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BACKGROUND: Vascular calcification, a risk factor for cardiovascular disease, is common among patients with CKD and is an independent contributor to increased vascular stiffness and vascular risk in this patient group. Vitamin K is a cofactor for proteins involved in prevention of vascular calcification. Whether or not vitamin K supplementation could improve arterial stiffness in patients with CKD is unknown. METHODS: To determine if vitamin K supplementation might improve arterial stiffness in patients in CKD, we conducted a parallel-group, double-blind, randomized trial in participants aged 18 or older with CKD stage 3b or 4 (eGFR 15–45 ml/min per 1.73 m(2)). We randomly assigned participants to receive 400 μg oral vitamin K2 or matching placebo once daily for a year. The primary outcome was the adjusted between-group difference in carotid-femoral pulse wave velocity at 12 months. Secondary outcomes included augmentation index, abdominal aortic calcification, BP, physical function, and blood markers of mineral metabolism and vascular health. We also updated a recently published meta-analysis of trials to include the findings of this study. RESULTS: We included 159 randomized participants in the modified intention-to-treat analysis, with 80 allocated to receive vitamin K and 79 to receive placebo. Mean age was 66 years, 62 (39%) were female, and 87 (55%) had CKD stage 4. We found no differences in pulse wave velocity at 12 months, augmentation index at 12 months, BP, B-type natriuretic peptide, or physical function. The updated meta-analysis showed no effect of vitamin K supplementation on vascular stiffness or vascular calcification measures. CONCLUSIONS: Vitamin K2 supplementation did not improve vascular stiffness or other measures of vascular health in this trial involving individuals with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Vitamin K therapy to improve vascular health in patients with chronic kidney disease, ISRCTN21444964 (www.isrctn.com)

OBJECTIVE We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression. RESULTS Faster HbA1c progression was independently associated with faster deterioration of OGIS and GS and increasing CLIm; visceral or liver fat, HDL-cholesterol, and triglycerides had further independent, though weaker, roles (R2 = 0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from area under the receiver operating characteristic = 0.94). The proportion of fast progressors was reduced from 56% to 8–10% in subgroups in which only one trait among OGIS, GS, and CLIm was relatively stable (odds ratios 0.07–0.09). T2D polygenic risk score and baseline pancreatic fat, glucagon-like peptide 1, glucagon, diet, and physical activity did not show an independent role. CONCLUSIONS Deteriorating insulin sensitivity and β-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of patients with T2D in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, β-cell function, and insulin clearance may be relevant to prevent progression.

Aims/hypothesis Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has an independent prognostic association with major coronary events (MCE). However, no study has investigated whether type 2 diabetes status modifies the effect of Lp-PLA2 activity or inhibition on the risk of MCE. We investigate the interaction between diabetes status and Lp-PLA2 activity with risk of MCE. Subsequently, we test the resulting hypothesis that diabetes status will play a role in modifying the efficacy of an Lp-PLA2 inhibitor. Methods A retrospective cohort study design was utilised in two study populations. Discovery analyses were performed in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) cohort based in Scotland, UK. Participants were categorised by type 2 diabetes control status: poorly controlled (HbA1c ≥ 48 mmol/mol or ≥6.5%) and well-controlled (HbA1c n = 7420). In a secondary analysis of the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial of Lp-PLA2 inhibitor (darapladib) efficacy, 15,828 participants were stratified post hoc by type 2 diabetes diagnosis status (diabetes or no diabetes) at time of recruitment. Lp-PLA2 activity was then divided into population-specific quartiles. MCE were determined from linked medical records in GoDARTS and trial records in STABILITY. First, the interaction between diabetes control status and Lp-PLA2 activity on the outcome of MCE was explored in GoDARTS. The effect was replicated in the placebo arm of STABILITY. The effect of Lp-PLA2 on MCE was then examined in models stratified by diabetes status. This helped determine participants at higher risk. Finally, the effect of Lp-PLA2 inhibition was assessed in STABILITY in the higher risk group. Cox proportional hazards models adjusted for confounders were used to assess associations. Results In GoDARTS, a significant interaction between increased Lp-PLA2 activity (continuous and quartile divided) and diabetes control status was observed in the prediction of MCE (p p p p p = 0.008). In contrast, Lp-PLA2 inhibitor showed no efficacy in individuals with low activity, regardless of diabetes status, or among those with no baseline diabetes and high Lp-PLA2 activity. Conclusions/interpretation These results support the hypothesis that diabetes status modifies the association between Lp-PLA2 activity and MCE. These results suggest that cardiovascular morbidity and mortality associated with Lp-PLA2 activity is especially important in patients with type 2 diabetes, particularly those with worse glycaemic control. Further investigation of the effects of Lp-PLA2 inhibition in diabetes appears warranted. Data availability STABILITY trial data are available from clinicaltrials.gov repository through the GlaxoSmithKline clinical study register https://clinicaltrials.gov/ct2/show/NCT00799903. GoDARTS datasets generated during and/or analysed during the current study are available following request to the GoDARTS Access Managements Group https://godarts.org/scientific-community/. Graphical abstract

Background Advanced chronic kidney disease is common in older people and is frequently accompanied by metabolic acidosis. Oral sodium bicarbonate is used to treat this acidosis, but evidence is lacking on whether or not this provides a net gain in health or quality of life for older people. Objectives The objectives were to determine whether or not oral bicarbonate therapy improves physical function, quality of life, markers of renal function, bone turnover and vascular health compared with placebo in older people with chronic kidney disease and mild acidosis; to assess the safety of oral bicarbonate; and to establish whether or not oral bicarbonate therapy is cost-effective in this setting. Design A parallel-group, double-blind, placebo-controlled randomised trial. Setting The setting was nephrology and geriatric medicine outpatient departments in 27 UK hospitals. Participants Participants were adults aged ≥ 60 years with advanced chronic kidney disease (glomerular filtration rate category 4 or 5, not on dialysis) with a serum bicarbonate concentration of Interventions Eligible participants were randomised 1 : 1 to oral sodium bicarbonate or matching placebo. Dosing started at 500 mg three times daily, increasing to 1 g three times daily if the serum bicarbonate concentration was Main outcome measures The primary outcome was the between-group difference in the Short Physical Performance Battery score at 12 months, adjusted for baseline. Other outcome measures included generic and disease-specific health-related quality of life, anthropometry, 6-minute walk speed, grip strength, renal function, markers of bone turnover, blood pressure and brain natriuretic peptide. All adverse events were recorded, including commencement of renal replacement therapy. For the health economic analysis, the incremental cost per quality-adjusted life-year was the main outcome. Results In total, 300 participants were randomised, 152 to bicarbonate and 148 to placebo. The mean age of participants was 74 years and 86 (29%) were female. Adherence to study medication was 73% in both groups. A total of 220 (73%) participants were assessed at the 12-month visit. No significant treatment effect was evident for the primary outcome of the between-group difference in the Short Physical Performance Battery score at 12 months (–0.4 points, 95% confidence interval –0.9 to 0.1 points; p = 0.15). No significant treatment benefit was seen for any of the secondary outcomes. Adverse events were more frequent in the bicarbonate arm (457 vs. 400). Time to commencement of renal replacement therapy was similar in both groups (hazard ratio 1.22, 95% confidence interval 0.74 to 2.02; p = 0.43). Health economic analysis showed higher costs and lower quality of life in the bicarbonate arm at 1 year, with additional costs of £564 (95% confidence interval £88 to £1154) and a quality-adjusted life-year difference of –0.05 (95% confidence interval –0.08 to –0.01); placebo dominated bicarbonate under all sensitivity analyses for incremental cost-effectiveness. Limitations The trial population was predominantly white and male, limiting generalisability. The increment in serum bicarbonate concentrations achieved was small and a benefit from larger doses of bicarbonate cannot be excluded. Conclusions Oral sodium bicarbonate did not improve a range of health measures in people aged ≥ 60 years with chronic kidney disease category 4 or 5 and mild acidosis, and is unlikely to be cost-effective for use in the NHS in this patient group. Once other current trials of bicarbonate therapy in chronic kidney disease are complete, an individual participant meta-analysis would be helpful to determine which subgroups, if any, are more likely to benefit and which treatment regimens are more beneficial. Trial registration Current Controlled Trials ISRCTN09486651 and EudraCT 2011-005271-16. The systematic review is registered as PROSPERO CRD42018112908. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 27. See the NIHR Journals Library website for further project information.

Background Chronic kidney disease with metabolic acidosis is common in older people, but the effectiveness of oral sodium bicarbonate therapy in this group is unclear. We tested whether oral sodium bicarbonate provides net health benefit for older people with advanced chronic kidney disease and serum bicarbonate concentrations Methods Pragmatic multicentre, parallel group, double-blind, placebo-controlled randomised trial. We recruited adults aged ≥ 60 years with estimated glomerular filtration rate of 2, not receiving dialysis, with serum bicarbonate concentration Results We randomised 300 participants between May 2013 and February 2017, mean age 74 years, 86 (29%) female. At 12 months, 116/152 (76%) participants allocated to bicarbonate and 104/148 (70%) allocated to placebo were assessed; primary outcome data were available for 187 participants. We found no significant treatment effect for the SPPB: bicarbonate arm 8.3 (SD 2.5) points, placebo arm 8.8 (SD 2.2) and adjusted treatment effect − 0.4 (95% CI − 0.9 to 0.1, p = 0.15). We found no significant treatment effect for glomerular filtration rate (0.6 mL/min/1.73 m2, 95% CI − 0.8 to 2.0, p = 0.39). The bicarbonate arm showed higher costs and lower quality of life as measured by the EQ-5D-3L tool over 1 year (£564 [95% CI £88 to £1154]); placebo dominated bicarbonate under all sensitivity analyses. Adverse events were more frequent in those randomised to bicarbonate (457 versus 400). Conclusions Oral sodium bicarbonate did not improve physical function or renal function, increased adverse events and is unlikely to be cost-effective for use by the UK NHS for this patient group. Trial registration European Clinical Trials Database (2011-005271-16) and ISRCTN09486651; registered 17 February 2012.

BackgroundNon-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in type 2 diabetes (T2D) and beyond. Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and ultimately hepatocellular carcinomas.Methods and FindingsUtilizing the baseline data from the IMI DIRECT participants (n=1514) we sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. Multi-omic (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, and measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI image-derived liver fat content (ConclusionsWe have developed clinically useful liver fat prediction models (see:www.predictliverfat.org) and identified biological features that appear to affect liver fat accumulation.

Summary The presentation and underlying pathophysiology of type 2 diabetes (T2D) is complex and heterogeneous. Recent studies attempted to stratify T2D into distinct subgroups using data-driven approaches, but their clinical utility may be limited if categorical representations of complex phenotypes are suboptimal. We apply a soft-clustering (archetype) method to characterize newly diagnosed T2D based on 32 clinical variables. We assign quantitative clustering scores for individuals and investigate the associations with glycemic deterioration, genetic risk scores, circulating omics biomarkers, and phenotypic stability over 36 months. Four archetype profiles represent dysfunction patterns across combinations of T2D etiological processes and correlate with multiple circulating biomarkers. One archetype associated with obesity, insulin resistance, dyslipidemia, and impaired β cell glucose sensitivity corresponds with the fastest disease progression and highest demand for anti-diabetic treatment. We demonstrate that clinical heterogeneity in T2D can be mapped to heterogeneity in individual etiological processes, providing a potential route to personalized treatments., Graphical abstract, Highlights • Soft clustering based on 32 phenotypes identified 4 quantitative archetypes • These reflect different patterns of dysfunction across T2D etiological processes • The four archetypes are different in disease progression, GRSs, and omics signals • Some patients are dominated by one archetype, but many have etiological combinations, Wesolowska-Andersen et al. represent the clinical heterogeneity of newly diagnosed T2D as four quantitative archetype profiles reflecting patterns of dysfunction in disease etiological processes, rather than clustering individuals into categorical subgroups as attempted by others. The archetype profiles differ in genetic risk scores, disease progression, and circulating omics biomarkers.

Aims/hypothesis The aim of the study was to examine the association between lipoprotein-associated phospholipase A2 (Lp-PLA2) activity levels and incident diabetic retinopathy and change in retinopathy grade. Methods This was a cohort study of diabetic participants with serum collected at baseline and routinely collected diabetic retinal screening data. Participants with type 2 diabetes from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) cohort were used. This cohort is composed of individuals of white Scottish ancestry from the Tayside region of Scotland. Survival analysis accounting for informative censoring by modelling death as a competing risk was performed for the development of incident diabetic retinopathy from a disease-free state in a 3 year follow-up period (n = 1364) by stratified Lp-PLA2 activity levels (in quartiles). The same analysis was performed for transitions to more severe grades. Results The hazard of developing incident diabetic retinopathy was 2.08 times higher (95% CI 1.64, 2.63) for the highest quartile of Lp-PLA2 activity compared with the lowest. Higher Lp-PLA2 activity levels were associated with a significantly increased risk for transitions to all grades. The hazards of developing observable (or more severe) and referable (or more severe) retinopathy were 2.82 (95% CI 1.71, 4.65) and 1.87 (95% CI 1.26, 2.77) times higher for the highest quartile of Lp-PLA2 activity compared with the lowest, respectively. Conclusions/interpretation Higher Lp-PLA2 levels are associated with increased risk of death and the development of incident diabetic retinopathy, as well as transitions to more severe grades of diabetic retinopathy. These associations are independent of calculated LDL-cholesterol and other traditional risk factors. Further, this biomarker study shows that the association is temporally sensitive to the proximity of the event to measurement of Lp-PLA2. Electronic supplementary material The online version of this article (10.1007/s00125-018-4601-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Background Neutrophil elastase (NE) has been linked to lung neutrophil dysfunction in bronchiectasis and cystic fibrosis (CF), making NE inhibition a potential therapeutic target. NE inhibitor trials have given mixed result perhaps because not all patients have elevated airway NE activity. Methods We tested whether a single baseline sputum NE measurement or a combination of clinical parameters could enrich patient populations with elevated NE activity for “personalised medicine”. Intra- and interindividual variations of total and active NE levels in induced sputum from patients with CF or bronchiectasis were monitored over 14 days. Patients with established CF and bronchiectasis (n=5 per group) were recruited. NE was measured using three different methods: one total and two active NE assays. Subsequently, we analysed the association between clinical parameters and NE from a large bronchiectasis cohort study (n=381). Results All three assays showed a high degree of day-to-day variability (0–233% over 14 days). There were strong correlations found between all assays (p, NE at baseline can enrich studies for “high” NE patients, while in bronchiectasis, inclusion of patients with Pseudomonas aeruginosa, purulent sputum and frequent exacerbations provides a high degree of certainty of including patients with high NE http://ow.ly/mPTS30nI8ec

Background: Theoretical links between seasonal lack of sunlight, hypovitaminosis D and excess cardiovascular disease and death prompted our adding novel to conventional cohort analyses. Methods: We tested three postulates on 13 224 Scottish Heart Health Extended Cohort participants, assayed for 25-hydroxyvitamin D (25OHD) and followed for 22 years. (i) Endpoints enumerated by month of occurrence mirror annual seasonal oscillation in 25OHD. (ii) Endpoint seasonality is increased in people with below median 25OHD. (iii) Low 25OHD predicts endpoints independently of major risk factors. Results: Baseline median 25OHD level was 36.4 (other quartiles 26.7, 51.7) nmol/l. The March trough was half the August peak, both well after seasonal solstices. (i) There was no demonstrable monthly variation in First Cardiovascular Event (n = 3307). Peaks and troughs for All Death and Cardiovascular Death (n = 2987, 1350) were near the solstices, earlier than extremes of 25OHD. (ii) Endpoint variability showed no difference between those above and below median 25OHD. (iii) Cox model hazard ratios (HR), by decreasing 25OHD, increased modestly and nonspecifically for all endpoints examined, with no threshold, the gradients diminishing by ∼ 60% following multiple adjustment. For Cardiovascular Disease, HR, by 20 (∼SD) nmol/l decrease, = 1.224 (1.175, 1.275) adjusted for age and sex; additionally adjusted for family history, deprivation index, smoking, systolic blood pressure, total and HDL cholesterol, = 1.093 (1.048, 1.139); All Deaths = 1.238 (1.048, 1.139) and 1.098 (1.050, 1.149). 25OHD made no independent contribution to cardiovascular discrimination and reclassification. Conclusions: Our analyses challenge vitamin D’s alleged role as major prime mover in cardiovascular disease and mortality.

BNP (B-type natriuretic peptide) has been reported to be elevated in preclinical states of vascular damage. To elucidate the relationship between plasma BNP and endothelial function, we have investigated the relationship between BNP and endothelial function in a cohort of subjects comprising healthy subjects as well as at-risk subjects with cardiovascular risk factors. To also clarify the relative contribution of different biological pathways to the individual variation in endothelial function, we have examined the relationship between a panel of multiple biomarkers and endothelial function. A total of 70 subjects were studied (mean age, 58.1±4.6 years; 27% had a history of hypertension and 18% had a history of hypercholesterolaemia). Endothelium-dependent vasodilatation was evaluated by the invasive ACH (acetylcholine)-induced forearm vasodilatation technique. A panel of biomarkers of biological pathways was measured: BNP, haemostatic factors PAI-1 (plasminogen-activator inhibitor 1) and tPA (tissue plasminogen activator), inflammatory markers, including cytokines [hs-CRP (high sensitive C-reactive protein), IL (interleukin)-6, IL-8, IL-18, TNFα (tumour necrosis factor α) and MPO (myeloperoxidase] and soluble adhesion molecules [E-selectin and sCD40 (soluble CD40)]. The median BNP level in the study population was 26.9 pg/ml. Multivariate regression analyses show that age, the total cholesterol/HDL (high-density lipoprotein) ratio, glucose and BNP were independent predictors of endothelial function, and BNP remained an independent predictor (P=0.009) in a binary logistic regression analysis using FBF (forearm blood flow) as a dichotomous variable based on the median value. None of the other plasma biomarkers was independently related to ACH-mediated vasodilatation. In a strategy using several biomarkers to relate to endothelial function, plasma BNP was found to be an independent predictor of endothelial function as assessed by endothelium-dependent vasodilatation in response to ACH.

The aim of this study was to study the effects of rosuvastatin in patients with rheumatoid arthritis (RA) looking at the C-reactive protein (CRP), interleukin-6 (IL-6) and joint disease activity. Fifty RA patients were randomized in a double-blind placebo-controlled trial to receive either 10 mg of rosuvastatin or placebo as an adjunct to existing disease-modifying antirheumatic therapy. Patients were followed up for a six-month period. Measurements were done at baseline and six months. CRP and IL-6 were measured in the blood. RA disease activity was measured using disease activity score based on 28 joint counts (DAS 28). When analysing from baseline to six months there was no difference between the rosuvastatin and placebo groups in rheumatoid disease activity (–0.01; standard deviation [SD], 1.08; and +0.18; SD, 0.95; respectively; P value 0.509). There was a trend towards improvement in CRP in the rosuvastatin group (–3.23; SD, 18.18) compared with the placebo group (+17.43; SD, 38.03); P value, 0.161. IL-6 showed a trend towards worsening in the rosuvastatin group (+0.15; SD, 1.09) compared with placebo (–0.73; SD, 1.4); P value, 0.054. These data show that rosuvastatin with might decrease the CRP independent to IL-6 in patients with RA but does not improve the overall rheumatoid disease activity.

OBJECTIVE: The aim of this study was to compare self-reported and parent-reported quality of life for a group of pediatric patients with chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) and age- and gender-matched healthy control children, to determine the extent of functional and physical impairment. METHODS: The Child Health Questionnaire was completed by 25 children with CFS/ME, who were recruited throughout the United Kingdom, and by 23 age-, gender-, and Tanner scale-matched control children. In addition, patients were asked questions about the background to their illness (ie, precipitating factors), the status of their illness, and school attendance. RESULTS: The median illness duration for patients was 3 years. Sixty-eight percent of the children said that their illness developed quickly, and the illness had an infectious onset for 88%. Only 1 child (4%) attended school full-time, whereas 12 (48%) attended school part-time and 8 (32%) received home tuition only. Children with CFS/ME scored significantly lower for 10 of 14 Child Health Questionnaire concepts; the lowest scores were observed for global health (scores of 21.4 and 84.1 for patients and control subjects, respectively; P < .0001) and role/social limitations attributable to physical health problems (scores of 24.9 and 100, respectively; P < .0001). Quality of life for the children with CFS/ME compared unfavorably with previously published results for pediatric patients with type 1 diabetes mellitus or asthma. CONCLUSION: The quality of life of children with CFS/ME was profoundly reduced, compared with that of their healthy counterparts.

The aim of the current study was to investigate the levels of interleukin-6 (IL-6), its soluble receptors (sIL-6R and sgp130) and F(2)-isoprostanes, at rest and during exercise, in patients with chronic fatigue syndrome (CFS). Six male CFS patients and six healthy controls performed an incremental exercise test to exhaustion and a submaximal exercise bout to exhaustion. Blood samples taken in the submaximal test at rest, immediately post-exercise and 24 h post-exercise were analyzed for IL-6, sIL-6R, sgp130 and F(2)-isoprostanes. A further 33 CFS and 33 healthy control participants gave a resting blood sample for IL-6 and sIL-6R measurement. During the incremental exercise test only power output at the lactate threshold was lower (P

Some of the symptoms reported by people with CFS (chronic fatigue syndrome) are associated with various cardiovascular phenomena. Markers of cardiovascular risk, including inflammation and oxidative stress, have been demonstrated in some patients with CFS, but little is known about the relationship between these and prognostic indicators of cardiovascular risk in this patient group. In the present study, we investigated the relationship between inflammation and oxidative stress and augmentation index, a measure of arterial stiffness, in 41 well-characterized patients with CFS and in 30 healthy subjects. AIx@75 (augmentation index normalized for a heart rate of 75 beats/min) was significantly greater in patients with CFS than in control subjects (22.5±1.7 compared with 13.3±2.3% respectively; P=0.002). Patients with CFS also had significantly increased levels of CRP (C-reactive protein) (2.58±2.91 compared with 1.07±2.16 μg/ml respectively; P

Macrovascular disease is an important cause of the increased morbidity and mortality rates associated with type 1 diabetes, and this vascular impairment begins in childhood. The aim of this study was to determine whether introducing intensive diabetes management [intensive insulin therapy (IIT) and ‘Sweet Talk’ text-messaging support] produces measurable improvements in endothelial function. One hundred and twenty-six patients fulfilled the eligibility criteria (type 1 diabetes for >1 year; on conventional insulin therapy (CIT); aged between 8 and 18 years), of whom 92 enrolled. Patients were randomised to group 1, CIT only (n = 28); group 2, CIT and Sweet Talk (n = 33); or group 3, IIT and Sweet Talk (n = 31). Vascular assessments (including measures of endothelial damage, activation, dysfunction and oxidative stress) and HbA1c were performed at baseline and repeated after 12 months of the study. Glycaemic control deteriorated in patients on CIT, but improved significantly in patients allocated to IIT (p = 0.007). IIT was associated with significantly greater improvements in E-selectin (p

Inflammation is the reaction of the body to injury. Acute inflammation is an important component in the healing of tissue and the initiation of the immune response. Once initiated, the inflammatory response is a complex cascade of processes and the endothelium is active throughout these processes. Chronic inflammation is where exacerbation of the inflammatory response has occurred and further tissue damage ensues. The inflammatory response involves the inflammatory cells (leukocytes), the endothelium and smooth muscle cells and various products produced by them. Initially, leukocyte recruitment and adherence to the endothelium occurs. Activated leukocytes adhere to the endothelium via cell-adhesion molecules and this is followed by transmigration of the leukocyte through the wall of the blood vessel and finally migration towards the site of injury or infection. Cytokines play important roles in the inflammatory process; some are pro-inflammatory and other anti-inflammatory and a balance is required for maintaining control of the inflammatory process. A pro-inflammatory state can alter the function of the endothelium (e.g. homeostasis can change and the endothelium will become predominately pro-coagulant). The inflammatory response is a necessary and required part of wound healing and, when it is maintained as a regulated and orchestrated response, it repairs structural and functional aspects of the injured tissue. Thereby, it can aid in the recovery of a patient after surgery. However, excessive stimulation of the inflammatory process can aggravate tissue damage.

In the present study, we have investigated whether the peripheral cholinergic abnormalities that we have reported previously [Spence, Khan and Belch (2000) Am. J. Med. 108, 736–739] in patients with chronic fatigue syndrome (CFS) are also present in those with Gulf War syndrome (GWS) and agricultural workers exposed to organophosphate pesticides, where cholinesterase inhibition is specifically implicated. We also looked at whether these abnormalities might be due to a reduction in the activity of cholinesterase expressed on the vascular endothelium. We used laser Doppler imaging to measure the forearm skin blood flow responses to iontophoresis of acetylcholine and of methacholine (which is resistant to breakdown by cholinesterase) in patients with CFS, GWS and those with a history of ill health after definite organophosphate exposure, as well as in matched healthy controls. The response to acetylcholine was significantly higher in patients with CFS than in controls (P=0.029, repeated-measures ANOVA), but was normal in those with GWS and those exposed to organophosphates. The methacholine response was higher than the acetylcholine response in all patient groups except for those with CFS, where there was no difference between the responses. Although there are many clinical similarities between these three illnesses, our results indicate peripheral cholinergic abnormalities in the vascular endothelium of only patients with CFS, suggesting that this syndrome has a different aetiology, which might involve inhibition of vascular cholinesterase.

Although the aetiology of chronic fatigue syndrome (CFS) is unknown, there have been a number of reports of blood flow abnormalities within the cerebral circulation and systemic blood pressure defects manifesting as orthostatic intolerance. Neither of these phenomena has been explained adequately, but recent reports have linked cerebral hypoperfusion to abnormalities in cholinergic metabolism. Our group has previously reported enhanced skin vasodilatation in response to cumulative doses of transdermally applied acetylcholine (ACh), implying an alteration of peripheral cholinergic function. To investigate this further, we studied the time course of ACh-induced vasodilatation following a single dose of ACh in 30 patients with CFS and 30 age- and gender-matched healthy control subjects. No differences in peak blood flow was seen between patients and controls, but the time taken for the ACh response to recover to baseline was significantly longer in the CFS patients than in control subjects. The time taken to decay to 75% of the peak response in patients and controls was 13.7 +/- 11.3 versus 8.9 +/- 3.7 min (P = 0.03), respectively, and time taken to decay to 50% of the peak response was 24.5 +/- 18.8 versus 15.1 +/- 8.9 min (P = 0.03), respectively. Prolongation of ACh-induced vasodilatation is suggestive of a disturbance to cholinergic pathways, perhaps within the vascular endothelium of patients with CFS, and might be related to some of the unusual vascular symptoms, such as hypotension and orthostatic intolerance, which are characteristic of the condition.

Study objectives: To evaluate the effect of adding zafirlukast or low-dose theophylline to a beclomethasone dipropionate (BDP) extra-fine hydrofluoroalkane aerosol on bronchial hyperresponsiveness as the primary outcome variable. Methods: Twenty-four patients with mild-to-moderate asthma were studied using a randomized crossover design with the following three treatment blocks: (1) beclomethasone, 100 g/d, alone for the first 2 weeks followed by 400 g/d alone for the next 2 weeks; (2) beclomethasone, 100 g/d, followed by 400 g/d, with the addition of zafirlukast, 20 mg bid; (3) beclomethasone, 100 g/d, followed by 400 g/d, with the addition of theophylline, 200 to 300 mg bid. Measurements were made after 2 and 4 weeks of each treatment and at pretreatment baseline. Results: The mean trough plasma theophylline concentration was 6.7 mg/L, coinciding with the anti-inflammatory target range (ie, 5 to 10 mg/L). The provocative dose of methacholine causing a 20% fall in FEV1 (as doubling dose difference from baseline) was significantly (p < 0.05) greater with beclomethasone, 100 g, plus zafirlukast (1.1 doubling dose) but not with beclomethasone, 100 g, plus theophylline (0.7 doubling dose) compared to beclomethasone, 100 g alone (0.4 doubling dose), but not compared to beclomethasone, 400 g alone (1.1 doubling dose). There were also significant (p < 0.05) differences between beclomethasone, 100 g, plus zafirlukast (but not BDP, 100 g, plus theophylline) vs beclomethasone, 100 g, alone in terms of nitric oxide level, midexpiratory phase of forced expiratory flow, and peak expiratory flow. There were no further significant improvements observed with the addition of zafirlukast or theophylline to beclomethasone, 400 g. Conclusions: A leukotriene receptor antagonist, but not low-dose theophylline, conferred significant additive anti-inflammatory effects to therapy with a low-dose inhaled corticosteroid but not to that with a medium dose of an inhaled corticosteroid. Thus, optimizing the dose of inhaled corticosteroid as monotherapy would seem to be the logical first step, which is in keeping with current guidelines. (CHEST 2002; 122:151–159)

Background and aims Low 25-hydroxyvitamin D levels are common in patients with chronic fatigue syndrome; such patients also manifest impaired vascular health. We tested whether high-dose intermittent oral vitamin D therapy improved markers of vascular health and fatigue in patients with chronic fatigue syndrome. Methods and results Parallel-group, double-blind, randomised placebo-controlled trial. Patients with chronic fatigue syndrome according to the Fukuda (1994) and Canadian (2003) criteria were randomised to receive 100,000 units oral vitamin D3 or matching placebo every 2 months for 6 months. The primary outcome was arterial stiffness measured using carotid-femoral pulse wave velocity at 6 months. Secondary outcomes included flow-mediated dilatation of the brachial artery, blood pressure, cholesterol, insulin resistance, markers of inflammation and oxidative stress, and the Piper Fatigue scale. As many as 50 participants were randomised; mean age 49 (SD 13) years, mean baseline pulse wave velocity 7.8 m/s (SD 2.3), mean baseline office blood pressure 128/78 (18/12) mmHg and mean baseline 25-hydroxyvitamin D level 46 (18) nmol/L. 25-hydroxyvitamin D levels increased by 22 nmol/L at 6 months in the treatment group relative to placebo. There was no effect of treatment on pulse wave velocity at 6 months (adjusted treatment effect 0.0 m/s; 95% CI −0.6 to 0.6; p = 0.93). No improvement was seen in other vascular and metabolic outcomes, or in the Piper Fatigue scale at 6 months (adjusted treatment effect 0.2 points; 95% CI −0.8 to 1.2; p = 0.73). Conclusion High-dose oral vitamin D3 did not improve markers of vascular health or fatigue in patients with chronic fatigue syndrome. Trial registration: www.controlled-trials.com, ISRCTN59927814.

To compare the effect of a fixed combination of an oestrogen (17-beta oestradiol) with a cyclical progestagen (norethisterone) on glycaemic control, plasma lipoproteins and haemostatic factors in women with Type 2 diabetes.Oral and transdermal hormone replacement therapy (HRT) were compared to no HRT treatment in 33 postmenopausal women with Type 2 diabetes, in a 12-week randomised prospective open parallel group study.In the 11 women who received 12 weeks of oral HRT, there was a significant fall in total cholesterol (5.9+/-1.0 (S.D.) to 4.7+/-1.0 mmol l(-1), P=0.005), low density lipoprotein cholesterol (3.44+/-0.89 to 2.77+/-0.92 mmol l(-1), P=0.005) and triglyceride values (median (range)), (2.46 (0.96-5.52) to 2.29 (1.00-3.87) mmol l(-1), P0.05). Oral HRT improved glycated haemoglobin (HbA(1c)) (7.4+/-1.4 to 6.8+/-1.2%, Por =0.005). Oral HRT additionally reduced the cell adhesion factor E-selectin (82+/-33 to 60+/-20 microg l(-1), P0.01) and factor VII (143+/-25 to 109+/-24% pooled plasma activity, P0.01). No improvement in any of these parameters, except E-selectin (65+/-19 to 58+/-18 microg l(-1), P0.01), occurred in the nine women receiving transdermal HRT, and no improvement occurred in the 13 controls randomised to no treatment.In women with Type 2 diabetes, cyclical oestrogen and progestagen taken orally for 12 weeks significantly improved glycaemic control and lipoprotein concentrations. These metabolic benefits were not apparent when a similar HRT preparation was administered transdermally.

Inadequate intake of the recommended five-a-day fruit and vegetable portions might contribute to increased cardiovascular disease risk. We assessed the effects of dietary intake of a blackcurrant juice drink, rich in vitamin C and polyphenols, on oxidative stress and vascular function. This was a double-blind, placebo-controlled, parallel group study of 66 healthy adults who habitually consume

Background Endothelial cell dysfunction is an early feature of vascular disease and oxidative stress may be involved in its pathogenesis. Methods Fifty-one children, adolescents and young people with Type 1 diabetes with no clinical diabetic angiopathy, mean age±SD of 16±4 years, diabetes duration of 8±5 years, and HbA1c of 8.5±1.6%, and 29 age, sex matched normal controls had blood samples assayed for E-selectin, intercellular cell adhesion molecule-1, von Willebrand Factor, red cell superoxide dismutase, plasma thiol and red cell glutathione. Results E-selectin and ICAM-1 levels were significantly higher in the diabetic patients at 72±24 ng/ml and 287±57 ng/ml, respectively vs 43±16 ng/ml and 248±71 ng/ml in the normal controls (p

Background Hand–arm vibration syndrome (HAVS) is a form of secondary Raynaud's phenomenon (RP) of occupational origin. In other forms of RP, blood and blood vessel wall interaction is one factor in the pathophysiology. Cytokines and cell adhesion molecules both play an important role in this interaction, and basal vascular tone and vasodilatation are regulated by nitric oxide. Methods Blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP) and levels of soluble intercellular adhesion molecule-1 (sICAM-1) and the inflammatory cytokine interleukin 8 (IL-8) were measured in eight male patients with vibration white finger disease, which is part of HAVS, and in eight healthy matched male control subjects. Results sICAM-1 levels were statistically higher (P = 0.02, Mann–Whitney U-test) and IL-8 levels (P

Objective: Low vitamin D levels and risk factors for vascular disease are both common in South Asian women. This trial evaluated whether vitamin D supplementation could improve markers of vascular health in South Asian women with low 25-hydroxyvitamin D levels. Methods: Parallel-group, double-blind, randomised placebo-controlled trial. Healthy South Asian women with baseline serum 25-hydroxyvitamin D levels of

Low circulating 25 hydroxyvitamin D (25OHD) levels have been associated with increased blood pressure, impaired vascular health and an increased risk of cardiovascular events [1]. We have previously shown that patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) have vascular dysfunction [2,3], which is related to increased levels of low grade inflammation and oxidative stress [2]. Vitamin D may affect the cardiovascular system through multiple pathways— via influence on the inflammatory process [1] and oxidative stress [4], by effects on cardiac myocyte hypertrophy, vascular stiffness and calcification, and by direct effects on endothelial function [1]. The purpose of this pilot investigation in CFS/ME patients was to explore the association between serum 25-hydroxyvitamin D (25(OH)D) and markers of cardiovascular disease risk, including endothelial function, arterial stiffness, low grade inflammation and oxidative stress. Participants were recruited from a local register of CFS/ME patients and fulfilled the Centres for Disease Control (CDC) classification for CFS [5]. The local medical ethics committee approved the study (Ref 07/S1402/65) and all volunteers gave written informed consent. The study was conducted in accordance with the Declaration of Helsinki. Serum 25(OH)D, CRP and TNFα were measured using commercially available ELISA kits (IDS Ltd. UK, Kalon Biological Ltd., UK and RD Sigma-Aldrich Co. Ltd.) and sodium nitroprusside (SNP; David Bull Laboratories). Skin perfusion was measured using a laser Doppler imager (moorLDI, Moor Instruments, Axminster, UK). Two baseline scans of skin perfusion were taken before the iontophoresis protocol was administered. The peak response to ACh and SNP was recorded. An index of arterial stiffness was assessed non-invasively using the SphygmoCor pulse waveform analysis system (Scanmed Medical Instruments, Moreton-in-Marsh, UK). We measured the augmentation index (AIx) [7], normalised for a heart rate of 75 beats/min, and aortic pulse wave velocity (PWV) by sequentially recording gated ECG carotid and radial waveforms. Descriptive statistics for baseline characteristics were calculated. All variables were normally distributed save for CRP and TNFα, which were log-transformed prior to further analysis. Pearson's correlation coefficients were calculated to analyse the relationship between 25(OH) results and each marker of vascular risk. Linear regression analysis was used to adjust for factors known to affect both 25(OH)D levels and vascular risk, i.e. age, sex, smoking and body mass index. Forty one participants (19–63 years old) were included in the study and were assessed between 1st November 2009 and 31st March 2010. The mean length of illness was 9.7 years (SD 5.7 years) and all patients were of white European descent. None had a history of renal disease. Seventeen patients were on more than one medication. Eight patients were on low dose amitriptyline taken at night for sleeping problems, 7 were on thyroxine,13 patients were on paracetamol based drugs, 2 were on β-blockers, and 5 were on benzodiazepine derivatives. Table 1 displays the details of the patients and data for markers of vascular function, inflammation and oxidative stress. Levels of 25(OH)D ranged from 7 to 108 nmol/l. We found significant correlations between 25(OH)D levels and markers of inflammation, oxidative stress, endothelial function and arterial stiffness as shown in Table 2. Levels of 25(OH)D correlated significantly with age (r = 0.40, P = 0.01), but not with gender (r = 0.05, P = 0.69) or BMI (r = 0.03, P = 0.85). We found significant correlations between 25(OH)D levels and markers of cardiovascular risk, inflammation and oxidative stress in this group of patients with CFS/ME. Our results thus extend findings in other populations to patients with CFS/ME, who have recently been shown to have impaired vascular function [2,3]. The relationship between impaired vascular function, low 25(OH) D levels and symptoms in CFS/ME is likely to be complex. It is possible that microvascular dysfunction might contribute to impaired muscle function in the syndrome, but vitamin D is also known to have direct effects on neuromuscular function [8]. Conversely, the low levels of physical activity that are a hallmark of CFS/ME are likely to lead to