Clinically significant chronic liver disease in people with Type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

BACKGROUND: Type 2 diabetes is an independent risk factor for chronic liver disease, however disease burden estimates and knowledge of prognostic indicators are lacking in community populations. AIMS: To describe the prevalence and incidence of clinically significant chronic liver disease amongst community-based older people with Type 2 diabetes and to determine risk factors which might assist in discriminating patients with unknown prevalent or incident disease. DESIGN: Prospective cohort study. METHODS: Nine hundred and thirty-nine participants in the Edinburgh Type 2 Diabetes Study underwent investigation including liver ultrasound and non-invasive measures of non-alcoholic steatohepatitis (NASH), hepatic fibrosis and systemic inflammation. Over 6-years, cases of cirrhosis and hepatocellular carcinoma were collated from multiple sources. RESULTS: Eight patients had known prevalent disease with 13 further unknown cases identified (prevalence 2.2%) and 15 incident cases (IR 2.9/1000 person-years). Higher levels of systemic inflammation, NASH and hepatic fibrosis markers were associated with both unknown prevalent and incident clinically significant chronic liver disease (allP < 0.001). CONCLUSIONS: Our study investigations increased the known prevalence of clinically significant chronic liver disease by over 150%, confirming the suspicion of a large burden of undiagnosed disease. The disease incidence rate was lower than anticipated but still much higher than the general population rate. The ability to identify patients both with and at risk of developing clinically significant chronic liver disease allows for early intervention and clinical monitoring strategies. Ongoing work, with longer follow-up, including analysis of rates of liver function decline, will be used to define optimal risk prediction tools.

Hepatic steatosis and non-alcoholic fatty liver disease are not associated with decline in renal function in people with Type 2 diabetes.

AIMS: We aimed to determine whether the presence of hepatic steatosis and/or non-alcoholic fatty liver disease was associated with decline in renal function or onset of microalbuminuria in a cohort of people with Type 2 diabetes, including those managed in both primary and secondary care. METHODS: Nine hundred and thirty-three patients from the Edinburgh Type 2 Diabetes Study, a cohort of Scottish men and women aged 60-74 years with Type 2 diabetes, underwent assessment for hepatic steatosis by liver ultrasonography 1 year after recruitment. Non-alcoholic fatty liver disease was defined as the presence of steatosis following exclusion of secondary causes of liver disease. Patients were followed for 4 years and decline in renal function was assessed by the change in estimated glomerular filtration rate over time. RESULTS: Of the 933 subjects, 530 had hepatic steatosis and, of those with hepatic steatosis, 388 had non-alcoholic fatty liver disease. Neither hepatic steatosis nor non-alcoholic fatty liver disease were significantly associated with rate of decline in renal function, with the mean rate of decline in estimated glomerular filtration rate being -1.55 ml min(-1) 1.73 m(-2) per year for participants with hepatic steatosis compared with -1.84 ml min(-1) 1.73 m(-2) for those without steatosis (P = 0.19). Similar results were obtained when the analysis was restricted to participants with and without non-alcoholic fatty liver disease (-1.44 vs. -1.64 ml min(-1) 1.73 m(-2) per year, respectively; P = 0.44). Additionally, neither hepatic steatosis nor non-alcoholic fatty liver disease were associated with the onset or regression of albuminuria during follow-up (all P ≥ 0.05). CONCLUSIONS: The presence of hepatic steatosis/non-alcoholic fatty liver disease was not associated with decline in renal function during a 4-year follow-up in our cohort of older people with Type 2 diabetes.

Diagnosis of cystic fibrosis in London and South East England before and after the introduction of newborn screening.

INTRODUCTION: Newborn screening (NBS) for cystic fibrosis (CF) was introduced to London and South East England in 2007. We wished to assess the details of missed cases, and to compare the age at diagnosis and other clinical parameters, prescreening and postscreening. METHODS: Retrospective and prospective case notes and database review of all newly diagnosed CF patients in our 7 CF centres, for 18 months before and 4 years after NBS started. RESULTS: 347 patients were diagnosed with CF. 126 patients were not screened (born before or abroad), and had a median age at diagnosis of 2.4 years, excluding those with meconium ileus (MI). Their median time to diagnosis from initial symptoms was 1 year, and in 10% it was >6 years. After NBS started, 170 were diagnosed by NBS (48% were already symptomatic); 7 moved into the region after NBS elsewhere; 34 presented with MI (6 were negative on NBS); and 10 screened children were missed (false negative cases). Median age of diagnosis was 3 weeks. Prevalence was 1 in 3991 live births. By 2 years of age (with data on 104 patients), 49 children (47%) had their first isolation of Pseudomonas aeruginosa, while 37 (36%) had their first growth of Staphylococcus aureus from respiratory cultures. CONCLUSIONS: NBS has significantly reduced the age of diagnosis, although many were symptomatic even at 3 weeks of age. A small number of patients with CF can still be missed by the screening programme, and the diagnosis should be considered even with a negative screen result.

Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events.

BACKGROUND: The ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS. DESIGN: An analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events. METHODS: Subjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events. RESULTS: In predicting events in the external validation dataset, C-index for the FRS was 0.672 (95% CI 0.599 to 0.737) in men and 0.578 (95% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95% CI 0.612 to 0.749) and large increase in women to 0.690 (95% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3% (95% CI 0.0 to 7.6%, p = 0.050) and 9.6% (95% CI 6.1 to 16.4%, p < 0.001), respectively. Restricting the FRS + ABI model to those with FRS intermediate 10-year risk of 10 to 19% resulted in higher NRI of 15.9% (95% CI 6.1 to 20.6%, p < 0.001) in men and 23.3% (95% CI 13.8 to 62.5%, p = 0.002) in women. However, incorporating ABI in an improved newly fitted risk factor model had a nonsignificant effect: NRI 2.0% (95% CI 2.3 to 4.2%, p = 0.567) in men and 1.1% (95% CI 1.9 to 4.0%, p = 0.483) in women. CONCLUSIONS: An ABI risk model may improve prediction especially in individuals at intermediate risk and when performance of the base risk factor model is modest.

Common carotid intima-media thickness does not add to Framingham risk score in individuals with diabetes mellitus: the USE-IMT initiative.

AIMS/HYPOTHESIS: The aim of this work was to investigate whether measurement of the mean common carotid intima-media thickness (CIMT) improves cardiovascular risk prediction in individuals with diabetes. METHODS: We performed a subanalysis among 4,220 individuals with diabetes in a large ongoing individual participant data meta-analysis involving 56,194 subjects from 17 population-based cohorts worldwide. We first refitted the risk factors of the Framingham heart risk score on the individuals without previous cardiovascular disease (baseline model) and then expanded this model with the mean common CIMT (CIMT model). The absolute 10 year risk for developing a myocardial infarction or stroke was estimated from both models. In individuals with diabetes we compared discrimination and calibration of the two models. Reclassification of individuals with diabetes was based on allocation to another cardiovascular risk category when mean common CIMT was added. RESULTS: During a median follow-up of 8.7 years, 684 first-time cardiovascular events occurred among the population with diabetes. The C statistic was 0.67 for the Framingham model and 0.68 for the CIMT model. The absolute 10 year risk for developing a myocardial infarction or stroke was 16% in both models. There was no net reclassification improvement with the addition of mean common CIMT (1.7%; 95% CI -1.8, 3.8). There were no differences in the results between men and women. CONCLUSIONS/INTERPRETATION: There is no improvement in risk prediction in individuals with diabetes when measurement of the mean common CIMT is added to the Framingham risk score. Therefore, this measurement is not recommended for improving individual cardiovascular risk stratification in individuals with diabetes.

Prevalence of abnormal plasma liver enzymes in older people with Type 2 diabetes.

AIMS: To determine the prevalence and distribution of abnormal plasma liver enzymes in a representative sample of older adults with Type 2 diabetes. METHODS: Plasma concentrations of alanine aminotransferase, aspartate aminotransferase and γ-glutamyltransferase were measured in a randomly selected, population-based cohort of 1066 men and women aged 60-75 years with Type 2 diabetes (the Edinburgh Type 2 Diabetes Study). RESULTS: Overall, 29.1% (95% CI 26.1-31.8) of patients had one or more plasma liver enzymes above the upper limit of the normal reference range. Only 10.1% of these patients had a prior history of liver disease and a further 12.4% reported alcohol intake above recommended limits. Alanine aminotransferase was the most commonly raised liver enzyme (23.1% of patients). The prevalence of abnormal liver enzymes was significantly higher in men (odds ratio 1.40, 95% CI 1.07-1.83), in the youngest 5-year age band (odds ratio 2.02, 95% CI 1.44-2.84), in patients with diabetes duration < 5 years (odds ratio 1.38, 95% CI 1.01-1.90), plasma HbA(1c) ≥ 58 mmol/mol (7.5%) (odds ratio 1.43, 95% CI 1.09-1.88), obese BMI (odds ratio 2.84, 95% CI 1.59-3.06) and secondary care management for their diabetes (odds ratio 1.40, 95% CI 1.05-1.87). However, all these factors combined accounted for only 7.6% of the variation in liver enzyme abnormality. CONCLUSIONS: The prevalence of elevated liver enzymes in people with Type 2 diabetes is high, with only modest variation between clinically defined patient groups. Further research is required to determine the prognostic value of raised, routinely measured liver enzymes to inform decisions on appropriate follow-up investigations.

A novel mechanism for hypofibrinolysis in diabetes: the role of complement C3.

AIMS/HYPOTHESIS: Impaired fibrin clot lysis is a key abnormality in diabetes and complement C3 is one protein identified in blood clots. This work investigates the mechanistic pathways linking C3 and hypofibrinolysis in diabetes using ex vivo/in vitro studies. METHODS: Fibrinolysis and C3 plasma levels were determined in type 1 diabetic patients and healthy controls, and the effects of glycaemia investigated. C3 incorporation into fibrin clots and modulation of fibrinolysis were analysed by ELISA, immunoblotting, turbidimetric assays and electron and confocal microscopy. RESULTS: Clot lysis time was longer in diabetic children than in controls (599 ± 18 and 516 ± 12 s respectively; p < 0.01), C3 levels were higher in diabetic children (0.55 ± 0.02 and 0.43 ± 0.02 g/l respectively; p < 0.01) and both were affected by improving glycaemia. An interaction between C3 and fibrin was confirmed by the presence of lower protein levels in sera compared with corresponding plasma and C3 detection in plasma clots by immunoblot. In a purified system, C3 was associated with thinner fibrin fibres and more prolongation of lysis time of clots made from fibrinogen from diabetic participants compared with controls (244 ± 64 and 92 ± 23 s respectively; p < 0.05). Confocal microscopy showed higher C3 incorporation into diabetic clots compared with controls, and fully formed clot lysis was prolonged by 764 ± 76 and 428 ± 105 s respectively (p < 0.05). Differences in lysis, comparing diabetes and controls, were not related to altered plasmin generation or C3-fibrinogen binding assessed by plasmon resonance. CONCLUSIONS/INTERPRETATION: C3 incorporation into clots from diabetic fibrinogen is enhanced and adversely affects fibrinolysis. This may be one novel mechanism for compromised clot lysis in diabetes, potentially offering a new therapeutic target.

Severe hypoglycaemia and late-life cognitive ability in older people with Type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

OBJECTIVE: To determine the association between lifetime severe hypoglycaemia and late-life cognitive ability in older people with Type 2 diabetes. METHODS: Cross-sectional, population-based study of 1066 men and women aged 60-75 years, with Type 2 diabetes. Frequency of severe hypoglycaemia over a person's lifetime and in the year prior to cognitive testing was assessed using a previously validated self-completion questionnaire. Results of age-sensitive neuropsychological tests were combined to derive a late-life general cognitive ability factor, 'g'. Vocabulary test scores, which are stable during ageing, were used to estimate early life (prior) cognitive ability. RESULTS: After age- and sex- adjustment, 'g' was lower in subjects reporting at least one prior severe hypoglycaemia episode (n = 113), compared with those who did not report severe hypoglycaemia (mean 'g'-0.34 vs. 0.05, P < 0.001). Mean vocabulary test scores did not differ significantly between the two groups (30.2 vs. 31.0, P = 0.13). After adjustment for vocabulary, difference in 'g' between the groups persisted (means -0.25 vs. 0.04, P < 0.001), with the group with severe hypoglycaemia demonstrating poorer performance on tests of Verbal Fluency (34.5 vs. 37.3, P = 0.02), Digit Symbol Testing (45.9 vs. 49.9, P = 0.002), Letter-Number Sequencing (9.1 vs. 9.8, P = 0.005) and Trail Making (P < 0.001). These associations persisted after adjustment for duration of diabetes, vascular disease and other potential confounders. CONCLUSIONS: Self-reported history of severe hypoglycaemia was associated with poorer late-life cognitive ability in people with Type 2 diabetes. Persistence of this association after adjustment for estimated prior cognitive ability suggests that the association may be attributable, at least in part, to an effect of hypoglycaemia on age-related cognitive decline.

Prevalence and markers of advanced liver disease in type 2 diabetes.

BACKGROUND: Type 2 diabetes is a risk factor for progression of non-alcoholic fatty liver disease (NAFLD) to fibrosis and cirrhosis. We examined the prevalence of advanced liver disease in people with type 2 diabetes and analysed the effectiveness of liver function tests (LFTs) as a screening tool. METHODS: Participants (n = 939, aged 61-76 years) from the Edinburgh Type 2 Diabetes Study, a randomly selected population of people with type 2 diabetes, underwent abdominal ultrasonography. Hyaluronic acid (HA) and platelet count/spleen diameter ratio (PSR) were used as non-invasive markers of hepatic fibrosis and portal hypertension. Subjects were screened for secondary causes of liver disease that excluded them from a diagnosis of NAFLD. The efficacy of LFTs [alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT)] in screening for liver disease was determined. RESULTS: Cirrhosis was identified by ultrasound in four participants (0.4%). Ten (1.1%) had evidence of portal hypertension (PSR < 909), and two (0.2%) had hepatocellular carcinoma. Fifty-three participants (5.7%) had evidence of hepatic fibrosis (HA > 100 ng/ml in the absence of joint disease); a further 169 had HA > 50 ng/ml. In participants with NAFLD-related fibrosis (HA > 100 ng/ml), 12.5% had an elevated ALT level and 17.5% had an elevated GGT level. CONCLUSION: The prevalence of hepatic fibrosis and cirrhosis were lower than expected. The use of LFTs to screen for liver disease missed most cases of fibrosis predicted by raised HA levels.

Association of retinal arteriolar dilatation with lower verbal memory: the Edinburgh Type 2 Diabetes Study.

AIMS/HYPOTHESIS: Retinal vascular calibre changes may reflect early subclinical microvascular disease in diabetes. Because of the considerable homology between retinal and cerebral microcirculation, we examined whether retinal vascular calibre, as a proxy of cerebral microvascular disease, was associated with cognitive function in older people with type 2 diabetes. METHODS: A cross-sectional analysis of 954 people aged 60-75 years with type 2 diabetes from the population-based Edinburgh Type 2 Diabetes Study was performed. Participants underwent standard seven-field binocular digital retinal photography and a battery of seven cognitive function tests. The Mill Hill Vocabulary Scale was used to estimate pre-morbid cognitive ability. Retinal vascular calibre was measured from an image field with the optic disc in the centre using a validated computer-based program. RESULTS: After age and sex adjustment, larger retinal arteriolar and venular calibres were significantly associated with lower scores for the Wechsler Logical Memory test, with standardised regression coefficients -0.119 and -0.084, respectively (p < 0.01), but not with other cognitive tests. There was a significant interaction between sex and retinal vascular calibre for logical memory. In male participants, the association of increased retinal arteriolar calibre with logical memory persisted (p < 0.05) when further adjusted for vocabulary, venular calibre, depression, cardiovascular risk factors and macrovascular disease. In female participants, this association was weaker and not significant. CONCLUSIONS/INTERPRETATION: Retinal arteriolar dilatation was associated with poorer memory, independent of estimated prior cognitive ability in older men with type 2 diabetes. The sex interaction with stronger findings in men requires confirmation. Nevertheless, these data suggest that impaired cerebral arteriolar autoregulation in smooth muscle cells, leading to arteriolar dilatation, may be a possible pathogenic mechanism in verbal declarative memory decrements in people with diabetes.

The use of ultrasound to diagnose hepatic steatosis in type 2 diabetes: intra- and interobserver variability and comparison with magnetic resonance spectroscopy.

AIM: To compare ultrasound gradings of steatosis with fat fraction (FF) on magnetic resonance spectroscopy (MRS; the non-invasive reference standard for quantification of hepatic steatosis), and evaluate inter- and intraobserver variability in the ultrasound gradings. MATERIALS AND METHODS: Triple grading of hepatic ultrasound examination was performed by three independent graders on 131 people with type 2 diabetes. The stored images of 60 of these individuals were assessed twice by each grader on separate occasions. Fifty-eight patients were pre-selected on the basis of ultrasound grading (normal, indeterminate/mild steatosis, or severe steatosis) to undergo (1)H-MRS. The sensitivity and specificity of the ultrasound gradings were determined with reference to MRS data, using two cut-offs of FF to define steatosis, ≥9% and ≥6.1%. RESULTS: Median (intraquartile range) MRS FF (%) in the participants graded on ultrasound as normal, indeterminate/mild steatosis, and severe steatosis were 4.2 (1.2-5.7), 4.1 (3.1-8.5) and 19.4 (12.9-27.5), respectively. Using a liver FF of ≥6.1% on MRS to denote hepatic steatosis, the unadjusted sensitivity and specificity of ultrasound gradings (severe versus other grades of steatosis) were 71 and 100%, respectively. Interobserver agreement within one grade was observed in 79% of cases. Exact intraobserver agreement ranged from 62 to 87%. CONCLUSION: Hepatic ultrasound provided a good measure of the presence of significant hepatic steatosis with good intra- and interobserver agreement. The grading of a mildly steatotic liver was less secure and, in particular, there was considerable overlap in hepatic FF with those who had a normal liver on ultrasound.

Safety of formoterol in children and adolescents: experience from asthma clinical trials.

BACKGROUND: The safety of long-acting ß(2) agonist (LABA) therapy in asthma remains controversial but no large scale analyses have been published of LABA safety in children. METHODS: The frequency of asthma-related deaths and hospitalisations following formoterol use in children (4-11 years) and adolescents (12-17 years), compared with non-LABA treatment, was assessed in all AstraZeneca-sponsored, randomised, controlled, parallel-group trials (≥3 months) where formoterol was used as maintenance and/or as reliever therapy. RESULTS: 11,849 children and adolescents under the age of 18 years from 41 trials were identified, 82% of whom used an inhaled corticosteroid (ICS) as concomitant medication. The number of asthma-related deaths (one 13-year-old boy among 7796 formoterol-treated patients, and none among 4053 non-LABA-treated patients) was too low to allow any between-group comparison. The frequency of patients with asthma-related hospitalisations was not different in formoterol-treated versus non-LABA-treated patients, either in children (1.16% (38/3263) vs 1.11% (24/2165)) or in adolescents (0.51% (23/4533) vs 0.85% (16/1888)). Asthma-related hospitalisations based on daily dose of formoterol were: (A) 4.5 or 9 µg: 1.9% (18/980); (B) 18 µg: 0.5% (14/2870); (C) 36 µg: 0% (0/67); and (D) variable dosing: 0.75% (29/3879). There was no difference between formoterol-treated and non-LABA-treated patients as regards ethnicity. CONCLUSIONS: Formoterol use in children and adolescents (4-17 years) with asthma in this large study where the majority are prescribed concomitant ICS is not associated with any increased risk of asthma-related hospitalisations. The results are not influenced by dose or ethnicity.

Associations between polymorphisms in five inflammation-related genes and cognitive ability in older persons.

Several studies have found associations between inflammatory biomarker levels and cognitive ability. This study tested the relationship between polymorphisms in genes that are associated with or encode the biomarkers and cognitive ability and estimated lifetime cognitive change. Data came from the aspirin for asymptomatic atherosclerosis trial (n = 2091, mean age = 67.2 years ). Twelve single nucleotide polymorphisms (SNPs) were genotyped from five genes (IL-1alpha, IL-1beta, IL-6, HNF-1A and F13A1). Cognition was assessed via administration of a five-test battery of psychometric tests, which were used to derive a general intelligence factor, g. A vocabulary-based cognitive test was also administered and adjusted for in the analysis to enable an estimation of lifetime cognitive change. Age- and sex-adjusted analyses yielded one weakly significant association between the IL-1alpha rs2856838 SNP and a measure of mental flexibility/processing speed (P = 0.044). Adjustment for the vocabulary-based scores resulted in a single, significant association between the IL-1alpha rs3783546 SNP and a measure of processing speed (P = 0.048). There is little evidence to suggest an association between SNPs in the inflammation-related genes IL-1alpha, IL-1beta, IL-6, TCF-1 and F13A1 and cognition in an elderly population of community-dwelling Scottish citizens.

Symptoms of depression but not anxiety are associated with central obesity and cardiovascular disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

AIMS/HYPOTHESIS: The aim of the study was to identify risk factors for depression and anxiety in a well-characterised cohort of individuals with type 2 diabetes mellitus. METHODS: We used baseline data from participants (n = 1,066, 48.7% women, aged 67.9 +/- 4.2 years) from the Edinburgh Type 2 Diabetes Study. Symptoms of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS). Obesity was characterised according to both overall (body mass index, fat mass) and abdominal (waist circumference) measurements. Cardiovascular disease was assessed by questionnaire, physical examination and review of medical records. Stepwise multiple linear regression was performed to identify explanatory variables related to either anxiety or depression HADS scores. RESULTS: Abdominal obesity (waist circumference) and cardiovascular disease (ischaemic heart disease and ankle-brachial pressure index) were related to depression but not anxiety. Lifetime history of severe hypoglycaemia was associated with anxiety. Other cardiovascular risk factors or microvascular complications were not related to either anxiety or depressive symptoms. CONCLUSIONS/INTERPRETATION: Depression but not anxiety is associated with abdominal obesity and cardiovascular disease in people with type 2 diabetes mellitus. This knowledge may help to identify depressive symptoms among patients with type 2 diabetes who are at greatest risk.

Circulating plasma cortisol concentrations are not associated with coronary artery disease or peripheral vascular disease.

BACKGROUND: Although the prevalence of cardiovascular disease is declining, the obesity epidemic with associated metabolic syndrome may reverse this trend. Hypothalamic-pituitary-adrenal (HPA) axis activation may underlie the metabolic syndrome, but whether circulating cortisol levels predict vascular disease is less clear. A recent study reported a positive correlation between cortisol levels measured prior to coronary angiography and disease severity, but others have not demonstrated such a relationship. This may be due to different sampling conditions, reflecting basal cortisol levels, vs. responsiveness of HPA axis activity, which may have diverse influences on the pathogenesis of atherosclerosis. AIMS: To determine whether basal circulating cortisol levels predict coronary artery (CAD) or peripheral vascular disease. METHODS: Basal plasma cortisol levels were measured in 278 subjects with suspected CAD, who had undergone elective coronary angiography and in 76 cases and 85 controls with and without peripheral vascular disease, respectively. RESULTS: After adjustment for potential confounding factors, circulating cortisol levels tended to be lower in those with confirmed coronary vessel disease at angiography (P = 0.10), and in those requiring intervention following angiography (P = 0.07). Lower cortisol levels also predicted those with more symptoms of angina (P = 0.01). Cortisol levels were no different in those with or without peripheral vascular disease. CONCLUSION: A single measurement of circulating cortisol is a poor predictor of vascular disease. More detailed characterization of the HPA axis is necessary to determine the role of circulating endogenous glucocorticoids and their responsiveness to stress in atherosclerosis.

Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.

CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

Retinal microvascular abnormalities and cognitive dysfunction: a systematic review.

OBJECTIVE: To examine the evidence for an association between cognitive impairment or dementia and the presence of retinal microvascular abnormalities. METHODS: A systematic review of observational studies identified through searching five electronic databases and reference lists. Studies were required to have both a recognised cognitive function assessment (either a structured neuropsychological test or a clinical evaluation of dementia), and assessment of the retinal microvasculature (either characteristics associated with generalised retinopathy or changes specific to arterioles or venules). RESULTS: 6 studies were included. Studies were clinically and methodologically heterogeneous and of variable quality. Some degree of cognitive impairment was found to be associated with the presence of retinal microvascular abnormalities in all studies, although the extent of the association varied. The presence of retinal vascular signs was mostly associated with poorer verbal memory, mental speed and executive function in the general population, but not consistently associated with other cognitive modalities. CONCLUSIONS: There is some evidence suggesting a positive association between retinal microvascular abnormalities and cognitive impairment or dementia in elderly people and in patients with diabetes. Findings are inconclusive, and further better designed studies are required, with standardised and objective retinal vascular assessment and a range of sensitive cognitive tests.

Lipid-lowering for peripheral arterial disease of the lower limb.

BACKGROUND: Lipid-lowering therapy is recommended for secondary prevention in people with coronary artery disease. It may also reduce cardiovascular events and/or local disease progression in people with lower limb peripheral arterial disease (PAD). OBJECTIVES: To assess the effects of lipid-lowering therapy on all-cause mortality, cardiovascular events and local disease progression in patients with PAD of the lower limb. SEARCH STRATEGY: The authors searched The Cochrane Peripheral Vascular Diseases Group's Specialised Register (last searched February 2007) and the Cochrane Central Register of Controlled Trials (CENTRAL) (last searched Issue 2, 2007) for publications describing randomised controlled trials of lipid-lowering therapy in peripheral arterial disease of the lower limb. SELECTION CRITERIA: Randomised controlled trials of lipid-lowering therapy in patients with PAD of the lower limb. DATA COLLECTION AND ANALYSIS: Three authors independently assessed trial quality and extracted data. MAIN RESULTS: Eighteen trials were included, involving a total of 10,049 participants. Trials differed considerably in their inclusion criteria, outcomes measured, and type of lipid-lowering therapy used. Only one trial (PQRST) reported a detrimental effect of active treatment on blood lipid/lipoprotein levels. The pooled results from all eligible trials indicated that lipid-lowering therapy had no statistically significant effect on overall mortality (Odds Ratio (OR) 0.86; 95% Confidence Interval (CI) 0.49 to 1.50) or on total cardiovascular events (OR 0.8; 95% CI 0.59 to 1.09). However, subgroup analysis which excluded PQRST showed that lipid-lowering therapy significantly reduced the risk of total cardiovascular events (OR 0.74; CI 0.55 to 0.98). This was primarily due to a positive effect on total coronary events (OR 0.76; 95% CI 0.67 to 0.87). Greatest evidence of effectiveness came from the use of simvastatin in people with a blood cholesterol >/= 3.5 mmol/litre (HPS). Pooling of the results from several small trials on a range of different lipid-lowering agents indicated an improvement in total walking distance (Weighted Mean Difference (WMD) 152 m; 95% CI 32.11 to 271.88) and pain-free walking distance (WMD 89.76 m; 95% CI 30.05 to 149.47) but no significant impact on ankle brachial index (WMD 0.04; 95% CI -0.01 to 0.09). AUTHORS' CONCLUSIONS: Lipid-lowering therapy is effective in reducing cardiovascular mortality and morbidity in people with PAD. It may also improve local symptoms. Until further evidence on the relative effectiveness of different lipid-lowering agents is available, use of a statin in people with PAD and a blood cholesterol level >/=3.5 mmol/litre is most indicated.

A prospective evaluation of nesiritide in the treatment of pediatric heart failure.

This study sought to determine the potential of recombinant B-type natriuretic peptide (nesiritide) for the treatment of pediatric decompensated heart failure. Nesiritide is a widely used and effective treatment for decompensated heart failure (HF) in adults, but its safety and efficacy in pediatric patients is unclear. Outcomes of 55 separate nesiritide infusions of varying durations in 32 patients (13 males and 19 females; mean age, 8.01 years; range, 0.01-20.4) were evaluated prospectively. All patients received nesiritide in the intensive care unit. The starting dose (0.01 microg/kg/min) was titrated to a maximum of 0.03 microg/kg/min. All patients were monitored for clinical signs and symptoms, hemodynamics, urine output, electrolytes, oxygen requirements, and oral intake. Functional status was assessed by patients and/or their parents. All patients successfully underwent initiation and titration of nesiritide infusion. No hypotension or arrhythmias were noted during 478 cumulative days of therapy. Nesiritide was given safely with vasoactive medications. Mean urine output improved from 2.35 +/- 1.71 cc/kg/hr on the day before nesiritide initiation (baseline) to 3.10 +/- 1.94 cc/kg/hr on day 4 of treatment (p < 0.01). Serum creatinine decreased from 1.04 to 0.92 mg/dl (p = 0.096), mean central venous pressure from 13 to 7 mmHg (p = 0.018), and mean weight from 30.4 to 29.7 kg (p < 0.001) with therapy. Thirst, as subjectively assessed by patients old enough to respond, decreased with infusion in 31 of 42 cases (74%). Mean New York Heart Association functional class improved significantly (p < 0.001). Nesiritide infusion, alone or in combination, is a safe treatment for decompensated HF in pediatric patients. It is associated with decreased thirst and improved urine output and functional status, and it may be efficacious in the treatment of pediatric HF.

Risk of mortality and cardiovascular disease associated with the ankle-brachial index: Systematic review.

OBJECTIVE: To determine the strength and consistency with which a low ankle brachial pressure index (ABI), measured in the general population, is associated with an increased risk of subsequent death and/or cardiovascular events. DESIGN: Systematic review. DATA SOURCES: Medline, Embase, reference lists and grey literature were searched; studies known to experts were also retrieved. MAIN OUTCOME MEASURES: All cause mortality, fatal and non-fatal coronary heart disease and stroke. REVIEW METHODS: Longitudinal studies in which participants were representative of the general population (all ages, either sex) and which used any standard method for measurement and calculation of the ABI. Studies in which participants were selected according to presence of pre-existing disease or were post intervention (e.g. angioplasty or peripheral arterial grafting) were excluded. RESULTS: 11 studies comprising 44,590 subjects from six different countries were included. Despite clinical heterogeneity between studies, the findings were remarkably consistent in demonstrating an increased risk of clinical cardiovascular disease associated with a low ABI. A low ABI (<0.9) was associated with an increased risk of subsequent all cause mortality (pooled RR 1.60, 95% CI 1.32-1.95), cardiovascular mortality (pooled RR 1.96, 95% CI 1.46-2.64), coronary heart disease (pooled RR 1.45, 95% CI 1.08-1.93) and stroke (pooled RR 1.35, 95% CI 1.10-1.65) after adjustment for age, sex, conventional cardiovascular risk factors and prevalent cardiovascular disease. CONCLUSIONS: The ABI may help to identify asymptomatic individuals in the general population who are at increased risk of subsequent cardiovascular events. Evaluation is now required of the potential of incorporating ABI measurement into cardiovascular prevention programmes.