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Background Non-resolving inflammation associates with obesity and insulin resistance, and may be dependent on the balance of inflammatory substances and specialised pro-resolving mediators of inflammation (SPM) that act to halt the inflammatory response. This controlled trial examined the effect of weight loss on neutrophil synthesis of SPM in volunteers with the metabolic syndrome (MetS). Methods Volunteers with MetS (n = 42) were matched for age and gender and randomly assigned to a 12-wk weight loss program followed by 4-wk weight stabilization or a 16-wk weight maintenance program. At baseline and 16 weeks, isolated neutrophils were stimulated with calcium ionophore and the released SPM were measured by LC-MS/MS. Results At baseline the SPM resolvin (Rv) E1, 18R-RvE3, RvD2 and Maresin-1 (MaR-1) were detected from stimulated neutrophils. The concentration of released RvE1 was at least 6-fold that of other detected SPM. Weight loss of 4.7 ± 0.8 kg, led to a 2-fold increase in RvE1, P = 0.013, relative to the weight maintenance group. The increase in RvE1 after weight loss was related to, but independent of leukotriene B4. Conclusion Following weight loss, human neutrophils from individuals with the metabolic syndrome are capable of releasing larger amounts of RvE1 upon stimulation.

Objective(s) Cardiovascular disease (CVD) remains a leading cause of mortality in chronic kidney disease (CKD) patients. Interventions targeting traditional risk factors have largely proven ineffective in CKD patients in part because of the increased role of nontraditional risk factors such as chronic inflammation. Omega-3 fatty acids (ω3FA) are inexpensive and safe natural agents, which target inflammation and have potential cardioprotective benefits. The aim of the study was to determine the effects of ω3FA supplementation upon serum interleukin (IL)-12, IL-18, and highly sensitive C-reactive protein (hsCRP) in patients with Stage 3-4 CKD. Methods We performed a post-hoc analysis of a randomized placebo-controlled trial in 73 nondiabetic CKD patients to determine the effects of ω3FA supplementation (4 g daily for 8 weeks) upon serum levels of IL-12, IL-18, and hsCRP. Results There were no preintervention differences in IL-12, IL-18, or hsCRP between treatment groups. Postintervention levels of IL-12, IL-18, and hsCRP were similar between the treatment groups. However, IL-12 and IL-18 increased in both treatment groups over the intervention period, whereas hsCRP remained unchanged. The magnitude of increase in serum IL-18 (ΔIL-18) was significantly less in participants in the ω3FA treatment group compared to placebo (P = .047). Conclusion(s) This study has shown that 4 g daily ω3FA supplementation may lower serum IL-18 levels in patients with moderate CKD. Although there were no apparent effects on several other markers of inflammation, this study provides evidence for a specific effect of ω3FA on inflammatory pathways.

Background: Workforce decisions of medical students with prior tertiary education, relative to those without, are not known.Methods: Rural workforce outcomes for three separate streams of medical s...

BACKGROUND Diastolic dysfunction (DD) is an important cause of cardiovascular disease (CVD) mortality in chronic kidney disease (CKD) patients. Non-traditional risk factors, such as arterial stiffness and inflammation, are implicated in the pathogenesis of DD in CKD patients. AIM To determine the association between inflammatory markers (interleukin (IL)-12, IL-18, highly sensitive C-reactive protein (hsCRP)) and non-invasive markers of arterial stiffness (24-h pulse pressure (PP)) with DD in stages 3-4 CKD patients. METHODS We performed a sub-analysis of 78 non-diabetic stages 3-4 CKD subjects to determine the relationship between 24-h PP, IL-12, IL-18 and hsCRP with DD. RESULTS DD was present in 38 subjects (49%). Subjects with DD were significantly older (61.0 ± 1.9 vs 50.2 ± 2.0 years; P < 0.001) and had higher 24-h PP (48(95% confidence interval 45, 52) vs 43(95% confidence interval 41, 45) mmHg; P < 0.005); 24-h PP was associated with DD (P = 0.02), but this was no longer significant after adjustment for age (P = 0.31). Serum IL-12, IL-18 and hsCRP levels were not significantly different between subjects with or without DD. CONCLUSION Asymptomatic subclinical DD was present in 50% of a cohort of stages 3-4 CKD patients but was not associated with IL-12, IL-18 or hsCRP. The association between 24-h PP and DD was no longer apparent following adjustment for age, but given the small sample size, our findings will need to be explored in larger-sized cohorts of individuals with moderate-stage CKD.

In the original publication of this article [1], an error occurred during the publication of this article in Table 2.

Background: Type 2 diabetes mellitus is a metabolic disorder characterized by high glucose and insulin resistance. It is strongly linked to lifestyle, including poor diet and physical inactivity. Lupin is a novel food ingredient, rich in protein and fibre with negligible sugar and starch, which can be incorporated into various foods to reduce glycaemic load. Regular consumption of lupin-enriched foods may be a novel and easily achievable means of reducing overall glycaemic load and improving glycaemic control in diabetes. Objective: To determine whether regular consumption of lupin-enriched foods can improve glycaemic control and lower blood pressure in people with type 2 diabetes mellitus. Design: Fourteen men and 8 women (mean age 58.0 ± 6.6 years and BMI 29.0 ± 3.5 kg m−2) with type 2 diabetes mellitus were recruited from the general population to take part in a double-blind, randomised, controlled cross-over study. Participants consumed lupin or control foods for breakfast and lunch every day, and for dinner at least 3 days per week during the 8-week treatment periods. Lupin-enriched foods consisted of bread, pasta, Weetbix™ cereal and crumbs, with energy-matched control products. Treatments were completed in random order with an 8-week washout period. All participants monitored their blood glucose levels pre- and post-breakfast and lunch, and their blood pressure in the morning and evening, 3 days per week for the duration of each treatment period. Results: Seventeen participants completed both treatment arms, with all 22 participants (14 males, 8 females) analysed on an intention-to-treat basis. Eight weeks consumption of lupin-enriched food had no significant effect on mean blood glucose levels (mean difference: −0.08 ± 0.06 mmol L−1, p = 0.214) or post-prandial blood glucose levels (−0.13 ± 0.10 mmol L−1, p = 0.196). There was no effect on home systolic (−0.4 ± 0.4 mmHg, p = 0.33) or diastolic (0.3 ± 0.3 mmHg, p = 0.321) blood pressure and heart rate (0.5 ± 0.3 bpm, p = 0.152), and no effect on body weight throughout the treatment periods. Conclusion: Regular consumption of lupin-enriched foods had no significant effect on glycaemic control or blood pressure in people with type 2 diabetes mellitus.

Background Type 2 diabetes mellitus is characterized by peripheral insulin resistance and low-grade systemic inflammation. Inflammation resolution is recognised as an important process driven by specialised pro-resolving mediators of inflammation (SPMs) and has the potential to moderate chronic inflammation. Alcohol has the potential to affect synthesis of SPMs by altering key enzymes involved in SPM synthesis and may influence ongoing inflammation associated with Type 2 diabetes mellitus. Aims (i) To examine the effects of alcohol consumed as red wine on plasma SPM in men and women with Type 2 diabetes in a randomised controlled trial and (ii) compare baseline plasma SPM levels in the same patients with those of healthy volunteers. Methods Twenty-four patients with Type 2 diabetes mellitus were randomized to a three-period crossover study with men drinking red wine 300 ml/day (∼31 g alcohol/day) and women drinking red wine 230 ml/day (∼24 g alcohol/day), or equivalent volumes of dealcoholized red wine (DRW) or water, each for 4 weeks. The SPM 18-hydroxyeicosapentaenoic acid (18-HEPE), E-series resolvins (Rv) (RvE1-RvE3), 17-hydroxydocosahexaenoic acid (17-HDHA), and D-series resolvins (RvD1, 17R-RvD1, RvD2, RvD5), 14-hydroxydocosahexaenoic acid (14-HDHA) and Maresin 1 were measured at the end of each period. A baseline comparison of plasma SPM, hs CRP, lipids and glucose was made with healthy volunteers. Results Red wine did not differentially affect any of the SPM measured when compared with DRW or water. Baseline levels of the hs-CRP and the SPM 18-HEPE, 17-HDHA, RvD1 and 17R-RvD1 in patients with Type 2 diabetes mellitus were all significantly elevated compared with healthy controls and remained so after adjusting for age and gender. Conclusion Moderate alcohol consumption as red wine does not alter plasma SPM in patients with Type 2 diabetes mellitus. The elevation of SPM levels compared with healthy volunteers may be a homeostatic response to counter ongoing inflammation.

Background Emerging evidence suggests that increasing intakes of nitrate-rich vegetables may be an effective approach to reduce blood pressure. Objective Our primary aim was to determine whether daily consumption of nitrate-rich vegetables over 4 wk would result in lower blood pressure. Design Thirty participants with prehypertension or untreated grade 1 hypertension were recruited to a randomized controlled crossover trial with 4-wk treatment periods separated by 4-wk washout periods. Participants completed 3 treatments in random order: 1) increased intake (∼200 g/d) of nitrate-rich vegetables [high-nitrate (HN); ∼150 mg nitrate/d], 2) increased intake (∼200 g/d) of nitrate-poor vegetables [low-nitrate (LN); ∼22 mg nitrate/d], and 3) no increase in vegetables (control; ∼6 mg nitrate/d). Compliance was assessed with the use of food diaries and by measuring plasma nitrate and carotenoids. Nitrate metabolism was assessed with the use of plasma, salivary, and urinary nitrate and nitrite concentrations. The primary outcome was blood pressure assessed by using 24-h ambulatory, home, and clinic measurements. Secondary outcomes included measures of arterial stiffness. Results Plasma nitrate and nitrite concentrations increased with the HN treatment in comparison to the LN and control treatments (P 0.05) after adjustment for pretreatment values, treatment period, and treatment order. Similarly, no differences were observed between treatments for arterial stiffness measures (P > 0.05). Conclusion Increased intake of nitrate-rich vegetables did not lower blood pressure in prehypertensive or untreated grade 1 hypertensive individuals when compared with increased intake of nitrate-poor vegetables and no increase in vegetables. This trial was registered at www.anzctr.org.au as ACTRN12615000194561.

Background Deficits in the rural medical workforce is an international issue. In Australia, The Rural Clinical School intervention is effective for initial recruitment of rural doctors. However, the extent of survival is not yet established. This paper summarises rural survival over a 10-year period. Methods Rural Clinical School graduates of Western Australia were surveyed annually, 2006–2015, and post Graduate Years (PGY) 3–12 included. Survival was described as “tours of service”, where a tour was either a period of ≥1 year, or a period of ≥2 weeks, working rurally. A tour ended with a rural work gap of ≥52 weeks. Considering each exit from urban as an event, semi-parametric repeated measures survival models were fitted. Results Of 468 graduates, using the ≥2 weeks definition, 239 PGY3–12 graduates spent at least one tour rurally (average 61.1, CI 52.5–69.7 weeks), and a total length of 14,607 weeks. Based on the tour definition of ≥1 year, 120 graduates completed at least one tour (average 1.89, 1.69–2.10 years), and a total of 227 years’ rural work. For both definitions, the number of tours increased from one to four by PGY10/11, giving 17,786 total weeks (342 years) across all PGYs for the ≥2 weeks tour definition, and 256 years total for ≥1 year. Significantly more graduates exited from urban work for the 2007–09 middle cohort compared with 2010–11 (HR 1.876, p = 0.022), but no significant difference between 2002 and 06 and 2010–11. Rural origin, age and gender were not statistically significant. Conclusions PGY3–12 RCS graduates contributed substantially to the rural workforce: 51% did so by short rotations, while 26% contributed whole years of service. There was an apparent peak in entry and survival for the middle cohort and decline thereafter, likely attributable to lack of advanced/specialist vocational training. These data indicate a real commitment to rural practice by RCS graduates, and the need for rural vocational training as a key element of a successful rural survival strategy.

To examine outstanding issues in the relationship of alcohol to hypertension. These include whether the increase in BP with alcohol is causally related, the nature of the relationship in women, the contribution of alcohol-related increases in BP to cardiovascular disease and the aetiology of alcohol-related hypertension. Intervention studies and Mendelian randomisation analyses confirm the alcohol–BP relationship is causal. The concept that low-level alcohol intake reduces BP in women is increasingly unsustainable. Alcohol-related hypertension is in the causal pathway between alcohol use and increased risk for several cardiovascular outcomes. The aetiology of alcohol-related hypertension is multifactorial with recent data highlighting the effects of alcohol on the vasoconstrictor 20-HETE and oxidative stress. The high prevalence of both alcohol use and hypertension mandates a careful alcohol history in every patient with elevated BP. Early intervention for excessive alcohol use offers the promise of lower levels of BP and reduced risk of adverse cardiovascular outcomes.

Background Whether graduate entrants to medical school perform better academically than undergraduate entrants remains controversial. Differences in the discipline backgrounds of graduates may, at least in part, have accounted for differences in the results of comparative studies reported to date. This study aimed to address the dual issues of whether academic performance and progression rates were different between GE and UG students and the extent to which the discipline background of GE students may underpin any differences observed. Methods Relative academic performance as well as indicators of student progression (supplementary examinations, repeat years, leave of absence, withdrawal from the programme) were compared between graduate entrants (GE) (N = 410) and both school leaver entrants (SLE) (N = 865) and non-standard entrants (some prior tertiary education) (NSE) (N = 148) who combined for the final 4 yr. of a 6 yr. MBBS undergraduate programme in 8 consecutive cohorts from 2006 to 2013 in Western Australia. Results Examination scores were generally at or very close to a distinction grade or higher across all groups. Higher mean examination scores were seen for GE versus both SLE and NSE in the first 2 years with no significant differences in the final 2 years. GE from biological science / science backgrounds (N = 241) or physical science backgrounds (N = 26) performed the same as SLE and NSE throughout the programme. GE with a health / allied health background (N = 91), however, performed better throughout. They also performed better when compared to their GE counterparts from a humanities (N = 32) or a biological science / science background. GE had increased odds of withdrawing when compared to SLE (OR 2.50, 95% CI 1.30, 4.79, P = 0.006), but not compared to NSE. NSE had increased odds of repeating at least one level when compared to either GE (OR 2.74, 95% CI 1.21, 6.21, P = 0.016) or SLE (OR 4.10, 95% CI 1.93, 8.70, P

OBJECTIVE Rural exposure during medical school is associated with increased rural work after graduation. How much of the increase in rural workforce by these graduates is due to pre-existing interest and plans to work rurally and how much is related to the extended clinical placement is not known. DESIGN This cohort study compared the employment location of medical graduates who professed no rural interest as undergraduates (negative control), with those who applied but did not participate in Rural Clinical School of Western Australia (RCSWA) (positive control), and those who applied and participated in RCSWA (participants). PARTICIPANTS All 1026 University of Western Australia students who had an opportunity to apply for a year-long rotation in RCSWA from 2004 to 2010, and who had subsequently graduated by the end of 2011, were included. MAIN OUTCOME MEASURE Graduates' principal workplace location (AHPRA, Feb 2014). RESULT The three groups differed significantly in their graduate work locations (χ2 = 39.2, P < 0.001). In multivariate analysis, only being of older age at graduation (OR 2.28 (95% CI 1.40, 3.72), P = 0.001), being from a rural background (OR 2.99 (95% CI 1.85, 4.85), P < 0.001), being a recipient of a Medical Rural Bonded Scholarship (OR 3.36 (95% CI 1.68, 6.73, P = 0.001) and actually participating in the RCSWA remained significantly related to rural work (OR 3.10 (95% CI 1.95, 4.93), P < 0.001). CONCLUSION After accounting for other factors relating to rural work, RCSWA graduates were three times more likely to work rurally than either control group. These data suggest that RCSWA has a significant independent effect on rural workforce.

summary Background and objective: The high incidence of cardiovascular disease (CVD) in chronic kidney disease (CKD) is related partially to chronic inflammation. n-3 Fatty acids have been shown to have antiinflammatory effects and to reduce the risk of CVD. Specialized Proresolving Lipid Mediators (SPMs) derived from the n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) actively promote the resolution of inflammation. This study evaluates the effects of n-3 fatty acid supplementation on plasma SPMs in patients with CKD. Methods: In a double-blind, placebo-controlled intervention of factorial design, 85 patients were randomized to either n-3 fatty acids (4 g), Coenzyme Q10 (CoQ) (200 mg), both supplements, or control (4 g olive oil), daily for 8 weeks. The SPMs 18-HEPE, 17-HDHA, RvD1, 17R-RvD1, and RvD2, were measured in plasma by liquid chromatographyetandem mass spectrometry before and after intervention. Results: Seventy four patients completed the 8 weeks intervention. n-3 Fatty acids but not CoQ significantly increased (P < 0.0001) plasma levels of 18-HEPE and 17-HDHA, the upstream precursors to the Eand D-series resolvins, respectively. RvD1 was significantly increased (P ¼ 0.036) after n-3 fatty acids, but no change was seen in other SPMs. In regression analysis the increase in 18-HEPE and 17-HDHA after n-3 fatty acids was significantly predicted by the change in platelet EPA and DHA, respectively. Conclusion: SPMs are increased after 8 weeks n-3 fatty acid supplementation in patients with CKD. This may have important implications for limiting ongoing low grade inflammation in CKD.

Open Access Article. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence., Coffee is a rich source of polyphenols, primarily chlorogenic acids (CGA). Certain polyphenols and polyphenol-rich foods and beverages have been shown to improve endothelial function and lower blood pressure (BP). The aim of the present study was to investigate the acute effect of two doses of CGA (5-CGA) on endothelial function and BP. In a cross-over study, 16 healthy men and women received: (i) 0 mg purified 5-CGA (control group); (ii) 450 mg purified 5-CGA; (iii) 900 mg purified 5-CGA; and (iv) 200 mg purified (−)-epicatechin (positive control) in random order one week apart. Peak and continuous mean (60 to 240 s post ischaemia) flow-mediated dilation (FMD) was measured at baseline, 1 h and 4 h. BP was measured at baseline and every 30 min to 4 h. Plasma CGA and epicatechin levels were significantly increased at both 1 h and 4 h post their respective treatments. Peak FMD was not significantly altered by either dose of 5-CGA or the epicatechin, relative to control (p > 0.05). Relative to control, effects on continuous mean FMD response following 450 mg 5-CGA and 900 mg of 5-CGA (0.47 ± 0.16%, p = 0.016 and 0.65 ± 0.16%, p < 0.001, respectively) at 1 h and (0.18 ± 0.17%, p = 0.99 and 0.44 ± 0.16%, p < 0.05, respectively) at 4 h. There was no significant effect of any of the treatments on BP. In conclusion, the present study has found no significant effect of 5-CGA, at 450 and 900 mg, on peak FMD response. However, there were significant improvements in mean post-ischaemic FMD response, particularly at the 1 h time point in this group of healthy individuals.

Metabolism of arachidonic acid by cytochrome P450 ω-hydroxylase leads to the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) that regulates vascular function, sodium homeostasis and blood pressure (BP). Supplementation with n-3 fatty acids is known to alter arachidonic acid metabolism and reduce the formation of the lipid peroxidation products F2-isoprostanes, but the effect of n-3 fatty acids on 20-HETE has not been studied.We previously reported a significant effect of n-3 fatty acids but not coenzyme Q10 (CoQ) to reduce BP in a double-blind, placebo-controlled intervention, wherein patients with chronic kidney disease (CKD) were randomized to n-3 fatty acids (4 g), CoQ (200 mg), both supplements or control (4 g olive oil), daily for 8 weeks. This study examined the effect of n-3 fatty acids on plasma and urinary 20-HETE in the same study, as well as plasma and urinary F2-isoprostanes, and relate these to changes in BP.Seventy-four patients completed the 8-week intervention. n-3 fatty acids but not CoQ significantly reduced plasma 20-HETE (P = 0.001) and F2-isoprostanes (P 0.001). In regression models adjusted for BP at baseline, postintervention plasma 20-HETE was a significant predictor of the fall in SBP (P 0.0001) and DBP (P 0.0001) after n-3 fatty acids.This is the first report that n-3 fatty acid supplementation reduces plasma 20-HETE in humans and that this associates with reduced BP. These results provide a plausible mechanism for the reduction in BP observed in patients with CKD following n-3 fatty acid supplementation.

Background Neutrophils release leukotriene (LT)B4 and myeloperoxidase (MPO) that may be important mediators of chronic inflammation in chronic kidney disease (CKD). The n-3 fatty acids (n-3 FA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have the potential to attenuate inflammation through production of LTB5 and the Specialized Proresolving Lipid Mediators (SPM) that promote the resolution of inflammation. In animal models, coenzyme Q10 (CoQ) also attenuates inflammation by reducing MPO and LTB4. Objective This study evaluated the independent and combined effects of n-3 FA and CoQ supplementation on neutrophil leukotrienes, the pro-inflammatory eicosanoid 5-hydroxyeicosatetraenoic acid (5-HETE), SPM, and plasma MPO, in patients with CKD. Design In a double-blind, placebo-controlled intervention of factorial design, 85 patients with CKD were randomized to either n-3 FA (4 g), CoQ (200 mg), both supplements, or control (4 g olive oil), daily for 8 weeks. Plasma MPO and calcium ionophore-stimulated neutrophil release of LTs, 5-HETE and SPM were measured at baseline and after 8 weeks. Results Seventy four patients completed the intervention. n-3 FA, but not CoQ, significantly increased neutrophil LTB5 (P Conclusion n-3 FA supplementation in patients with CKD leads to increased neutrophil release of LTB5 and several SPM, as well as a reduction in plasma MPO that may have important implications for limiting chronic inflammation.

Background Cardiovascular effects of alcohol consumption may be influenced by both pro- and anti-inflammatory mechanisms. We previously showed that chronic alcohol consumption increased blood pressure (BP), oxidative stress, and 20-hydroxyeicosatetraenoic acid (20-HETE), a vasoconstrictor and pro-inflammatory eicosanoid synthesized by cytochrome P450 (CYP450) enzymes from arachidonic acid. This study in men examined the effect of consuming red wine (RW) on BP in relation to changes in 20-HETE, oxidative stress (F2-isoprostanes), markers of inflammation, anti-inflammatory CYP450 epoxyeicosatrienoic acids (EETs), and specialized pro-resolving mediators of inflammation (SPMs) derived from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Methods Normotensive men (n = 22) were randomly allocated to drink RW (375 ml/d) or the equivalent volume of dealcoholized red wine (DRW) or water for 4 weeks in a 12-week, 3-period crossover trial. BP, heart rate, 20-HETE, F2-isoprostanes, and SPM were measured at baseline, 4, 8, and 12 weeks. Results Drinking RW increased BP (p

Evidence for a beneficial effect of dietary nitrate, through the nitrate-nitrite-NO pathway, on measures of cardiovascular function in healthy individuals is accumulating. It is less clear whether increased dietary nitrate intake from green leafy vegetables would have similar beneficial vascular effects in those at increased risk of developing hypertension. Our aim was to assess the effects of short-term regular consumption of increased nitrate from green leafy vegetables on blood pressure and arterial stiffness in individuals with high-normal blood pressure. Thirty-eight men and women ages 30-70 years with systolic blood pressure 120 to 139 mm Hg were recruited to a randomized controlled crossover trial. The effects of a 7-day high-nitrate diet intervention (increased nitrate intake by at least 300 mg/day from green leafy vegetables) were compared to a 7-day low-nitrate diet intervention. Outcome measures included pre- and postintervention salivary and plasma nitrate and nitrite concentrations; ambulatory, home, and office blood pressure; augmentation index; and carotid-femoral pulse wave velocity. The high-nitrate diet intervention resulted in at least a fourfold increase in salivary and plasma nitrate and nitrite (P

Endothelial nitric oxide (NO) is fundamental to cardiovascular health. Dietary nitrate and nitrate from endothelial derived NO metabolism provides a significant contribution to the circulating NO pool through the nitrate-nitrite-NO pathway. A critical step in this pathway is the reduction of nitrate to nitrite by the oral microbiota. We aimed to assess the effects of antibacterial mouthwash use on markers of nitrate-nitrite-NO metabolism and blood pressure in treated hypertensive men and women.Fifteen treated hypertensive men and women (mean age 65 years) were recruited to a randomized controlled cross-over trial. The effects of 3-day use of antibacterial mouthwash on oral nitrate to nitrite reduction, salivary and plasma nitrate and nitrite, plasma cyclic guanosine monophosphate (cGMP) and systolic and diastolic blood pressure were compared to control (water).Relative to control, 3-day antibacterial mouthwash use resulted in decreased oral nitrate to nitrite reduction (P = 0.02), decreased salivary nitrite (P = 0.01) and increased salivary nitrate (P0.001), and there was a trend toward a decrease in plasma nitrite concentration (P = 0.09). Use of antibacterial mouthwash over 3 days also resulted in higher systolic blood pressure (2.3mm Hg; 95% CI: 0.5, 4.0; P = 0.01), but not diastolic blood pressure (P = 0.4) or plasma cGMP (P = 0.7), relative to control.Interruption of the nitrate-nitrite-NO pathway through the use of antibacterial mouthwash was paralleled by a small elevation of systolic blood pressure in treated hypertensive men and women.

Genetic background partly determines the efficacy of interventions to lower blood pressure (BP). The CYP4F2 and CYP4A11 enzymes are renal 20-hydroxyeicosatetraenoic acid (20-HETE) synthases that regulate BP. Gene variants of CYP4F2 and CYP4A11 associate with hypertension and stroke. We showed that a gene variant of CYP4F2 but not CYP4A11 was associated with increased 20-HETE excretion and BP.To compare BP and 20-HETE responses in carriers of the CYP4F2 1347G/A polymorphism and controls CYP4F2-GG (wildtype), during weight loss.Volunteers genotyped as CYP4F2GA/AA (n = 26) and controls genotyped as CYP4F2 GG (n = 27) were counselled to reduce weight for 12 weeks, followed by 4 weeks of weight stabilization. Weight, 24-h BP, pulse pressure and urinary 20-HETE were measured at baseline, 12 and 16 weeks.At baseline, SBP was (+1.7 mmHg, P = 0.047) in the CYP4F2 GA/AA genotype. Compared with baseline, weight fell by 3.9 kg, P = 0.0001, in both genotypes, and was maintained to 16 weeks. SBP fell by (-7.6 mmHg, P = 0.004) in both genotypes after 12 weeks. However, after weight stabilization, SBP was +3.6 mmHg, P = 0.004 in CYP4F2 GA/AA genotype. DBP and heart rate changed similarly over time. Pulse pressure fell with weight loss (P0.001), but was elevated in the CYP4F2 GA/AA genotype at all time-points (+3.1 mmHg, P0.001). Urinary 20-HETE was similar at baseline and 12 weeks but elevated in the CYP4F2 GA/AA genotype (P = 0.017) after weight stabilization.Maintenance of lower BP after weight loss is more difficult for carriers of the CYP4F2 G1347A polymorphism and may be related to increased arterial stiffness and increased 20-HETE synthesis.

Background Characteristics of short-term blood pressure (BP) variation may influence cardiovascular disease risk via effects on vascular function. Objective In a cross-sectional study of a group of treated hypertensive and untreated largely normotensive subjects we investigated the relationships of measures of short-term BP variation with brachial artery vasodilator function. Methods A total of 163 treated hypertensive ( n = 91) and untreated largely normotensive ( n = 72) men and women were recruited from the general population. Measures of systolic and diastolic BP variation were calculated from 24 h ambulatory BP assessments and included: (i) rate of measurement-to-measurement BP variation (SBP-var and DBP-var); and (ii) day-to-night BP dip (SBP-dip and DBP dip). Endothelium-dependent vasodilation was assessed as flow-mediated dilation (FMD) and endothelium-independent vasodilation was assessed in response to glyceryl trinitrate (GTN). Relationships were explored using univariate and multivariate linear regression. Results The relationships of brachial artery vasodilator function with BP variation were not significantly different between treated hypertensive and untreated subjects, therefore these groups were combined for analysis. In univariate analysis, higher SBP-var ( P P = 0.004) were associated with lower FMD; and higher SBP-var ( P = 0.002) and lower SBP-dip ( P = 0.003) and DBP-dip ( P = 0.001) were associated with lower GTN-mediated dilation. In multivariate analysis, lower SBP-dip ( P = 0.007) and DBP-dip ( P = 0.03) were independently associated with lower GTN response. Conclusions Our results indicate that a lower day-to-night BP dip is independently associated with impaired smooth muscle cell function. Although rate of BP variation was associated with measures of endothelial and smooth muscle cell function, relationships were attenuated after accounting for age and BP.

The vasodilation accompanying acute alcohol ingestion is hard to reconcile with the strong evidence linking chronic alcohol consumption with hypertension. Cytochrome P450 (CYP450) eicosanoids derived from arachidonic acid include vasodilator epoxyeicosatrienoic acids (EETs) and the vasoconstrictor 20-hydroxyeicosatrienoic acid (20-HETE). This study aimed to examine the relationship between CYP450 eicosanoids and blood pressure (BP), and compared the effect of single session of drinking red wine with de-alcoholized red wine (DRW) or water over 24 h.Twenty-five normotensive men were randomly assigned to drink either 375 ml of red wine (41 g of alcohol) or the equivalent volume of DRW or water, with a light meal on 3 separate days. Ambulatory BP and heart rate were measured over 24 h. Blood samples were obtained before and 2, 4 and 24 h after beverage consumption.Blood pressure fell in the first 4 h after red wine consumption (P = 0.001), but was significantly higher after 20 h (P = 0.037). Plasma 20-HETE fell in the 2 h after consumption of all beverages, but over the 24-h period was relatively higher after red wine consumption (P = 0.025). The largest difference in 20-HETE was 2 h after consuming red wine and coincided with the highest blood alcohol level. There were no significant effects of red wine on plasma EETs.Acute consumption of alcohol as red wine results in a relative increase in plasma levels of the vasoconstrictor 20-HETE over 24 h without affecting EETs, and may contribute to the BP elevation that associates with a binge drinking pattern or be a homeostatic response to the acute fall in BP induced by alcohol.

Introduction Medical schools are in general over-represented by students from high socio-economic status backgrounds. The University of Western Australia Medical School has been progressively widening the participation of students from a broader spectrum of the community both through expanded selection criteria and quota-based approaches for students of rural, indigenous and other socio-educationally disadvantaged backgrounds. We proposed that medical students entering medical school from such backgrounds would ultimately be more likely to practice in areas of increased socio-economic disadvantage. Methods The current practice address of 2829 medical students who commenced practice from 1980 to 2011 was ascertained from the Australian Health Practitioner Regulation Agency (AHPRA) Database. Logistic regression was utilised to determine the predictors of the likelihood of the current practice address being in the lower 8 socio-economic deciles versus the top 2 socio-economic deciles. Results Those who were categorised in the lower 8 socio-economic deciles at entry to medical school had increased odds of a current practice address in the lower 8 socio-economic deciles 5 or more years after graduation (OR 2.05, 95% CI 1.72, 2.45, P

Cross-sectional and longitudinal population studies have provided a considerable corpus of evidence for an inverse association between light to moderate alcohol intake and both coronary artery disease and stroke. The formulation of balanced public health advice on the basis of such studies, however, needs to take into account the full spectrum of the effects of alcohol on the cardiovascular system, particularly its equally well documented effect to increase level of blood pressure and prevalence of hypertension. In this review, the broader implications of the association of alcohol with hypertension are discussed, principally in the context of the effect of higher levels of alcohol consumption to increase ischaemic and haemorrhagic stroke, left ventricular hypertrophy, congestive cardiomyopathy, cardiac arrhythmia and sudden cardiac death.

Although prospective studies suggest light-to-moderate chronic alcohol intake protects against coronary artery disease in type 2 diabetic patients, the balance of effects on individual cardiovascular risk factors needs further assessment. We examined the effects of alcohol consumption on 24-h ambulatory blood pressure (BP) and heart rate (HR), high-density lipoprotein cholesterol, fibrinogen, C-reactive protein, homocysteine, and glycaemic control in well controlled type 2 diabetes.Twenty-four participants aged 49-66 year were randomized to a three-period crossover study with women drinking red wine 230 ml/day (∼24 g alcohol/day) and men drinking red wine 300 ml/day (∼31 g alcohol/day), or equivalent volumes of dealcoholized red wine (DRW) or water, each for 4 weeks. Ambulatory BP and HR were monitored every 30 min for 24 h at the end of each period. Home blood glucose monitoring was carried out twice weekly throughout.Red wine increased awake SBP and DBP relative to water by 2.5 ± 1.2 /1.9 ± 0.7 mmHg (P = 0.033, P = 0.008, respectively), with a similar nonsignificant trend relative to DRW. Asleep DBP fell with red wine relative to DRW (2.0 ± 0.8 mmHg, P = 0.016) with a similar nonsignificant trend relative to water. Red wine increased 24-h, awake and asleep HR relative to water and DRW. Relative to DRW, red wine did not affect glycaemic control or any other cardiovascular risk factor.In well controlled type 2 diabetic individuals 24-31 g alcohol/day (∼2-3 standard drinks) raises awake BP and 24-h HR and lowers asleep BP but does not otherwise favourably or adversely modify cardiovascular risk factors.

Overall there is good evidence that alcohol consumption induces oxidative stress, and leads to lipid peroxidation, effects which have been linked to alcohol-related toxicity and disease and may be relevant to alcoholatherosclerosis interrelationships. On the other hand, a protective effect of light to moderate alcohol consumption against cardiovascular disease is well recognized, with the further hypothesis that red wine offers extra cardiovascular protection due to its rich content of antioxidant phenolic compounds. Although this hypothesis is given some credence from in vitro data, controlled studies in humans have produced conflicting results. Clearly, the equally well described pro-oxidant effects of alcohol and its metabolism have been insufficiently considered in the pursuit of what to many is an intuitively attractive hypothesis. Further studies are required to determine if red wine phenolics are actually absorbed from the gut and whether they offer any overall antioxidant protection in vivo. The hypothesis that red wine offers extra cardiovascular protection compared to other alcoholic beverages is not proven and must await the outcome of studies in which the full spectrum of the pro-oxidant and antioxidant effects of alcoholic beverages are duly considered. In the absence of such studies, there are no grounds at present for the promotion of the consumption of alcoholic beverages on the basis of their putative "antioxidant" properties.

In 1998, in addition to previous academic achievement, an aptitude test (UMAT) and a structured interview were introduced into selection for the Bachelor of Dental Science (BDSc), the undergraduate dental course at the University of Western Australia. The aim of this study was to determine the relationship between the combination of school-leaver dental students' entry scores, some demographic characteristics and subsequent student performance in the undergraduate course. Three hundred and ninety-eight school-leavers who enrolled in the BDSc from 1999 through 2011 were studied. Regression models were constructed comprising entry scores, gender and age as predictors in relation to subsequent academic performance. The main outcome measure was the weighted average mark (WAM) for each of five academic year levels as well as results in specific units, defined as either 'knowledge' based or 'clinically' based. Of the variables studied, previous academic performance and female gender had the strongest relationship with yearly WAM for Years 1 through 4 and for both 'knowledge' based and 'clinically' based units. The interview score showed a strong relationship in the major clinical years and in a range of 'clinically' based units. UMAT scores were less consistent in relationship to WAM. These results support assessment through a highly structured interview together with prior academic achievement as an evidence-based approach to selection of students for this undergraduate dental course.

Flavonoids and nitrates in fruits and vegetables may protect against cardiovascular disease. Dietary flavonoids and nitrates can augment nitric oxide status via distinct pathways, which may improve endothelial function and lower blood pressure. Recent studies suggest that the combination of flavonoids and nitrates can enhance nitric oxide production in the stomach. Their combined effect in the circulation is unclear. Here, our objective was to investigate the independent and additive effects of flavonoid-rich apples and nitrate-rich spinach on nitric oxide status, endothelial function, and blood pressure. A randomized, controlled, crossover trial with healthy men and women (n=30) was conducted. The acute effects of four energy-matched treatments (control, apple, spinach, and apple+spinach), administered in random order, were compared. Measurements included plasma nitric oxide status, assessed by measuring S-nitrosothiols+other nitrosylated species (RXNO) and nitrite, blood pressure, and endothelial function, measured as flow-mediated dilatation of the brachial artery. Results are means and 95% CI. Relative to control, all treatments resulted in higher RXNO (control, 33 nmol/L, 26, 42; apple, 51 nmol/L, 40, 65; spinach, 86 nmol/L, 68, 110; apple+spinach, 69 nmol/L, 54, 88; P

Background Cholesterol and blood pressure lowering therapies are effective in the secondary prevention of ischemic stroke. Aim To determine whether 30 days of treatment with atorvastatin, or irbesartan, initiated within 96 h of symptom onset improves recovery from acute ischemic stroke. Methods Eighty-one patients with acute ischemic stroke participated in this double-blind, placebo-controlled, randomized trial of atorvastatin (80 mg) vs. placebo, and/or irbesartan (150 mg) vs. placebo. Fifty-two patients (randomized 53 ± 22 h after onset of symptoms) completed the 30-day primary outcome follow-up. Results The primary outcome, maximal brain infarct size at days 3 and 30 measured by perfusion computed tomography, was not significantly altered by random assignment to irbesartan (1088 (IQR 216, 2594) mm2 at day 3, compared with 398 (144, 2053) mm2 among the placebo group, P=0·79 controlling for baseline values; and 822 (159, 1717) mm2 at day 30, cf 280 (76, 1330) mm2; P=0·63); or atorvastatin (454 (107, 1765) mm2 cf 825 (265, 2509) mm2 at day 3; P=0·33; and 462 (43, 1399) mm2 cf 280 (128, 1559) mm2 at day 30, P=0·79). There were no other significant differences among the treatment groups with the exception of: • high sensitivity C-reactive protein concentrations, which were lower in the irbesartan treatment group at day 30 (mean difference 12·6 mg/L; 95% CI: −25·1, −0·1; P=0·048); and • the mean cerebral blood flow in the affected cerebral hemisphere at 30 days after stroke, which was significantly reduced by random assignment to irbesartan compared with placebo in both the affected cerebral hemisphere (−7·5 mL/100 mL/min (95% CI: −1·7 to −13·4, P=0·01)) and in the unaffected hemisphere (−7·3 mL/100 mL/min (95% CI: −1·3, −13·4; P=0·02)). Atorvastatin therapy was well tolerated, but irbesartan therapy was associated with an increased rate of withdrawal from therapy ( n=10 (29%), compared with n=3 (9%) who withdrew from placebo, P=0·04). Conclusions Treatment with atorvastatin and irbesartan, initiated on day 3 after acute ischemic stroke, did not appear to substantially modify infarct growth.

Background: In 1998, a new selection process which utilised an aptitude test and an interview in addition to previous academic achievement was introduced into an Australian undergraduate medical course. Aims: To test the outcomes of the selection criteria over an 11-year period. Methods: 1174 students who entered the course from secondary school and who enrolled in the MBBS from 1999 through 2009 were studied in relation to specific course outcomes. Regression analyses using entry scores, sex and age as independent variables were tested for their relative value in predicting subsequent academic performance in the 6-year course. The main outcome measures were assessed by weighted average mark for each academic year level; together with results in specific units, defined as either ‘knowledge’-based or ‘clinically’ based. Results: Previous academic performance and female sex were the major independent positive predictors of performance in the course. The interview score showed positive predictive power during the latter years of the course and in a range of ‘clinically’ based units. This relationship was mediated predominantly by the score for communication skills. Conclusions: Results support combining prior academic achievement with the assessment of communication skills in a structured interview as selection criteria into this undergraduate medical course.

Addition of fibre or protein to carbohydrate-rich foods can reduce the glycaemic response to those foods. This may assist with glycaemic management in individuals with type 2 diabetes. Lupin is a legume rich in fibre and protein. We assessed the acute effects of lupin- and soya-based beverages on glucose and insulin responses in type 2 diabetic individuals. We hypothesised that the lupin and soya beverages would lower the acute glycaemic response compared with a control beverage containing no protein or fibre, and that lupin would reduce the postprandial glucose more than soya. In a randomised, controlled, cross-over trial, twenty-four diabetic adults (nineteen men and five women) attended three testing sessions, each 1 week apart. At each session, participants consumed a beverage containing 50 g glucose (control), 50 g glucose plus lupin kernel flour with 12·5 g fibre and 22 g protein (lupin), or 50 g glucose plus 12·5 g fibre and 22 g protein from soya isolates (soya). Serum glucose, insulin and C-peptide were measured periodically for 4 h following beverage consumption. Compared with the control beverage, the 4 h post-beverage glucose response was lower (P P P = 0·25) and C-peptide (P = 0·07) responses did not differ significantly between lupin and soya, but lupin resulted in a lower insulin response compared with soya (P = 0·013). Adding lupin or soya to a carbohydrate-rich beverage reduces glycaemia acutely in type 2 diabetic individuals. This may have a beneficial role in glycaemic management.

Regular consumption of diets with increased protein or fibre intakes may benefit body weight and composition and cardiovascular disease risk factors. Lupin flour is a novel food ingredient high in protein and fibre.To investigate the effects of a lupin-enriched diet, during and following energy restriction, on body weight and composition and cardiovascular disease risk factors in overweight individuals.Participants (n = 131) were recruited to a 12-month parallel-design trial. They were randomly assigned to consume lupin-enriched foods or matching high-carbohydrate control foods. All participants underwent 3 months of weight loss, 1 month of weight stabilization and 8 months of weight maintenance. Body weight and composition and cardiovascular disease risk factors were assessed at baseline, 4 and 12 months.Lupin, relative to control, did not significantly influence (mean difference (95% CI)) weight loss at 4 months (0.1 kg (-1.2, 1.4)) and 12 months (-0.6 kg (-2.0, 0.8)), maintenance of weight loss from 4 to 12 months (-0.7 kg (-1.83, 0.48)) or measures of body fat and fat-free mass. Relative to control, 24-h ambulatory systolic (-1.3 mm Hg (-2.4, -0.3), P = 0.016) and diastolic (-1.0 mm Hg (-1.9, -0.2), P = 0.021) blood pressures were lower at 12 months but not at 4 months; fasting insulin concentrations and homeostasis model assessment (HOMA) scores were significantly lower at 4 months (-1.2 mU l(-1) (-1.3, -1.1), P = 0.004 and -0.6 units (-1.0, -0.19), P = 0.004) and 12 months (-1.3 mU l(-1) (-1.4, -1.1), P0.001 and -0.7 units (-1.1, -0.24), P = 0.002).A diet higher in protein and fibre derived from lupin-enriched foods does not enhance weight loss or improve the maintenance of weight loss. However, such a diet may provide cardiovascular health benefits in terms of insulin sensitivity and blood pressure.

Chronic kidney disease (CKD) associates with increased cardiovascular disease (CVD) risk. Hypertension is a major determinant of progression of CKD. Omega-3 fatty acids (omger3FA) protect against CVD via improvements in blood pressure, heart rate, vascular reactivity and serum lipids. Coenzyme Q(10) (CoQ) may improve blood pressure and vascular function. This study determined whether omega3FA and CoQ have independent or additive effects in improving the cardiovascular profile, particularly blood pressure and heart rate, in nondiabetic patients with CKD stages 3-4.In a double-blind, placebo-controlled intervention, patients were randomized to either omega3FA (4 g), CoQ (200 mg), both supplements or control (4 g), daily for 8 weeks.Eighty-five patients aged 56.5 +/- 1.4 years; BMI 27.3 +/- 0.5 kg/m(2); supine blood pressure 125.0/72.3mmHg; and glomerular filtration rate 35.8 +/- 1.2 ml/min/1.73m(2), were randomized. Seventy-four completed the study. omega3FA, but not CoQ, reduced 24-h ambulatory heart rate (P0.0001) and blood pressure (P0.0001). Main effects for omega3FA on 24-h measurements were -3.3 +/- 0.7/ -2.9 +/- 0.5mmHg and -4.0 +/- 0.5 bpm. Postintervention blood pressure showed significant interactions between treatments. omega3FA reduced triglycerides 24% (P0.001). There were no changes in glomerular filtration rate, urinary albumin or total protein excretion, cholesterol, HDL-cholesterol (C), LDL-C, glucose, insulin, or high-sensitivity C-reactive protein.This study has shown that omega3FA reduce blood pressure, heart rate and triglycerides in patients with CKD. CoQ had no independent effect on blood pressure but increased heart rate. These results show that omega3FA lower blood pressure and may reduce cardiovascular risk in nondiabetic patients with moderate-to-severe CKD.

Background: Several studies show that proteins, including whey and casein, are more satiating than carbohydrates. It follows that skim milk would be more satiating than sugar-rich beverages. However, this has yet to be shown. Objective: The objective was to investigate the effects of drinking skim milk in comparison with a fruit drink at breakfast on selfreported postmeal satiety and energy intake at lunch. Design: In a randomized crossover trial, 34 overweight women (n = 21) and men (n = 13) attended 2 sessions 1 wk apart. At each session, participants consumed a fixed-energy breakfast together with either 600 mL skim milk (25 g protein, 36 g lactose, , 1g fat; 1062 kJ) or 600 mL fruit drink (,1 g protein, 63 g sugar, , 1g fat; ’1062 kJ). Participants provided satiety ratings throughout the morning. Four hours after breakfast they consumed an ad libitum lunch, and energy intake was assessed. Results: Participants consumed significantly less energy at lunch after consuming skim milk (mean: 2432 kJ; 95% CI: 2160, 2704 kJ) than after consuming the fruit drink (mean: 2658 kJ; 95% CI: 2386, 2930 kJ), with a mean difference of ’8.5% (P , 0.05). In addition, self-reports of satiety were higher throughout the morning after consumption of skim milk than after consumption of the fruit drink (P , 0.05) with the differences becoming larger over the 4h( P , 0.05). Conclusion: Consumption of skim milk, in comparison with a fruit drink, leads to increased perceptions of satiety and to decreased energy intake at a subsequent meal. This trial was registered with the Australian New Zealand Clinical Trials Registry at www.anzctr.org. au as ACTRN12608000510347. Am J Clin Nutr 2009;90:70‐5.

Medical student education in Western Australia is expanding to secondary level metropolitan hospitals and rural sites to accommodate workforce demands and increasing medical student numbers.To determine if students' perceptions of the teaching environment for obstetrics and gynaecology differ between tertiary, secondary level metropolitan hospitals and rural sites, and to determine if students' perceptions of their learning environment are associated with improved academic performance.An evaluation was conducted of medical students' perceptions of their learning environment during an obstetrics and gynaecology program at a variety of sites across metropolitan and rural Western Australia. The evaluation was based on the Dundee Ready Education Environmental Measure (DREEM) questionnaire.There were no significant differences in students' perceptions of their learning environment between the tertiary hospital, combined programs involving a tertiary and secondary metropolitan hospital, rural sites with a population of more than 25,000 and rural sites with a population less than 25,000 people. Perceptions were similar in male and female students. The overall mean score for all perceptions of the learning environment in obstetrics and gynaecology were in the range considered to be favorable. Higher scores of perceptions of the learning environment were associated positively with the measures of academic achievement in the clinical, but not written, examination.Medical students' perceptions of their learning environment in obstetrics and gynaecology were not influenced by the geographical site of delivery or their gender but were positively related to higher academic achievement. Providing appropriate academic and clinical support systems have been put in place the education of medical students can be extended outside major hospitals and into outer metropolitan and rural communities without any apparent reduction in perceptions of the quality of their learning environment.

To examine in previously sedentary older women the effects of exercise mode and a behavioural intervention on short and long-term retention and adherence.Healthy, sedentary women aged 50-70 years (N=116) were randomly assigned to a supervised 6-month swimming or walking program 3 sessions a week. They were further randomised to usual care or a behavioural intervention. The same program was further continued unsupervised for 6 months. We assessed retention, adherence, stage of exercise behaviour and changes in fitness.One hundred women (86%) completed 6 months and 86 (74%) continued for 12 months. Retention rates were similar for both exercise modes at 6 and 12 months. Adherence to swimming or walking was similar after 6 months (76.3 (95% CI: 69.5, 83.1)% vs. 74.3 (67.7, 80.9)%) and 12 months (65.8 (57.9, 73.8)% vs. 62.2 (54.6, 70.0)%). The behavioural intervention did not enhance retention or adherence. Fitness improved for both exercise modes after 6 months and was maintained at 12 months.Either swimming or walking programs initiated with careful supervision over 6 months resulted in similar high retention and adherence rates by highly motivated older women over 12 months. Behavioural intervention in this setting did not improve these rates further.

Context: Neutrophil (polymorphonuclear neutrophil) production of leukotriene B4 (LTB4) may be associated with alterations in immune and inflammatory function that characterize the metabolic syndrome (MetS).Objective: We investigated whether polymorphonuclear neutrophil production of LTB4 and its metabolites 20-hydroxy-LTB4 (20-OH-LTB4) and 20-carboxyl-LTB4 were altered in subjects with features of the MetS before and after weight reduction.Design, Setting, Patients, and Intervention: In a case-controlled comparison, men and postmenopausal women with features of the MetS were matched with controls. Subjects with MetS were then matched and randomly assigned to either a 12-wk weight reduction study followed by 4-wk weight stabilization or 16-wk weight maintenance.Main Outcome Measures: Measurements were performed at baseline and at the end of the 16-wk period. Stimulated neutrophil LTB4 and its metabolites were measured by HPLC.Results: In the case-controlled study, body mass index, waist circumference, blood pressure, fasting triglycerides, and glucose were all significantly increased in subjects with features of the MetS (P < 0.05). Production of LTB4 and 20-OH-LTB4 was significantly lower compared with controls (P < 0.005). The weight loss intervention resulted in a 4.6-kg reduction in body weight and 6.6-cm decrease in waist circumference relative to controls and a significant increase in LTB4 and 20-OH-LTB4.Conclusions: Subjects with features of the MetS have lower stimulated LTB4, which is not due to increased metabolism of LTB4. Weight reduction restored the production of neutrophil LTB4, suggesting that in addition to modifying cardiovascular risk, weight loss may also help with the management of perturbed inflammatory responses in overweight subjects.

We examined whether macrophages from men and women with Type 2 diabetes mellitus (T2DM) exhibited differences in expression of key genes involved in fatty acid metabolism and in fatty acid composition compared with macrophages from non-diabetic controls. Peripheral blood monocytes from subjects with T2DM (n=9) and non-diabetic controls (n=10) were differentiated into macrophages in 10% autologous serum and normal (5mM) or high (22mM) glucose. Levels of PPARalpha, PPARgamma, LXRalpha, SCD and ABCA1 mRNAs were similar in macrophages from subjects with T2DM and controls. At 5mM glucose, macrophage stearic acid (C18:0) was 12.6+/-1.0% of total fatty acids for T2DM compared with 18.1+/-2.0% for controls (p=0.03). Macrophage linoleic acid (C18:2) was 15.5+/-0.8% for T2DM and 9.3+/-2.0% for controls (p=0.005). The ratio of macrophage stearic acid (C18:0)/oleic acid (C18:1) was 0.29 [0.25,0.48] for T2DM versus 0.54 [0.36,0.82] for controls (p=0.04). Compared with non-diabetic controls, macrophages from men and women with T2DM had significantly different fatty acid profiles consistent with increased stearoyl-CoA desaturase (SCD) activity and increased C18:2 accumulation. This pattern of altered macrophage fatty acid composition may be relevant to diabetic atherogenesis.

Objective To examine predictors of coronary heart disease (CHD) and all-cause mortality in Aboriginal Australians. Method In 1988–89, a survey of Western Australian Aborigines (256 women, 258 men) aged 15–88 years documented diet, alcohol and smoking habits. Linkage to mortality and hospital admissions to the end of 2002 provided longitudinal data for modelling of coronary heart disease endpoints and all-cause mortality using Cox regression. Results Coronary heart disease risk increased with smoking (HR 2.62, 95% CI: 1.19, 5.75), consumption of processed meats > once/week (HR 2.21, 95% CI: 1.05, 4.63), eggs > twice/week (HR 2.59, 95% CI: 1.11, 6.04) and using spreads on bread (HR 3.14. 95% CI: 1.03, 9.61). All-cause mortality risk was lower with exercise > once/week (HR 0.51, 95% CI 0.26, 1.05), increased in ex-drinkers (HR 3.66, 95% CI: 1.08, 12.47), heavy drinkers (HR5.26, 95% CI: 1.46, 7.52) and with consumption of takeaway foods > nine times/month (HR 1.78, 95% CI 0.96, 3.29). Greater alcohol intake, smoking and adverse dietary choices clustered in 53% of men and 56% of women and increased risk of coronary heart disease (HR 2.1, 95% CI: 1.1, 4.0) and all-cause mortality (HR 2.3, 95% CI: 1.2, 4.2). Conclusion Lifestyle in Aboriginal Australians predicts coronary heart disease and all-cause mortality. Clustering of adverse behaviours is common and increases risk of coronary heart disease and death.

Oxidative stress has been suggested to play a role in the development of diabetes, hypertension and vascular dysfunction. Vitamin E, a major lipid-soluble dietary antioxidant, has two major dietary forms, alpha-tocopherol and gamma-tocopherol. The potential importance of gamma-tocopherol has largely been overlooked. Our aim was to investigate the effect of alpha-tocopherol and gamma-tocopherol supplementation on 24-h ambulatory blood pressure (BP) and heart rate, vascular function and oxidative stress in individuals with type 2 diabetes.Fifty-eight individuals with type 2 diabetes were randomized in a double-blind, placebo-controlled trial. Participants were randomized to a daily dose of 500 mg/day RRR-alpha-tocopherol, 500 mg/day mixed tocopherols (60% gamma-tocopherol) or placebo for 6 weeks. Primary endpoints were 24-h ambulatory BP and heart rate, endothelium-dependent and independent vasodilation and plasma and urinary F2-isoprostanes.Treatment with alpha-tocopherol significantly increased systolic BP [7.0 (5.2, 8.8) mmHg, P0.0001], diastolic BP [5.3 (4.0, 6.5) mmHg, P0.0001], pulse pressure [1.8 (0.6, 3.0) mmHg, P0.005] and heart rate [2.0 (0.6, 3.3) bpm, P0.005] versus placebo. Treatment with mixed tocopherols significantly increased systolic BP [6.8 (4.9, 8.6) mmHg, P0.0001], diastolic BP [3.6 (2.3, 4.9) mmHg, P0.0001], pulse pressure [3.2 (2.0, 4.4) mmHg, P0.0001] and heart rate [1.8 (0.5, 3.2) bpm, P0.01] versus placebo. Treatment with alpha-tocopherol or mixed tocopherols significantly reduced plasma F2-isoprostanes versus placebo, but had no effect on urinary F2-isoprostanes. Endothelium-dependent and independent vasodilation was not affected by either treatment.In contrast to our initial hypothesis, treatment with either alpha- or mixed tocopherols significantly increased BP, pulse pressure and heart rate in individuals with type 2 diabetes.

SummaryType 2 diabetes is associated with disturbances in coagulation and fibrinolysis. Prospective studies show that increased tissue plasminogen activator (tPA) antigen increases the risk of cardiovascular mortality. The present study examined the hypothesis that combining a regime of moderate aerobic exercise with one daily fish meal as part of a low-fat diet (30% total energy) would improve coagulation and fibrinolytic factors in dyslipidaemic type 2 diabetic patients. In a randomised, controlled, 8-week trial, 55 sedentary type 2 diabetic subjects with serum triglycerides >1.8 mmol/l and/or HDL-C

Aims: To examine risk for coronary heart disease (CHD) and cardiovascular disease (CVD) in relation to alcohol in a cohort of Australian Aborigines. Methods: In 1988-1989, alcohol intake, drinking pattern, and beverage preference were elicited by interviewer-administered questionnaire in Western Australian Aborigines (258 men and 256 women) and cardiovascular outcomes ascertained through linkage to mortality and hospital admission records to 2002. Results: In proportional hazards models, risk for CHD, relative to lifetime abstainers, was significantly increased in ex-drinkers [Hazard ratio (HR), 2.29; 95% confidence intervals (CI), 1.23-4.27], those drinking 41-60 g/day in men or 21-40 g/day in women (HR 2.80; 95% CI, 1.04-7.53) and those drinking > 150 g/day for men or > 100 g/day for women (HR, 2.25; 95% CI, 1.03-4.90) with a J-shaped relationship. Low-to-moderate drinkers had lower waist girth, exercised more and had a lower prevalence of overweight and smoking than at-risk drinkers. A preference for wine was associated with lower HR (0.28; 95% CI, 0.10-0.95). With CVD, only ex-drinkers showed significantly increased risk (HR, 1.87; 95% CI, 1.20-2.91). Conclusions: More favourable health-related behaviours in low-to-moderate drinkers suggest that lower risk could be mediated by lifestyle, as proposed in other populations.

Hypertension is often associated with insulin resistance or hyperinsulinemia. Metabolism of arachidonic acid by cytochrome P450 to the vasoconstrictor 20-HETE is thought to be involved in the pathogenesis of hypertension, but the relationship of 20-HETE with insulin resistance is not clearly understood. Obesity is a major determinant of insulin resistance, and we have previously demonstrated a positive relationship between BMI and 20-HETE in untreated hypertensive and normotensive individuals. The present analysis sought to determine if this relationship was related to insulin levels or insulin resistance (HOMA). We analysed 24h urinary excretion of 20-HETE, serum insulin levels and insulin resistance in 66 lean to overweight untreated hypertensive and normotensive individuals. There was a significant positive association between 20-HETE and BMI (p0.001), and serum insulin and BMI (p=0.003). There were no associations between 20-HETE excretion and either serum insulin or insulin resistance, before or after adjustment for age, gender, BMI and BP, or when hypertensive and normotensive individuals were considered separately. The results of the present study suggest that the observed positive association between urinary 20-HETE excretion and BMI may not be related to circulating insulin levels or insulin resistance.

Fetal programming is now recognized as a key determinant of the adult phenotype, with major implications for adult-onset diseases including hypertension. Two mediators of fetal programming are maternal nutrition and fetal glucocorticoid exposure. Recent studies show that postnatal dietary manipulations can exacerbate programming effects, but whether programming effects can be attenuated by postnatal dietary manipulations, and thus provide a possible therapeutic strategy, is unknown. In this study, we tested the hypothesis that a postnatal diet enriched with long-chain omega-3 fatty acids attenuates programmed hyperleptinemia and hypertension. Pregnant rats were treated with dexamethasone (Dex) from d 13 to term, and offspring were cross-fostered to mothers on either a standard diet or a diet high in omega-3 fatty acids and remained on these diets postweaning. Maternal Dex reduced birthweight and delayed the onset of puberty in offspring. Hyperleptinemia (associated with elevated leptin mRNA expression in adipose tissue) and hypertension were evident in offspring by 6 months of age in Dex-exposed animals consuming a standard diet, but these effects were completely blocked by a high omega-3 diet. These results demonstrate for the first time that manipulation of postnatal diet can limit adverse outcomes of fetal programming, with programmed hyperleptinemia and hypertension prevented by a postnatal diet enriched with omega-3 fatty acids. This raises the possibility that dietary supplementation with omega-3 fatty acids may provide a viable therapeutic option for preventing and/or reducing adverse programming outcomes in humans.

BACKGROUND: There is growing evidence that oxidative stress contributes to the pathogenesis of hypertension and endothelial dysfunction. Thus, dietary antioxidants may beneficially influence blood pressure (BP) and endothelial function by reducing oxidative stress. OBJECTIVE: To determine if vitamin C and polyphenols, alone or in combination, can lower BP, improve endothelial function and reduce oxidative stress in hypertensive individuals. DESIGN: A total of 69 treated hypertensive individuals with a mean 24-h ambulatory systolic blood pressure > or = 125 mmHg participated in a randomized, double-blind, placebo-controlled, factorial trial. Following a 3-week washout, participants received 500 mg/day vitamin C, 1000 mg/day grape-seed polyphenols, both vitamin C and polyphenols, or neither for 6 weeks. At baseline and post-intervention, 24-h ambulatory BP, ultrasound-assessed endothelium-dependent and -independent vasodilation of the brachial artery, and markers of oxidative damage, (plasma and urinary F2-isoprostanes, oxidized low-density lipoproteins and plasma tocopherols), were measured. RESULTS: A significant interaction between grape-seed and vitamin C treatments for effects on BP was observed. Vitamin C alone reduced systolic BP versus placebo (-1.8 +/- 0.8 mmHg, P = 0.03), while polyphenols did not (-1.3 +/- 0.8 mmHg, P = 0.12). However, treatment with the combination of vitamin C and polyphenols increased systolic BP (4.8 +/- 0.9 mmHg versus placebo; 6.6 +/- 0.8 mmHg versus vitamin C; 6.1 +/- 0.9 mmHg versus polyphenols mmHg, each P < 0.0001) and diastolic BP (2.7 +/- 0.6 mmHg, P < 0.0001 versus placebo; 1.5 +/- 0.6 mmHg, P = 0.016 versus vitamin C; 3.2 +/- 0.7 mmHg, P < 0.0001 versus polyphenols). Endothelium-dependent and -independent vasodilation, and markers of oxidative damage were not significantly altered. CONCLUSION: Although the mechanism remains to be elucidated, these results suggest caution for hypertensive subjects taking supplements containing combinations of vitamin C and polyphenols.

Background Effects of regular exposure to polyphenolic compounds found in tea, leading to improved endothelial function and blood pressure, may reduce cardiovascular disease risk. Controlled trials in humans have found that ingestion of tea can improve endothelial function, but also cause a rapid onset acute increase in blood pressure. Objective To examine the acute effects of tea consumption on fasting and postprandial vascular function and blood pressure. Methods Endothelium-dependent dilatation of the brachial artery, assessed using ultrasound and blood pressure were measured in 20 participants with a history of coronary artery disease. Measurements were performed at baseline and at 3.5 h (blood pressure) and 4 h (endothelial function) after drinking three cups of black tea or hot water (consumed at time = 0, 1.5 and 3 h) with and without a high-fat (50 g) meal: a total of four treatments administered in random order. Results The high-fat meal did not impair endothelial function. In comparison to water alone, endothelium-dependent dilatation was increased by the meal with tea (1.7 (0.4, 3.0)%, P = 0.02), but was not significantly altered by the tea alone (0.7 (-0.6, 2.0)%, P = 0.32). Systolic blood pressure was significantly increased by tea alone in comparison to each of the other three groups: water alone (9.3 (4.5, 14.1) mmHg, P = 0.0003), meal with water (9.8 (5.0, 14.6) mmHg, P = 0.0001) and meal with tea (7.2 (2.4,12.0) mmHg, P = 0.004). Consumption of a meal negated the acute increase in systolic blood pressure found with tea in the fasting state. Conclusion Consumption of food may alter the acute effects of tea on vascular function and blood pressure.

OBJECTIVE—Population data suggest that alcohol consumption may influence the risk of diabetes in a biphasic manner, but this has not been tested by any controlled interventions. The object of this study was to determine whether reducing alcohol intake in moderate-to-heavy drinkers (40–110 g/day) results in improvement in insulin sensitivity. RESEARCH DESIGN AND METHODS—A 4-week run-in period where subjects maintained their usual drinking pattern was followed by randomization to a two-way cross-over intervention study. In each of two 4-week treatment interventions, subjects either substituted their usual alcohol intake with a 0.9% alcohol beer or maintained their usual alcohol intake. At the end of each 4-week period, insulin sensitivity as determined by the low-dose insulin glucose infusion test and the homeostasis model assessment (HOMA) score, and biomarkers of alcohol consumption (γ-glutamyl transpeptidase [γ-GT] and HDL cholesterol) were measured. RESULTS—A total of 16 healthy men aged 51.0 ± 2.7 (mean ± SEM) years with a BMI of 26.4 ± 0.61 kg/m2 completed the study. There was a large reduction in alcohol intake (72.4 ± 5.0 vs. 7.9 ± 1.6 g/day, P < 0.001) and significant reductions in γ-GT (geometric mean 24.4 units/l [95% CI 19.7–30.2] vs. 18.6 units/l [15.5–22.2], P < 0.01) and HDL cholesterol (1.36 ± 0.07 vs. 1.13 ± 0.07 mmol/l, P < 0.001). There was no effect of alcohol on insulin sensitivity index (ISI), fasting insulin, glucose, or HOMA score. CONCLUSIONS—A substantial reduction in alcohol intake from 7.2 to 0.8 standard drinks per day in healthy men did not change insulin sensitivity as measured by ISI or HOMA score.

The French Paradox relates to the observation that mortality rates due to coronary heart disease are relatively low in France despite a diet rich in saturated fats. Another paradox linked to alcohol is the diverse associations of acute and chronic alcohol use with respect to insulin resistance, incidence of type 2 diabetes and incidence of cardiovascular disease in type 2 diabetes. Reports consistently suggest that the acute affects of alcohol induce a state of insulin resistance following either an oral and/or intravenous glucose load. Contrary to the acute alcohol studies is a large body of epidemiological evidence from cross-sectional studies which suggests that long-term exposure to alcohol is associated with an improvement in insulin sensitivity. Furthermore, a substantial number of prospective studies point to a protective role for light to moderate chronic alcohol intake against the development of diabetes as well as a protective effect of regular mild to moderate drinking against coronary artery d...