponding regions on other, non- homologous, chromosomes. These findings suggest that the degenerate TTAGGG repeats identify a previously unrecognized, evolutionarily conserved boundary between remarkably different subtelomeric domains.      

Differences Between Treatment Seekers in an Obese Population: Medical Intervention vs. Dietary Restriction

This study examined two groups of people who were pursuing treatment for obesity: either medical intervention (a hospital group; N = 20) or support for dietary restriction (a community group; N = 18). This study addressed four questions: (1) Were there differences between the two groups in terms of their psychological distress (as measured by the Symptom Checklist)? (2) Does binge eating moderate psychological distress? (3) Do feelings of ineffectiveness moderate psychological distress? and (4) Which variables best accounted for group membership (i.e., type of treatment sought)? Results suggested that the hospital group was significantly more distressed than the community group. However, there were no differences between the two groups with respect to binge eating or feelings of ineffectiveness. These findings suggest that it is the effects of morbid obesity that are most likely to moderate psychological distress.     

ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome

It was shown recently that mutations of the ATRX gene give rise to a severe, X-linked form of syndromal mental retardation associated with alpha thalassaemia (ATR-X syndrome). In this study, we have characterised the full-length cDNA and predicted structure of the ATRX protein. Comparative analysis shows that it is an entirely new member of the SNF2 subgroup of a superfamily of proteins with similar ATPase and helicase domains. ATRX probably acts as a regulator of gene expression. Definition of its genomic structure enabled us to identify four novel splicing defects by screening 52 affected individuals. Correlation between these and previously identified mutations with variations in the ATR-X phenotype provides insights into the pathophysiology of this disease and the normal role of the ATRX protein in vivo.