Analysis of UDP-galactose 4'-epimerase mutations associated with the intermediate form of type III galactosaemia

Type III galactosaemia is a hereditary disease caused by reduced activity in the Leloir pathway enzyme, UDP-galactose 4'-epimerase (GALE). Traditionally, the condition has been divided into two forms-a mild, or peripheral, form and a severe, or generalized, form. Recently it has become apparent that there are disease states which are intermediate between these two extremes. Three mutations associated with this intermediate form (S81R, T150M and P293L) were analysed for their kinetic and structural properties in vitro and their effects on galactose-sensitivity of Saccharomyces cerevisiae cells that were deleted for the yeast GALE homologue Gal10p. All three mutations result in impairment of the kinetic parameters (principally the turnover number, k(cat)) compared with the wild-type enzyme. However, the degree of impairment was mild compared with that seen with the mutation (V94M) associated with the generalized form of epimerase deficiency galactosaemia. None of the three mutations tested affected the ability of the protein to dimerize in solution or its susceptibility to limited proteolysis in vitro. Finally, in the yeast model, each of the mutated patient alleles was able to complement the galactose-sensitivity of gal10 Delta cells as fully as was the wild-type human allele. Furthermore, there was no difference from control in metabolite profile following galactose exposure for any of these strains. Thus we conclude that the subtle biochemical and metabolic abnormalities detected in patients expressing these GALE alleles likely reflect, at least in part, the reduced enzymatic activity of the encoded GALE proteins.

Including disabled children at school: Is it really as simple as 'a, c, d'?

This paper presents and discusses a social justice strategy that may progress inclusion in schools. The framework for this strategy is grounded in the theoretical discussions by Nancy Fraser and Trevor Gale about distributive, redistributive, and recognitive models of social justice. None of these theoretical frameworks, however, in themselves, offer a clear way forward for marginalised and misrecognised groups, such as disabled children, who need both educational resources and recognition in inclusive classrooms. The authors propose, however, that the work of Fraser and Gale combines into a social justice strategy, which consists of three elements (agency, competency, and diversity, or ‘a, c, d’) that can lead to inclusion. When disabled children are provided with the opportunity to exercise their agency, demonstrate their competence, and transform and affirm notions of diversity, then inclusion is more likely to occur in the classroom. Data from two research projects are presented using this framework to illustrate this argument, and the proposed ‘a, c, d’ social justice strategy towards inclusion.

Cancer incidence and mortality in patients with insulin-treated diabetes: a UK cohort study

Raised risks of several cancers have been found in patients with type II diabetes, but there are few data on cancer risk in type I diabetes. We conducted a cohort study of 28 900 UK patients with insulin-treated diabetes followed for 520 517 person-years, and compared their cancer incidence and mortality with national expectations. To analyse by diabetes type, we examined risks separately in 23 834 patients diagnosed with diabetes under the age of 30 years, who will almost all have had type I diabetes, and 5066 patients diagnosed at ages 30 - 49 years, who probably mainly had type II. Relative risks of cancer overall were close to unity, but ovarian cancer risk was highly significantly raised in patients with diabetes diagnosed under age 30 years ( standardised incidence ratio ( SIR) = 2.14; 95% confidence interval (CI) 1.22 - 3.48; standardised mortality ratio (SMR) = 2.90; 95% CI 1.45 - 5.19), with greatest risks for those with diabetes diagnosed at ages 10 - 19 years. Risks of cancer at other major sites were not substantially raised for type I patients. The excesses of obesity- and alcohol-related cancers in type II diabetes may be due to confounding rather than diabetes per se.

Mortality from cerebrovascular disease in a cohort of 23 000 patients with insulin-treated diabetes

Background and Purpose-Disease of the cardiovascular system is the main cause of long-term complications and mortality in patients with type I (insulin-dependent) and type 11 (non-insulin-dependent) diabetes. Cerebrovascular mortality rates have been shown to be raised in patients with type 11 diabetes but have not previously been reported by age and sex in patients with type I diabetes.

Graham Connah - Writing About Archaeology

Review of Graham Connah Writing about archaeology. CUP book 2009.