A low glycaemic load breakfast can attenuate cognitive impairments observed in middle aged obese females with impaired glucose tolerance.

BACKGROUND AND AIMS: There has been no systematic investigation of the individual and combined effects of impaired glucose tolerance (IGT) and obesity on cognitive function in the absence of ageing. The aims were to examine the effects of IGT and increased waist circumference on cognitive function in ostensibly healthy adults, and to investigate whether a low glycaemic load (GL) breakfast can attenuate cognitive impairments in these populations. METHODS AND RESULTS: Sixty five females aged 30-50 years were classified into one of four groups following waist circumference (WC) measurements and an oral glucose tolerance test: NGT/low WC (n = 25), NGT/high WC (n = 22), IGT/low WC (n = 9), IGT/high WC (n = 9). Memory, psychomotor and executive functions were examined 30 and 120 min after consuming low GL, high GL and water breakfasts according to a randomised, crossover, counterbalanced design. IGT was associated with impairment of verbal and spatial memory, and psychomotor function relative to females with NGT, independent of waist circumference. Increased waist circumference was associated with impairment of verbal memory and executive function relative to females with low WC, independent of IGT. Consumption of the LGL breakfast attenuated verbal memory impairment in the IGT/high WC group relative to the HGL breakfast and no energy control. CONCLUSION: Increased central adiposity and abnormalities in glucose tolerance preceding type 2 diabetes can have demonstrable negative effects on cognitive function, even in ostensibly healthy, middle-aged females. The potential for GL manipulations to modulate glycaemic response and cognitive function in type 2 diabetes and obesity merits further investigation.

Multi-photon UV photolysis of gaseous polycyclic aromatic hydrocarbons: extinction spectra and dynamics.

The extinction spectra of static naphthalene and static biphenylene vapor, each buffered with a noble gas at room temperature, were measured as a function of time in the region between 390 and 850 nm after UV multi-photon laser photolysis at 308 nm. Employing incoherent broadband cavity enhanced absorption spectroscopy (IBBCEAS), the spectra were found to be unstructured with a general lack of isolated features suggesting that the extinction was not solely based on absorption but was in fact dominated by scattering from particles formed in the photolysis of the respective polycyclic aromatic hydrocarbon. Following UV multi-photon photolysis, the extinction dynamics of the static (unstirred) closed gas-phase system exhibits extraordinary quasi-periodic and complex oscillations with periods ranging from seconds to many minutes, persisting for up to several hours. Depending on buffer gas type and pressure, several types of dynamical responses could be generated (classified as types I, II, and III). They were studied as a function of temperature and chamber volume for different experimental conditions and possible explanations for the oscillations are discussed. A conclusive model for the observed phenomena has not been established. However, a number of key hypotheses have made based on the measurements in this publication: (a) Following the multi-photon UV photolysis of naphthalene (or biphenylene), particles are formed on a timescale not observable using IBBCEAS. (b) The observed temporal behavior cannot be described on basis of a chemical reaction scheme alone. (c) The pressure dependence of the system's responses is due to transport phenomena of particles in the chamber. (d) The size distribution and the refractive indices of particles are time dependent and evolve on a timescale of minutes to hours. The rate of particle coagulation, involving coalescent growth and particle agglomeration, affects the observed oscillations. (e) The walls of the chamber act as a sink. The wall conditions (which could not be quantitatively characterized) have a profound influence on the dynamics of the system and on its slow return to an equilibrium state.

Soluble P-selectin levels, P-selectin polymorphisms and cardiovascular disease.

P-selectin is a member of the selectin family of cell adhesion molecules which are important in the transient attachment of leukocytes to endothelial cells and platelets. A number of polymorphisms in the gene encoding P-selectin have been identified. Objectives were to investigate the relationship of soluble P (sP)-selectin with P-selectin gene polymorphisms and coronary artery disease (CAD). Two hundred and forty-nine patients, with extent of CAD characterized by >or=50% stenosis in one or more coronary arteries, and 252 healthy controls were studied. Soluble P-selectin was significantly higher in the patients than controls after adjustment for age, sex and smoking [patients 49.8 (47.5-52.1) ng mL-1; controls 46.7 (44.5-49.1) ng mL-1, P = 0.03). There was no association of sP-selectin with myocardial infarction (MI) or presence of >or=50% stenosis. The -1817 T/C, -1969 G/A and -2123 C/G (but not the Thr715Pro) polymorphisms were in strong linkage disequilibrium. The Thr715Pro polymorphism was significantly associated with sP-selectin even after adjustment for covariates [TT 48.9 (46.9-50.0) ng mL-1; TP + PP 40.7 (38.1-43.6) ng mL-1, P < 0.0001]. A significant interaction of Thr715Pro and smoking status was identified in the determination of sP-selectin levels. There was no significant association of genotype at any of the polymorphism in relation to MI or stenosis. The Thr715Pro polymorphisms is associated with plasma sP-selectin. This association is modulated by smoking, although the underlying mechanism remains unclear.

Genetic contribution to circulating levels of hemostatic factors in healthy families with effects of known genetic polymorphisms on heritability.

Levels of fibrinogen, factor VII (FVII), factor XIII (FXIII), plasminogen activator inhibitor (PAI)-1, and tissue plasminogen activator have been associated with coronary artery disease as have genetic polymorphisms. Quantitative genetic analyses allow determination of the genetic contribution to phenotypic variation. We investigated familial influences on these hemostatic factors in 537 adults from 89 randomly ascertained healthy families of white North European origin. We used maximum likelihood analysis to estimate the heritabilities of these factors and effects of covariates on the factors in these families. After adjustment for age and sex, the factors showed considerable heritability, varying from 26% (PAI-1) to 47% (FXIII complex). The influence of known polymorphisms was negligible for fibrinogen and contributed 2% to the variance of the FXIII complex and PAI-1 and 11% to the variance of FVII coagulant activity. Age, sex, body mass index, lifestyle, and metabolic covariates explained between 10% (FXIII) and 44% (PAI-1) of phenotypic variance. Childhood household influences significantly affected FVII (11%) and FXIII (18%). A significant degree of phenotypic variance of several hemostatic factors can be explained by additive genes and known covariates. The impact of certain well-characterized polymorphisms to the heritability is small in this population of healthy families, indicating the need to localize new genes influencing hemostatic factor levels.

Heritability of features of the insulin resistance syndrome in a community-based study of healthy families.

AIMS: To investigate genetic and environmental influences on anthropometric, metabolic and fibrinolytic traits of the insulin resistance syndrome (IRS) in a population not characterized by a high degree of insulin resistance. METHODS: We recruited 537 adults from 89 randomly ascertained healthy families of white north European origin from the general population. We used maximum likelihood analysis to estimate the heritabilities and effects of environmental covariates on traits of the IRS in these families. RESULTS: Adjusted for age, sex and body mass index, the traits showed considerable heritability. For waist-hip ratio, heritability was 15%. The heritabilities of fasting glucose, insulin and estimated insulin resistance were 20%, 23% and 23%, respectively. Heritabilities were 20%, 24% and 43% for triglycerides, LDL-cholesterol and HDL-cholesterol, respectively. For PAI-1 Ag and t-PA Ag they were 20% and 26%. Covariates explained 20-25% of the variance of lipids and insulin resistance and 35-36% of fibrinolytic factors. Childhood household influences significantly affected variance for waist-hip ratio (4%), fasting insulin (11%) and estimated insulin resistance (12%). CONCLUSIONS: These family data demonstrate significant genetic influence on anthropometric, fibrinolytic and glucose-related traits of the IRS in a healthy white North European population.

Coagulation factor XIII and cardiovascular disease in UK Asian patients undergoing coronary angiography.

Possession of the coagulation factor XIII Val34Leu (FXIIIVal34Leu) polymorphism is associated with protection against myocardial infarction (MI) in Caucasians, in the absence of features of insulin resistance. The role of this polymorphism in the UK Asian population, with its high prevalence of insulin resistance and ischaemic heart disease, is unknown. We investigated the frequency of genotypes at this polymorphism, and measures of circulating FXIII in a group of UK Asians attending for coronary angiography. Genotype at the FXIIIVal34Leu polymorphism was not associated with MI. FXIII B-subunit levels correlated with waist: hip ratio (r = 0.19, p <0.005), HbA1c (r = 0.18, p <0.05), fasting triglycerides (r = 0.21, p <0.005), total cholesterol (r = 0.29, p <0.0005) and PAI-1 antigen (r = 0.24, p <0.005). An association between FXIIIVal34Leu and FXIII cross-linking activity was confirmed in these subjects (one-way ANOVA p <0.0005). This evidence does not support the hypothesis that FXIIIVal34Leu is protective against MI in the UK Asian population. FXIII B-subunit levels are strongly linked to risk factors for cardiovascular disease, suggesting an underlying association with insulin resistance.

Apolipoprotein E polymorphism in cerebrovascular disease.

OBJECTIVES: The aim of this study was to investigate the relationship between the apo E genotype with acute cerebral infarction and primary intracerebral haemorrhage and to examine the relationship of the apo E genotype with mortality following acute stroke. MATERIALS AND METHODS: We studied 592 cases of acute stroke and 289 healthy control subjects clinically free of cerebrovascular disease. Pathological type of stroke was determined by cranial computed tomography and the subtype of cerebral infarction classified according to the Oxfordshire Community Stroke Project Classification (OCSP). Apo E genotype was determined using polymerase chain reaction. RESULTS: There was no difference in apo E genotype frequency between cases and controls (chi2 = 3.58, 5 d.f., P = 0.60). Apo E genotypes were not related to the pathological type of stroke (cerebral infarction, CI, n = 532 and primary intracranial haemorrhage, PICH, n = 60, (chi2 =3.738, 4 d.f., P=0.44) nor with the Oxfordshire Community Stroke Project Classification subtypes of cerebral infarction, lacunar infarction, LACI (n = 169), total anterior circulation infarction, TACI (n = 117), partial anterior circulation infarction, PACI (n = 173), posterior circulation infarction, POCS (n = 54) and including those cerebral infarcts which could not be classified (n= 19), chi2 =31.1, 20 d.f., P=0.153). At the time of the analysis, 243 cases (41.0%) had died. The median follow-up (including death) was 851 days. There was no relationship between time to death and apo E genotype in cases of either CI or PICH. CONCLUSION: In this population, there was no relationship between the apolipoprotein E polymorphism and the pathogenesis of cerebral infarction or primary intracerebral haemorrhage. Apo E genotype was not related to all-cause mortality following stroke.

Subunit antigen and activity levels of blood coagulation factor XIII in healthy individuals. Relation to sex, age, smoking, and hypertension.

Factor (F) XIII covalently cross-links and stabilizes the fibrin-clot. Recent evidence suggests a role for FXIII in atherothrombotic diseases, but no information is available regarding the association of FXIII with common risk factors. The aim of this study was to investigate the relationship of FXIII with age, sex, smoking, and hypertension. Plasma levels of FXIII A-subunit antigen, FXIII B-subunit antigen, and FXIII cross-linking activity were measured in 612 healthy individuals (250 men and 362 women). FXIII A- and B-subunit levels were correlated significantly with age in both men (r=0.21, P=0.001, and r=0.17, P=0.008, respectively) and women (r=0.20, P<0.0005, and r=0.13, P=0.011, respectively). FXIII B-subunit levels and activity were correlated significantly with FXIII A-subunit levels (r=0.60, P<0.0005, and r=0.14, P<0.0005, respectively) and fibrinogen (r=0.26, P<0.0005, and r=0.14, P=0.001, respectively). Women had higher levels of FXIII A-subunit (111.8% versus 105.2%, P<0.01) and B-subunit (109.5% versus 103.8%, P<0.01) than did men. FXIII A-subunit was significantly increased in smokers (117.0% versus 104.6%, P<0.0005) and in subjects with hypertension (114.9% versus 107.8%, P<0.05). In a multiple regression model, FXIII A-subunit was significantly increased by female sex (+6.4%, P<0.007), smoking (+12.3%, P<0.0005), and increasing age (+3.7% per 10 years, P<0.0005). FXIII B-subunit was significantly related to female sex and fibrinogen, and FXIII activity was significantly related to fibrinogen levels. In conclusion, the FXIII A-subunit level increases significantly with female sex, age, and smoking, whereas FXIII B-subunit and FXIII activity are associated with FXIII A-subunit level and fibrinogen. Although evidence for a causal relationship between FXIII A-subunit and vascular disease is not available, these results might suggest a role for elevated FXIII A-subunit levels in the pathogenesis of vascular disease.

Association of a common polymorphism in the factor XIII gene with venous thrombosis.

We have shown an association between a common mutation in the factor XIII a-subunit gene, coding for an amino acid change, 3 amino acids from the thrombin activation site (factor XIII Val34Leu) that may protect against myocardial infarction and predisposes to intracranial hemorrhage. To investigate the possible role of factor XIII Val34Leu in the pathogenesis of venous thromboembolism (VTE) and potential interactions with factor V Leiden (FV:Q506) and prothrombin G --> A 20210, we studied 221 patients with a history of VTE and 254 healthy controls. Patients with VTE showed an increased frequency of the FXIII Val/Val genotype (63% v 49%) and a lower frequency of the Val/Leu genotype (31% v 42%) than controls (P =. 007). FV:Q506 heterozygotes were more frequent in VTE patients (11%) than controls (5%; P =.04). The prothrombin G --> A 20210 mutation was present in only 3 patients and no controls (P =.10). In a logistic regression model for a history of VTE, the odds ratio (95% confidence interval) for FXIII Val/Leu or Leu/Leu genotype was 0.63 (0.38 to 0.82) and for possession of FV:Q506 2.40 (1.17 to 4.90). There was no evidence for an interaction between factor XIII Val34Leu genotype and FV:Q506, prothrombin G --> A 20210, sex, or age. It is concluded that possession of the Leu allele at factor XIII Val34Leu is protective against deep venous thrombosis.

Fibrinolytic measurements in type 2 diabetic patients with acute cerebral infarction.

The aim of this study was to investigate disturbances in fibrinolytic components in Type 2 diabetes patients with acute ischaemic stroke. Levels of plasminogen activator inhibitor-1 (PAI-1) activity and tissue PA (t-PA) antigen were measured in Type 2 diabetes subjects with (n=40) and without (r=80) acute stroke compared to non-diabetic subjects with (n=80) and without (n=80) acute ischaemic stroke. Diabetes was defined by WHO criteria and absence of diabetes by blood glucose <7.8 mmol(-1) and HbA(IC) <6% (reference range for assay 4.5-6.5%). Levels of t-PA antigen were lower in healthy controls (9.2 ng ml(-1) than in either stroke group (non-diabetic stroke patient: 12.6 ng ml(-1); diabetic patient with stroke: 13.5 ng ml(-1)(each at p<0.05)) and intermediate in diabetic patients without stroke (11.1 ng ml(-1), ns). In a regression model levels of t-PA were related to stroke, BMI and age but not to diabetes or sex. Diabetic subjects without stroke had higher PAI-1 activity levels than either non-diabetic group (17.7 U ml(-1) vs 12.1 U ml(-1) and 9.2 U ml(-1) (each at p<0.05)). Levels were intermediate in diabetic subjects with stroke (12.8 U ml(-1), ns). In a regression model levels of PAI-1 were related to Type 2 diabetes, female sex, and body mass index but not stroke or age. These data suggest that further suppression of fibrinolysis does not occur with ischaemic stroke in Type 2 diabetes. The findings contrast with the importance of impaired fibrinolysis in coronary artery disease previously reported in both Type 2 diabetic patients and non-diabetic subjects.

Polymorphisms of platelet glycoproteins in relation to macrovascular disease in type 2 diabetes mellitus.

We set out to determine the genotype distributions of the PI(A) polymorphism of platelet glycoprotein IIIa, the HPA-3 polymorphism of platelet glycoprotein IIb, and the variable number tandem repeat (VNTR) polymorphism of platelet glycoprotein Ib in subjects with Type 2 diabetes mellitus (Type 2 DM) with (n = 125) and without (n = 90) a clinical history of macrovascular disease. In 215 white European subjects with Type 2 DM, presence of coronary artery disease was determined as a clinical history of angina, myocardial infarction (MI), coronary angioplasty or coronary artery by-pass grafting. Presence of peripheral vascular disease was defined as a clinical history of intermittent claudication with confirmatory vascular ultrasound or angiography, intermittent claudication with undetectable foot pulses and no history of arthralgia or surgery for leg ischaemia, confirmed by reference to medical case notes. Polymorphisms were detected by polymerase chain reaction amplification of DNA. There was no difference in the genotype distributions of subjects with and without macrovascular disease. In subjects with a first MI before the age of 60 years (n = 26), there was a 38% incidence of PI(A2) compared to 29% in subjects free from clinically evident macrovascular disease, but this difference did not reach statistical significance. This study does not support the hypothesis that polymorphisms of platelet glycoproteins, in particular the PI(A) polymorphism of platelet glycoprotein IIIa, play an important role in the pathogenesis of macrovascular disease in subjects with Type 2 DM.

Soluble vascular cell adhesion molecule-1 and E-selectin levels in relation to vascular risk factors and to E-selectin genotype in the first degree relatives of NIDDM patients and in NIDDM patients.

To investigate the metabolic and genetic associations of levels of soluble adhesion molecules, plasma levels of soluble E-selectin and vascular cell adhesion molecule-1 were measured in 60 non-insulin-dependent diabetes mellitus (NIDDM) patients, 60 first-degree relatives of NIDDM patients and 60 control subjects, none of whom displayed clinical features of vascular disease. In addition, E-selectin A561C genotype, coding for a serine to arginine change, was determined. E-selectin levels were elevated in the patient group; 57 [52-63] (mean [95% confidence intervals]) ng/ml, compared with both relatives; 44 [39-50] ng/ml p = 0.001 and controls 39.5 [36-43] ng/ml p = 0.0001. E-selectin levels correlated with triglycerides, tissue-plasminogen activator and plasminogen activator inhibitor-1 activity in all groups. Levels of E-selectin were related to E-selectin genotype, being higher in subjects possessing the arginine allele (51.4 vs 44.5 ng/ml p < 0.05). E-selectin levels were higher in males than females in controls (female 35 [32-39] vs male 45 [40-51] ng/ml p = 0.004), and NIDDM relatives (female 38 [33-44] vs male 52 [45-61] ng/ml p = 0.004) but not in NIDDM patients where levels were similar (female 58 [49-69] vs male 56 [50-62] ng/ml, ns). There was no difference in soluble vascular cell adhesion molecule-1 levels between the three groups (control 640 [598-686] ng/ml, NIDDM relatives 634 [593-678] ng/ml and NIDDM patients 664 [608-725] ng/ml). In controls and patients vascular cell adhesion molecule-1 levels correlated with von Willebrand factor (vWF). The results indicate that levels of E-selectin relate to vascular risk factors in control subjects, NIDDM relatives and NIDDM patients.

Angiotensin-converting enzyme (ACE) gene polymorphisms in patients characterised by coronary angiography.

The angiotensin converting enzyme (ACE) gene is implicated as a risk factor for coronary artery disease and myocardial infarction (MI). An insertion/deletion (I/D) polymorphism is believed to be in linkage disequilibrium with a functional site elsewhere. Ten polymorphisms have recently been identified in the ACE gene. We screened patients undergoing coronary angiography (n = 258) for six of these polymorphisms (T-5491C, T-93C, A-240T, T1237C, D/I and 4656(CT)2/3), and identified a further two rare polymorphisms. ACE levels were associated with genotype for all polymorphisms analysed individually by one way ANOVA (P < 0.0005). The polymorphisms occurring in the 5' region were in negative linkage disequilibrium with the exonic and 3' region polymorphisms. The A-240T polymorphism had the greatest association with ACE levels (R2 = 14%); none of the others were significantly associated with levels when adjustment was made for A-240T. None of the polymorphisms were associated with the extent of coronary atheroma. Two of the promoter polymorphisms (A-240T and T-93C) were weakly related to the occurrence of MI (P = 0.03 and P = 0.05, respectively, by chi 2 analysis). The TT genotype of A-240T appeared to be protective against MI with an odds ratio of 0.31 (95% confidence interval, 0.12, 0.83). These findings indicate that polymorphisms in the ACE gene promoter region may have a stronger association with disease than the I/D polymorphism.