M. O'Kane

Treatment of Diabetic Ketoacidosis Using Normalization of Blood 3-Hydroxybutyrate Concentration as the Endpoint of Emergency Management: A randomized controlled study

OBJECTIVE To compare the efficacy of an extended insulin regimen using correction of hyperketonemia as endpoint with a more conventional regimen in the treatment of diabetic ketoacidosis. RESEARCH DESIGN AND METHODS A total of 22 patients admitted to a Belfast teaching hospital with clinical and biochemical features of diabetic ketoacidosis (pH < 7.25 and/or bicarbonate < 16 mmol/l) were randomized to either conventional or extended insulin regimens. In the conventional regimen, insulin was administered at 5 U/h until near-normoglycemia (blood glucose ≤ 10 mmol/l) and then administered at a reduced rate until clinical recovery. In the extended regimen, administration of insulin at 5 U/h was continued beyond attainment of normoglycemia, until resolution of hyperketonemia (3-hydroxybutyrate < 0.5 mmol/l). Main outcome measures were 3-hydroxybutyrate and bicarbonate levels during the 24 h after attainment of near-normoglycemia. RESULTS After near-normoglycemia, correction of hyperketonemia was achieved earlier with the extended treatment (5.9 ± 0.8 vs. 21.8 ± 3.4 h, P = 0.0004 [mean ± SD]). The area under the curve of 3-hydroxybutyrate against time for 24 h after near-normoglycemia was reduced with the extended treatment (24.9 ± 3.8 vs. 55.9 ± 6.7 mmol·l−1·h−1 P = 0.001). These differences remained statistically significant after adjustment for higher baseline levels of 3-hydroxybutyrate at near-normoglycemia in the extended treatment group. Bicarbonate levels at 6 and 12 h after near-normoglycemia were not significantly different between groups. CONCLUSIONS The extended insulin regimen, which was easy to implement at ward level, produced a more rapid resolution of ketosis than the conventional regimen.

Mutation screening and genotype:phenotype correlation in familial hypercholesterolaemia

The aim of this study was to develop a mutation screening protocol for familial hypercholesterolaemia (FH) patients and to assess genotype/phenotype effects in terms of pre-treatment lipid profiles and presentation of tendon xanthomata (TX). A total of 158 families with clinical definitions of possible (120) or definite (38) FH were studied using a tiered screening protocol. Mutations were identified in 52 families, 44 families showing 23 different LDLR gene defects and eight families showing the common Apo B100 gene defect R3500Q. LDLR defects were detected in various regions of the gene with 56% in the LDL binding domain (exons 2-6) and 37% in the EGF precursor homology domain (exons 7-14). The most common mutations were D461N(7), C210X(5), 932delA(5), and C163Y(4). Frameshift mutations accounted for 20% with nonsense 13%, mis-sense 35%, splice 3%, Apo B 13% and 2% large deletion, 13% of clinically definite FH remained undefined. In conclusion, DNA based diagnosis is possible in 79% (30/38) of clinically definite FH families and of the 120 possible FH families at the start of the screening program, 18% (22/120) now have defined mutations. Overall 60 families from the original 158 meet the clinical and/or genetic criteria for definite FH. Tendon xanthomata were present in only 58% (30/52) of genetically defined FH families, thus limiting its use as a strict diagnostic criteria. Families with low density lipoprotein receptor (LDLR) defects present with higher total and LDL cholesterol levels and a higher incidence of TX than do those with the common Apo B variant, and frameshift mutations appear to have the most severe presentation.

Very low density lipoprotein subfractions in Type II diabetes mellitus: alterations in composition and susceptibility to oxidation

Aims/hypothesis. Type II (non-insulin-dependent) diabetes mellitus is associated with raised triglycerides and increased very low density lipoprotein cholesterol. The aim of this study was to assess if very low density lipoprotein subfraction composition and potential to oxidise were altered in this condition.¶Methods. Very low density lipoprotein was separated into four subfractions (A→D) by a novel, rapid ultracentrifugation procedure. Analysis of each subfraction included lipid and fatty acid composition. Preformed peroxides were measured spectrophotometrically and conjugated dienes were used as an indicator of in vitro lipid oxidation.¶Results. In all results we compared patient and control subfractions. Mean fasting plasma glucose was 8.9 ± 2.0 mmol/l in patients vs 5.1 ± 0.4 mmol/l in control subjects (p < 0.001); patient HbA1 c was 7.6 ± 1.4 %. Patient total lipid standardised for apo B was higher than controls in subfractions A, B and C; A, 201 vs 60; B, 191 vs 40; C, 63 vs 21; D, 29 vs 34 μmol lipid per mg apo B (p < 0.05). Preformed peroxides were higher in all patient subfractions compared with controls: A, 340 vs 48; B, 346 vs 42; C, 262 vs 28; D, 54 vs 16 nmol per mg apo B (p < 0.001). Patient subfractions A and D were more susceptible to in vitro oxidation. Monounsaturated fatty acids were lower in patients subfractions, 35.2 vs 36.7; B, 35.1 vs 38.7; C, 34.4 vs 36.5; D, 33.0 vs 35.5 as per cent total (p < 0.05).¶Conclusions/interpretation. These results indicate abnormalities in very low density lipoprotein subfraction composition and oxidation profile in Type II diabetic subjects, which are characteristic of more atherogenic particles and that may contribute to the development of cardiovascular disease in these patients. [Diabetologia (2000) 43: 485–493]

A novel single base deletion in the LDLR gene (211delG): Effect on serum lipid profiles and the influence of other genetic polymorphisms in the ACE, APOE and APOB genes.

A single base deletion (211delG) in the low density lipoprotein receptor (LDLR) gene was shown to cause familial hypercholesterolaemia (FH) in a large family from Northern Ireland. Twenty-four of 52 family members tested had this mutation, 13 of which were newly diagnosed. Mutation-positive individuals had significantly higher mean total-cholesterol (TC) and LDL-cholesterol (LDL-C) than those without 211delG. LDL-C was a more accurate indicator of disease status than TC. When TC levels alone were considered, in individuals over 16 years, a false negative rate (TC < 7.5 mmol/l) of 40% was found; however this fell to 13% based on inclusion of LDL-C levels. Individuals with coronary artery disease (CAD) had significantly higher TC levels than those without CAD and tended to have tendinous xanthomas (TX) and corneal arcus (CA). Generic polymorphisms in the angiotensin converting enzyme (ACE) and apolipoprotein (apo) B genes did not appear to be associated with lipid levels or with the clinical severity of the disease; however, the apo E epsilon4 allele did show a lipid-raising effect in individuals with the mutation.

Computational modelling of atherosclerosis: developing a community resource

Rationale Atherosclerosis is a dynamical process that emerges from the interplay between lipid metabolism, inflammation and innate immunity. The arterial location of atherosclerosis makes it logistically and ethically difficult to study in vivo. To improve our understanding of the disease, we must find alternative ways to investigate its progression. There is currently no computational model of atherosclerosis openly available to the research community for use in future studies and for refinement and development. Objective Here we develop the first predictive computational model to be made openly available and demonstrate its use for therapeutic hypothesis generation. Methods and Results We compiled a dataset of relevant interactions from the literature along with available parameters. These were used to build a network model describing atherosclerotic plaque development. A visual map of the network model was produced using the Systems Biology Graphical Notation (SBGN) and a dynamic mathematical description of the network model that enables us to simulate plaque growth was developed and is made available using the Systems Biology Markup Language (SBML). We used this model to investigate whether multi-drug therapeutic interventions could be identified that stimulate plaque regression. The model produced comprised 20 cell types and 41 proteins with 89 species in total. The visual map is available for reuse and refinement using the SBGN Markup Language standard format and the mathematical model is available using the SBML standard format. We used a genetic algorithm to identify a multi-drug intervention hypothesis comprising five drugs that comprehensively reverse plaque growth within the model. Conclusions We have produced the first predictive mathematical and computational model of atherosclerosis that can be reused and refined by the cardiovascular research community. We demonstrated its potential as a tool for future studies of cardiovascular disease by using it to identify multi-drug intervention hypotheses. Subject Codes Atherosclerosis, Computational Biology, Lipids and Cholesterol, Cell Signaling/Signal Transduction, Cardiovascular Disease