The motherhood choices decision aid for women with rheumatoid arthritis increases knowledge and reduces decisional conflict: a randomized controlled trial.

BACKGROUND: For many women with Rheumatoid Arthritis (RA) motherhood decisions are complicated by their condition and complex pharmacological treatments. Decisions about having children or expanding their family require relevant knowledge and consultation with their family and physician as conception and pregnancy has to be managed within the RA context. Relevant information is not readily available to women with RA. Therefore a randomized controlled study was conducted to evaluate the effectiveness of a new motherhood decision aid (DA) developed specifically for women with RA. METHODS: One hundred and forty-four women were randomly allocated to either an intervention or control group. All women completed a battery of questionnaires at pre-intervention, including, the Pregnancy in Rheumatoid Arthritis Questionnaire (PiRAQ), the Decisional Conflict Scale (DCS), the Hospital Anxiety and Depression Scale (HADS), and the Arthritis Self-Efficacy Scale (ASES), and provided basic demographic information. Women in the DA group were sent an electronic version of the DA, and completed the battery of questionnaires for a second time post-intervention. RESULTS: Women who received the DA had a 13 % increase in relevant knowledge (PiRAQ) scores and a 15 % decrease in scores on the decisional conflict (DCS), compared to the control group (1 %, 2 % respectively). No adverse psychological effects were detected as evident in unchanged levels of depression and anxiety symptoms. CONCLUSIONS: The findings of this study suggest that this DA may be an effective tool in assisting women with RA when contemplating having children or more children. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au/ , ACTRN12615000523505.

Optimization of pulsed DEER measurements for Gd-based labels: choice of operational frequencies, pulse durations and positions, and temperature.

In this work, the experimental conditions and parameters necessary to optimize the long-distance (≥ 60 Å) Double Electron-Electron Resonance (DEER) measurements of biomacromolecules labeled with Gd(III) tags are analyzed. The specific parameters discussed are the temperature, microwave band, the separation between the pumping and observation frequencies, pulse train repetition rate, pulse durations and pulse positioning in the electron paramagnetic resonance spectrum. It was found that: (i) in optimized DEER measurements, the observation pulses have to be applied at the maximum of the EPR spectrum; (ii) the optimal temperature range for Ka-band measurements is 14-17 K, while in W-band the optimal temperatures are between 6-9 K; (iii) W-band is preferable to Ka-band for DEER measurements. Recent achievements and the conditions necessary for short-distance measurements (<15 Å) are also briefly discussed.

Measuring perinatal mental health risk.

The purpose of this review was to critically analyse existing tools to measure perinatal mental health risk and report on the psychometric properties of the various approaches using defined criteria. An initial literature search revealed 379 papers, from which 21 papers relating to ten instruments were included in the final review. A further four papers were identified from experts (one excluded) in the field. The psychometric properties of six multidimensional tools and/or criteria were assessed. None of the instruments met all of the requirements of the psychometric properties defined. Some had used large sample sizes but reported low positive predictive values (Antenatal Risk Questionnaire (ANRQ)) or insufficient information regarding their clinical performance (Antenatal Routine Psychosocial Assessment (ARPA)), while others had insufficient sample sizes (Antenatal Psychosocial Health Assessment Tool, Camberwell Assessment of Need-Mothers and Contextual Assessment of Maternity Experience). The ANRQ has fulfilled the requirements of this analysis more comprehensively than any other instrument examined based on the defined rating criteria. While it is desirable to recommend a tool for clinical practice, it is important that clinicians are made aware of their limitations. The ANRQ and ARPA represent multidimensional instruments commonly used within Australia, developed within large samples with either cutoff scores or numbers of risk factors related to service outcomes. Clinicians can use these tools, within the limitations presented here, to determine the need for further intervention or to refer women to mental health services. However, the effectiveness of routine perinatal psychosocial assessment continues to be debated, with further research required.

Dielectric Resonator for Ka-Band Pulsed EPR Measurements at Cryogenic Temperatures: Probehead Construction and Applications.

The construction and performance of a Ka-band pulsed electron paramagnetic resonance (EPR) cryogenic probehead that incorporates dielectric resonator (DR) is presented. We demonstrate that the use of DR allows one to optimize pulsed double electron-electron resonance (DEER) measurements utilizing large resonator bandwidth and large amplitude of the microwave field B1 . In DEER measurements of Gd-based spin labels, use of this probe finally allows one to implement the potentials of Gd-based labels in distance measurements. Evidently, this DR is well suited to any applications requiring large B1-fields and resonator bandwidths, such as electron spin echo envelope modulation spectroscopy of nuclei having low magnetic moments and strong hyperfine interactions and double quantum coherence dipolar spectroscopy as was recently demonstrated in the application of a similar probe based on an loop-gap resonator and reported by Forrer et al. (J Magn Reson 190:280, 2008).

An integrative collaborative care model for people with mental illness and physical comorbidities.

BACKGROUND: Many individuals with mental health problems have comorbid physical conditions, or may present with substance/alcohol misuse or abuse issues. This results in complex treatment challenges that may not be adequately addressed by a model of care that is solely delivered by an individual clinician using a sole intervention. Mainstream pharmacotherapeutic treatment of mental health problems often have limited effectiveness in completely resolving symptoms, and may cause adverse side effects. Adjunctive treatment approaches, including nutraceuticals, lifestyle and behaviour change interventions, are widely used to assist with treatment of mental health problems. However, whilst these can be generally safer with fewer side effects, they have varying levels of evidentiary support. These circumstances warrant reframing the current treatment approach towards a more evidence-based integrative model which may better address the real-world challenges of psychiatric disorders and comorbid physical conditions. In essence, this means developing an integrative model of care which embodies an evidence-informed, personalized stepwise approach using both conventional pharmacological treatments alongside novel adjunctive treatments (where applicable) via the application of a collaborative care approach. DISCUSSION: In order to inform this position, a brief review of findings on common patterns of comorbidity in mental illness is presented, followed by identification of limitations of conventional treatments, and potential applications of integrative medicine interventions. Advantages and challenges of integrative mental health care, collaborative models of care, review of research highlights of select integrative approaches, and comment on potential cost advantages are then discussed. We propose that a collaborative care model incorporating evidence-based integrative medicine interventions may more adequately address mental health problems with comorbid medical conditions. Robust research is now required of such a model, potentially within an integrative clinical practice.

A chronic 1 year assessment of MRI contrast agent-labelled neural stem cell transplants in stroke.

Non-invasive identification of transplanted neural stem cells in vivo by pre-labelling with contrast agents may play an important role in the translation of cell therapy to the clinic. Understanding the impact of these labels on the cells' ability to repair is therefore vital. In rats with middle cerebral artery occlusion (MCAo), a model of stroke, the transhemispheric migration of MHP36 cells labelled with the bimodal contrast agent GRID was detected on magnetic resonance images (MRI) up to 4 weeks following transplantation. However, compared to MHP36 cells labelled with the red fluorescent dye PKH26, GRID-labelled transplants did not significantly improve behaviour, and performance was akin to non-treated animals. Likewise, the evolution of anatomical damage as assessed by serial, T(2)-weighted MRI over 1 year indicated that GRID-labelled transplants resulted in a slight increase in lesion size compared to MCAo-only animals, whereas the same, PKH26-labelled cells significantly decreased lesion size by 35%. Although GRID labelling allows the in vivo identification of transplanted cells up to 1 month after transplantation, it is likely that some is gradually degraded inside cells. The translation of cellular imaging therefore does not only require the in vitro assessment of contrast agents on cellular functions, but also requires the chronic, in vivo assessment of the label on the stem cells' ability to repair in preclinical models of neurological disease.

Looking deeper into vertebrate development.

Magnetic resonance imaging (MRI) is a non-invasive imaging method that provides three-dimensional (3-D) images of the internal structure of opaque objects, such as humans and mice. In optimal situations, spatial resolution can approach the micron level. Arbitrarily oriented single-slice images can be obtained in seconds, with full 3-D volume images taking tens of minutes to collect. The exquisite sensitivity of MRI to the local physical and chemical environment provides a wide range of mechanisms giving rise to intrinsic contrast in the MR experiment, thus providing images with dramatic differences between different tissue types (e.g. white vs grey matter, myelinated vs unmyelinated fibres, and brain parenchyma vs ventricles). The recent advent of physiologically sensitive MRI contrast agents opens up a wealth of new avenues of study, even including the in vivo imaging of gene expression.

Long-term effects of hemostatic variables on fatal coronary heart disease: 30-year results from the first prospective Northwick Park Heart Study (NPHS-I).

BACKGROUND: The long-term associations of established risk factors for coronary heart disease (CHD), for example cholesterol, are well known, but not for the less familiar hemostatic variables. OBJECTIVES: To establish whether associations between hemostatic variables and CHD first identified nearly three decades ago have persisted long-term. METHODS: The first Northwick Park Heart Study (NPHS-I) recruited 2167 white men and 941 white women, average age at entry 48 years, on whom measures of factor (F) VII activity (VIIc) and plasma fibrinogen were carried out, both at entry and at follow-up approximately 6 years later. RESULTS: During a median follow-up of 29 years, 231 male and 36 female CHD deaths were recorded from notifications by the Office for National Statistics. VIIc at recruitment was significantly related to CHD mortality, corrected rate ratio, RR, per 1 SD increase 1.56 (95% CI 1.29, 1.88) in men and RR 1.78 (95% CI 1.17, 2.72) in women. Recruitment fibrinogen was also strongly related to CHD mortality in men, RR 1.63 (95% CI 1.33, 1.99) but not in women, RR 0.75 (95% CI 0.40, 1.43). The associations persisted after controlling for confounders and were confirmed using 6-year follow-up measurements and in analyses omitting deaths within 10 years of recruitment. CONCLUSIONS: The hemostatic system contributes to CHD mortality, and its effect is stable over time. For VIIc, the effect was similar in men and women, while for fibrinogen it appeared to be present only in men.

In vivo visualization of gene expression using magnetic resonance imaging.

High-resolution in vivo imaging of gene expression is not possible in opaque animals by existing techniques. Here we present a new approach for obtaining such images by magnetic resonance imaging (MRI) using an MRI contrast agent that can indicate reporter gene expression in living animals. We have prepared MRI contrast agents in which the access of water to the first coordination sphere of a chelated paramagnetic ion is blocked with a substrate that can be removed by enzymatic cleavage. Following cleavage, the paramagnetic ion can interact directly with water protons to increase the MR signal. Here, we report an agent where galactopyranose is the blocking group. This group renders the MRI contrast agent sensitive to expression of the commonly used marker gene, beta-galactosidase. To cellular resolution, regions of higher intensity in the MR image correlate with regions expressing marker enzyme. These results offer the promise of in vivo mapping of gene expression in transgenic animals and validate a general approach for constructing a family of MRI contrast agents that respond to biological activity.

Associations of plasma fibrinogen and factor VII clotting activity with coronary heart disease and stroke: prospective cohort study from the screening phase of the Thrombosis Prevention Trial.

BACKGROUND: As with 'conventional' risk factors such as cholesterol and smoking, there is a need for large, long-term prospective studies on hemostatic factors. OBJECTIVES: To investigate the prospective relationship of fibrinogen and factor VII clotting activity (FVIIc) with risk of coronary heart disease (CHD) and stroke in a study with a large number of outcomes over a period of 15 years. PATIENTS/METHODS: A cohort of 22 715 men aged 45-69 years was screened for participation in the Thrombosis Prevention Trial. Men were followed up for fatal and non-fatal CHD and stroke events. There were 1515 CHD events (933 CHD deaths) and 391 strokes (180 stroke deaths). Hazard ratios (HRs) and 95% confidence intervals are expressed per standardized increase in log fibrinogen and log FVIIc, adjusting for age, trial treatment group, conventional CHD risk factors and regression dilution bias. RESULTS: Hazard ratios for fibrinogen were 1.52 (1.37-1.70) for all CHD events, and 1.36 (1.09-1.69) for all strokes. Exclusion of events within the first 10 years showed a persistent association between CHD and fibrinogen, with an adjusted HR of 1.93 (1.42-2.64). The HRs for FVIIc, adjusting for age and trial treatment, were 1.07 (1.01-1.12) for all CHD events and 1.07 (0.97-1.20) for all strokes, and the fully adjusted HRs were, respectively, 0.97 (0.84-1.05) and 1.07 (0.85-1.33). CONCLUSIONS: The persisting association between fibrinogen and CHD beyond 10 years may imply a causal effect. There is a small effect of FVIIc on CHD, after adjustment for age and trial treatment, but no association independent of other risk factors.

Gd(III) complexes as paramagnetic tags: Evaluation of the spin delocalization over the nuclei of the ligand.

Complexes of the Gd(III) ion are currently being established as spin labels for distance determination in biomolecules by pulse dipolar spectroscopy. Because Gd(III) is an f ion, one expects electron spin density to be localized on the Gd(III) ion - an important feature for the mentioned application. Most of the complex ligands have nitrogens as Gd(III) coordinating atoms. Therefore, measurement of the (14)N hyperfine coupling gives access to information on the localization of the electron spin on the Gd(III) ion. We carried out W-band, 1D and 2D (14)N and (1)H ENDOR measurements on the Gd(III) complexes Gd-DOTA, Gd-538, Gd-595, and Gd-PyMTA that serve as spin labels for Gd-Gd distance measurements. The obtained (14)N spectra are particularly well resolved, revealing both the hyperfine and nuclear quadrupole splittings, which were assigned using 2D Mims ENDOR experiments. Additionally, the spectral contributions of the two different types of nitrogen atoms of Gd-PyMTA, the aliphatic N atom and the pyridine N atom, were distinguishable. The (14)N hyperfine interaction was found to have a very small isotropic hyperfine component of -0.25 to -0.37MHz. Furthermore, the anisotropic hyperfine interactions with the (14)N nuclei and with the non-exchangeable protons of the ligands are well described by the point-dipole approximation using distances derived from the crystal structures. We therefore conclude that the spin density is fully localized on the Gd(III) ion and that the spin density distribution over the nuclei of the ligands is rightfully ignored when analyzing distance measurements.

Comparison of novel hemostatic factors and conventional risk factors for prediction of coronary heart disease.

BACKGROUND: This study sought to assess whether novel markers of hemostatic activity are predictive of coronary heart disease (CHD) and improve risk assessment. METHODS AND RESULTS: Conventional CHD risk factors, the activation peptides of factor IX and factor X, factor VII activity and antigen, activated factor XII, prothrombin fragment 1+2, fibrinopeptide A, and fibrinogen were measured in 1153 men aged 50 to 61 years who were free of myocardial infarction at recruitment. Activated factor VII (VIIa) was measured in 829 men. During 7.8 years of follow-up, 104 had a CHD event. Baseline status was related to outcome by logistic regression by using a modified nested case-control design. Screening performance was judged from receiver operating characteristic curves. A high activated factor XII was associated with increased CHD risk, but low levels were not protective. Plasma VIIa and factor X activation peptide were independently and inversely related to risk. Plasma factor IX activation peptide and fibrinogen were positively associated with risk, but the relations were no longer statistically significant after adjustment for other factors, including VIIa and apoA-I. Other hemostatic markers were not associated with CHD risk. CONCLUSIONS: Hemostatic status did not add significant predictive power to that provided by conventional CHD risk factors yet was able to substitute effectively for these factors.

Stretching and breaking duplex DNA by chemical force microscopy.

BACKGROUND: Specific interactions between complementary strands of DNA and other molecules are central to the storage, retrieval and modification of information in biological systems. Although in many cases the basic structures of duplex DNA and the binding energetics have been well characterized, little information is available about the forces in these systems. These forces are of critical importance because they must be overcome, for example, by protein machines during transcription and repair. Recent developments in atomic force microscopy make possible direct measurements of such forces between the individual oligonucleotide strands that form DNA duplexes. RESULTS: We used the chemical force microscopy technique, in which oligonucleotides are covalently linked to the force microscope probe tip and the sample surface, to measure the elongation and binding forces of individual DNA duplexes. The separation forces between complementary oligonucleotide strands were found to be significantly larger than the forces measured between noncomplementary strands, and to be consistent with the unbinding of a single DNA duplex. With increasing applied force, the separation of complementary strands proceeded in a stepwise manner: B-form DNA was stretched, then structurally transformed to a stable form of DNA approximately twice the length of the B form, and finally separated into single-stranded oligonucleotides. These data provide a direct measurement of the forces required to elastically deform and separate double-stranded DNA into single strands. CONCLUSIONS: Force microscopy provides a direct and quantitative measurement of the forces and energetics required to stretch and unbind DNA duplexes. Because the measurements can be carried out readily on synthetic oligonucleotides and in the presence of exogenous molecules, this method affords an opportunity for directly assessing the energetics of distorting and unbinding specific DNA sequences and DNA complexes. Such data could provide unique insights into the mechanistic steps following sequence-specific recognition by, for example, DNA repair and transcription factors.

Receptor-targeted co-transport of DNA and magnetic resonance contrast agents.

BACKGROUND: Ligand molecules conjugated to polylysine can be electrostatically bound to DNA and can bind receptors or antigens on the surface of cells, delivering the DNA into specific cells and tissues. Several researchers have used this approach to generate non-viral vehicles for the efficient delivery of DNA to specific cells. We have attempted to adopt this general approach to the cell-specific delivery of magnetic contrast agents for use in magnetic resonance imaging (MRI). RESULTS: We have synthesized a new class of agents capable of both transfecting genes into cells and enhancing the contrast of the targeted cells for MRI. DNA is used both to encode a marker gene and as a molecular scaffold, which electrostatically binds polylysine conjugated to transferrin, an iron uptake protein, and polylysine modified with gadolinium chelated to diethylenetriaminepetaacetic acid. When cells displaying the transferrin receptor are treated with these particles, high levels of gene expression are observed, higher than with control particles composed only of transferrin, polylysine and DNA. The treated cells show specific MRI contrast enhancement, which did not require expression of the marker gene. CONCLUSIONS: The development of this class of particles permits the use of novel protocols by which genes for genetic therapy and agents for MRI contrast are co-transported. These protocols may allow non-invasive MRI monitoring of DNA delivery for gene therapy in real time.

Minimum effective intensity of oral anticoagulant therapy in primary prevention of coronary heart disease.

BACKGROUND: There is mounting evidence that low-intensity oral anticoagulation is effective, particularly in primary prevention of thrombosis, with important implications for safety and the practicalities of using warfarin. Because it is desirable to know possible benefits for different indications so that optimal therapy can be administered in as wide a range of conditions as possible, we analyzed data from the Thrombosis Prevention Trial, a factorial trial that compared treatment with low-intensity, dose-adjusted warfarin and low-dose aspirin separately and together, to determine the minimum effective intensity of oral anticoagulation in the primary prevention of coronary heart disease. METHODS: The international normalized ratio (INR) most recent to an event and overall time at each INR were used to calculate the INR-related event rate for coronary events, strokes, and major and minor bleeding episodes in 2545 men receiving warfarin with or without aspirin (75 mg/d) and followed up for a total of 9952 person-years. RESULTS: Compared with placebo, warfarin alone at a dose that maintained the INR at 1.4 or more significantly reduced the risk of a coronary event by 47% (95% confidence interval, 4%-70%; P =.03), whereas the risk of a coronary event was not reduced at INRs below 1. 4. Coronary events, strokes, and major bleeding episodes combined were significantly reduced by 45% (95% confidence interval, 9%-67%; P =.02) in the warfarin group compared with the placebo group when the INR was 1.4 or more. Minor bleeding episodes increased as the INR rose above about 2.0. No significant association of INR with coronary events was observed with combined warfarin and aspirin, possibly reflecting the small number of such events that occurred in this group, therefore limiting the power to detect an association with INR. CONCLUSIONS: Warfarin alone is effective in the primary prevention of coronary heart disease when the dose is adjusted to maintain an INR of 1.4 or more. The results add to the evidence that low-intensity, dose-adjusted oral anticoagulation is effective for a range of conditions.

Hypercoagulability and ischaemic heart disease.

Thrombogenesis is increasingly recognised as an immediate cause of most major clinical episodes of ischaemic heart disease (IHD) and the haemostatic system makes a significant contribution to the development of atheroma. It is therefore important to consider how far concepts of increased thrombotic tendency and hypercoagulability can be demonstrated in reality. A number of general observations do suggest that characteristics of the circulating blood influence the course of events in IHD--for example, the occurrence of IHD or stroke in young women using oral contraceptives in whom advanced arterial wall changes are not a feature. Epidemiologically, the coagulation system has been more rewarding than the study of platelets. The Northwick Park Heart Study (NPHS) has demonstrated a strong relationship between the level of factor VII activity and the later incidence of IHD. Several biochemical characteristics of factor VII suggest that this relationship may well be one of cause and effect. There is growing evidence that high levels of factor VII activity lead to high levels of thrombin production. In addition to NPHS, three other prospective studies have shown an association between high levels of plasma fibrinogen and IHD incidence. Again, there are several reasons for believing that this association, too, is of pathogenetic significance. Dietary fat intake is a major determinant of the factor VII activity level, and smoking of the fibrinogen level. Hypercoagulability determining IHD is best defined, on present evidence, as over-activity of procoagulatory influences (whereas hypercoagulability leading to venous thrombosis is predominantly manifested as underactivity of natural defence mechanisms).(ABSTRACT TRUNCATED AT 250 WORDS)

Increased factor VII coagulant activity in the rabbit following diet-induced hypercholesterolaemia. Evidence for increased conversion of VII to alpha VIIa and higher flux within the coagulation pathway.

Factor VII coagulant activity (VIIc) is considerably higher in rabbits fed a 1% cholesterol-supplemented diet than in rabbits fed a standard diet. This increase was statistically significant 4-6 days from the beginning of treatment and rose to about 300% during the 100 days of treatment. Treatment is also associated with a 20-fold increase in plasma cholesterol concentration with the major fraction of excess cholesterol associated with the very low and intermediate density lipoprotein fractions. In both groups of rabbits, the direction and extent of variation in VIIc generally coincided with variation in cholesterol, so that over time there were significant and positive correlations between plasma cholesterol concentration in both the rabbits fed the standard diet and the rabbits fed the cholesterol-supplemented diet. The increase in VIIc was due to a higher proportion of the more active alpha VIIa in the plasma of hypercholesterolaemic rabbits rather than to an increase in the concentration of the single-chain protein. The plasma concentration of factor X and prothrombin had increased in the hypercholesterolaemic rabbits by 10 days from the beginning of treatment and both proteins were maintained at 150-200% of the concentrations in the plasma of rabbits fed the standard diet. However, these differences were only seen when the factor X and prothrombin were assayed using synthetic substrates. The specific coagulation assays for these two factors revealed no differences between the groups of animals up to 100 days.

Plasminogen activator inhibitor-1, the acute phase response and vitamin C.

Epidemiologial studies suggest that elevated plasma plasminogen activator inhibitor-1 (PAI-1) activity is associated with ischaemic heart disease. Based on our earlier work suggesting a link between plasma fibrinogen, infection and low vitamin C status, we sought to determine whether similar relationships existed for PAI-1 activity. We performed a longitudinal study of cardiovascular disease risk factors in 96 volunteers aged 65-74 years, living in the community in Cambridge. Each subject was visited at home 7 times over a 14 month period. Plasma PAI-1 activity, serum ascorbate, markers of the acute phase response, serum lipids and other cardiovascular disease risk factors were measured on each occasion. In a multiple regression analysis, the three significant predictors of PAI-1 activity were body mass index (P = 0.0001), blood neutrophil count (P = 0.03) and, inversely, serum ascorbate (P = 0.003). The inverse relationship between PAI-1 activity and serum ascorbate persisted even when vitamin C supplement takers or smokers were excluded from the analysis. Serum ascorbate was strongly related to estimated dietary intake of vitamin C (P < 0.0001). Low serum ascorbate is associated with high PAI-1 activity which is, in turn, associated with increased ischaemic heart disease risk. We hypothesise that activation of the acute phase response by infection could increase PAI-1 activity and, consequently, also increase the risk of coronary artery thrombosis. Furthermore, we suggest that vitamin C could attenuate this response.

Genetic determinants of the response to bezafibrate treatment in the lower extremity arterial disease event reduction (LEADER) trial.

Genetic determinants of baseline levels and the fall in plasma triglyceride and fibrinogen levels in response to bezafibrate treatment were examined in 853 men taking part in the lower extremity arterial disease event reduction (LEADER) trial. Three polymorphisms in the peroxisome proliferator activated receptor alpha (PPARalpha) gene were investigated (L162V, G>A in intron 2 and G>C in intron 7), two in the apolipoprotein CIII (APOC3) gene (-482C>T and -455T>C) and one in the beta-fibrinogen (FIBB) gene (-455G>A). The presence of diabetes (n=158) was associated with 15% higher triglyceride levels at baseline compared to non-diabetics (n=654) (P<0.05). Among the diabetic group, carriers of the PPARalpha intron 7 C allele had 20% lower triglyceride levels compared to homozygotes for the common G allele (P<0.05), with a similar (non-significant) trend for the L162V polymorphism, which is in linkage disequilibrium with the intron 7 polymorphism. For the APOC3 gene, carriers of the -482T allele had 13% lower baseline triglyceride levels compared to -482C homozygotes (P<0.02), but no effect was observed with the -455T>C substitution. In the non-diabetic patients, the PPARalpha V162 allele was significantly associated with 9% higher baseline triglyceride levels (P<0.03) and a similar, but non-significant trend was seen for the intron 7 polymorphism. Overall, triglyceride levels fell by 26% with 3 months of bezafibrate treatment, and current smokers showed a poorer response compared to ex/non-smokers (23% fall compared to 28% P=0.03), but none of the genotypes examined had a significant influence on the magnitude of response. Carriers of the -455A polymorphism of the FIBB gene had, as expected, marginally higher baseline fibrinogen levels, 3.43 versus 3.36 g/l (P=0.055), but this polymorphism did not affect response to treatment. Overall, fibrinogen levels fell by 12%, with patients with the highest baseline fibrinogen levels showing the greatest decrease in response to bezafibrate. For both the intron 2 and the L162V polymorphisms of the PPARalpha gene there was a significant interaction (both P<0.01) between genotype and baseline levels of fibrinogen on the response of fibrinogen levels to bezafibrate, such that individuals carrying the rare alleles in the lowest tertile showed essentially no overall decrease compared to a 0.18 g/l fall in homozygotes for the common allele. Thus while these genotypes are a minor determinant of baseline triglyceride and fibrinogen levels, there is little evidence from this study that the magnitude of response to bezafibrate treatment in men with peripheral vascular disease is determined by variation at these loci.

Dietary and other characteristics relevant for coronary heart disease in men of Indian, West Indian and European descent in London.

The origins of the high standardized mortality ratio (SMR) for coronary heart disease (CHD) among Indians in Britain, and the low SMR for West Indian immigrants, have been explored by a community survey in London. Serum lipoproteins, plasma glucose, haemostatic factors and other putative risk characteristics were measured in 75 Indian, 64 European and 24 West Indian men aged 45-54 years. These represented 81% of men registered with a general practice and resident within a defined area. In 51 men, diet was assessed by 5-day weighed inventory. Plasma phospholipid fatty acids (PFA) were measured in 18 Indians and 19 Europeans with dietary records. The relatively high HDL and HDL2-cholesterol concentrations, low LDL-cholesterol concentration, reduced fat intake, increased ratio of dietary polyunsaturated/saturated fat, relatively frequent use of alcohol, and lack of obesity in West Indians accorded with their low SMR from CHD. By contrast, only the relatively low HDL and HDL2-cholesterol concentrations, infrequency of alcohol consumption, and lower proportion of PFA as n-3 fatty acids of marine origin afforded explanations for the high SMR of Indians. Hyperglycaemia appeared similarly prevalent in Indians and West Indians, but less common in Europeans. Of the haemostatic factors, West Indians had a relatively low VIIc (not statistically significant), while Indians had an increased platelet count and reduced platelet volume. Improved understanding of these ethnic differences in CHD mortality may depend upon elucidation of the contrasts in HDL-cholesterol concentration.