Secondary data analysis investigating effects of marine omega-3 fatty acids on circulating levels of leptin and adiponectin in older adults.

BACKGROUND: Higher leptin and lower adiponectin levels have been linked to progressing systemic inflammation and diseases of aging. Among older adults with obesity and an inflammatory conditions, we quantified effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation on leptin, adiponectin, and the leptin-to-adiponectin ratio (LAR). We also examined associations among adipokine and cytokine levels. METHODS: Using a randomized, double-blind, placebo-controlled design, participants (mean age 61.3 ± 2.1) received 1.5 g EPA + 1.0 g DHA (n = 14) or mineral oil (n = 18) daily. Plasma adipokine and cytokine levels were quantified by electrochemiluminescence at all study intervals. RESULTS: While no between-group differences were detected, there was a reduction in the LAR (by 23%, p=.065) between weeks 4 and 8 among the EPA+DHA group. Adiponectin levels were negatively associated with IL-1ß levels at week 4 (p=.02) and TNF-α levels at week 8 (p=.03). CONCLUSION: Potential benefits of EPA+DHA supplementation among aging populations warrant further study.

Older age of childhood type 1 diabetes onset is associated with islet autoantibody positivity >30 years later: the Pittsburgh Epidemiology of Diabetes Complications Study.

AIMS: To examine the association between islet autoantibody positivity and clinical characteristics, residual ß-cell function (C-peptide) and prevalence of complications in a childhood-onset (age <17 years), long-duration (≥32 years) type 1 diabetes cohort. METHODS: Islet autoantibodies (glutamic acid decarboxylase, insulinoma-associated protein 2 and zinc transporter-8 antibodies) were measured in the serum of participants who attended the 2011-2013 Pittsburgh Epidemiology of Diabetes Complications study follow-up examination (n=177, mean age 51 years, diabetes duration 43 years). RESULTS: Prevalences of islet autoantibodies were: glutamic acid decarboxylase, 32%; insulinoma-associated protein 2, 22%; and zinc transporter-8, 4%. Positivity for each islet autoantibody was associated with older age at diabetes onset (glutamic acid decarboxylase antibodies, P=0.03; insulinoma-associated protein 2 antibodies, P=0.001; zinc transporter-8 antibodies, P<0.0001). Older age at onset was also associated with an increasing number of autoantibodies (P = 0.001). Glutamic acid decarboxylase antibody positivity was also associated with lower HbA1c (P = 0.02), insulinoma-associated protein 2 antibody positivity was associated with lower prevalence of severe hypoglycaemic episodes (P=0.02) and both distal and autonomic neuropathy (P=0.04 for both), and zinc transporter-8 antibody positivity was associated with higher total and LDL cholesterol (P=0.01). No association between autoantibody positivity and C-peptide was observed. CONCLUSIONS: The strong association between islet autoantibody positivity and older age at type 1 diabetes onset supports the hypothesis of a less aggressive, and thus more persistent, immune process in those with older age at onset. This observation suggests that there may be long-term persistence of heterogeneity in the underlying autoimmune process.

Effect of age at menarche on microvascular complications among women with Type 1 diabetes.

AIM: To test the hypothesis that delayed menarche is associated with an increased microvascular complication risk among women with Type 1 diabetes. METHODS: We studied the female participants of an ongoing prospective study of childhood-onset Type 1 diabetes diagnosed during the period 1950-1980. Of 325 women, we included data from 315 who had reached menarche by the study baseline (1986-1988) and who self-reported their age at menarche. Both cross-sectional and prospective analyses over the 25-year follow-up were used to assess the relationship of age at menarche with the prevalence, incidence and cumulative incidence of microvascular complications, comprising overt nephropathy, proliferative retinopathy and confirmed distal symmetric polyneuropathy. RESULTS: In cross-sectional analyses at baseline, the odds of overt nephropathy increased 1.24 times (P=0.02) with each annual increase in age at menarche, and 3.2 times (P=0.009) in those with delayed menarche compared with women with normal menarche onset, after adjustment. Similarly, the cumulative incidence of overt nephropathy increased 1.16 times (P=0.01) with each older year of menarche and women with delayed menarche were at twofold increased risk of overt nephropathy (hazard ratio 2.30, P=0.001) compared with women with normal menarche onset. However, age at menarche was not significantly associated with either proliferative retinopathy or confirmed distal symmetric polyneuropathy after adjusting for covariates. CONCLUSIONS: Age at menarche was significantly associated with the prevalence and cumulative incidence of overt nephropathy, but not with proliferative retinopathy or confirmed distal symmetric polyneuropathy in Type 1 diabetes. Women with delayed menarche may therefore be targeted for early screening and timely interventions to prevent the development of nephropathy.

Depressive symptoms and cerebral microvascular disease in adults with Type 1 diabetes mellitus.

AIM: To assess the prevalence of, and risk factors for, depressive symptoms, comparing a sample of middle-aged adults with and without juvenile-onset Type 1 diabetes mellitus, and to determine if depressive symptoms were associated with white matter hyperintensity volume among those with Type 1 diabetes. METHODS: Depressive symptoms and white matter hyperintensities were compared between adults (age range 30-65 years) with juvenile-onset Type 1 diabetes (n=130) and adults without Type 1 diabetes (n=133). The association of Type 1 diabetes with depression was computed before and after adjustment for white matter hyperintensities. Among the Type 1 diabetes group, the primary associations of interest were between depressive symptoms (Beck Depression Inventory score ≥10) and white matter hyperintensities (n=71), hyperglycaemia and physical activity. Associations between depressive symptoms and diabetes-related complications, cognitive impairment, smoking and self-reported disability were examined. Analyses were controlled for education, sex, age and antidepressant use. RESULTS: Depressive symptoms were more prevalent among those with vs those without Type 1 diabetes (28% vs 3%; P<0.001). White matter hyperintensities explained 40% of the association of Type 1 diabetes with depressive symptoms, while Type 1 diabetes had a direct effect of 68% on depressive symptoms. Among those with Type 1 diabetes, depressive symptoms were related to white matter hyperintensity volume, a 16-year average HbA1c ≥58 mmol/mol (7.5%), and lower physical activity levels. Associations with other characteristics were not significant. CONCLUSION: These findings suggest a cerebrovascular origin for depressive symptoms in adults with Type 1 diabetes, perhaps triggered by hyperglycaemia. Future longitudinal studies should investigate whether targeting hyperglycaemia and physical inactivity alleviates depressive symptoms, possibly by slowing the development of cerebral microvascular disease, in people with Type 1 diabetes.

Predictors of early renal function decline in adults with Type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes and the Pittsburgh Epidemiology of Diabetes Complications studies.

AIM: Diabetic kidney disease is one of the leading complications of Type 1 diabetes, but its prediction remains a challenge. We examined predictors of rapid decline in estimated GFR (eGFR) in two Type 1 diabetes cohorts: the Coronary Artery Calcification in Type 1 Diabetes (CACTI) and the Pittsburgh Epidemiology of Diabetes Complications (EDC). METHODS: A select subset of participants (CACTI: n = 210 and EDC: n = 98) diagnosed before 17 years of age with Type 1 diabetes duration ≥ 7 years, and follow-up data on eGFR by CKD-EPI creatinine for up to 8 years were included in the analyses. Early renal function decline was defined as annual decline in eGFR ≥ 3 ml/min/1.73 m2 , and normal age-related decline as eGFR ≤ 1 ml/min/1.73 m2 . Parallel logistic regression models were constructed in the two cohorts. RESULTS: Early renal function decline incidence was 36% in CACTI and 41% in EDC. In both cohorts, greater baseline eGFR (CACTI: OR 3.12, 95% CI 1.97-5.05; EDC: OR 1.92, 95% CI 1.17-3.15 per 10 ml/min/1.73 m2 ) and log albumin-to-creatinine (ACR) (CACTI: OR 3.24, 95% CI 1.80-5.83; EDC: OR 1.87, 95% CI 1.18-2.96 per 1 unit) predicted greater odds of early renal function decline in fully adjusted models. Conversely, ACE inhibition predicted lower odds of early renal function decline in women in CACTI, but similar relationships were not observed in women in EDC. CONCLUSIONS: A substantial proportion of people with Type 1 diabetes in the EDC and CACTI cohorts experienced early renal function decline over time. ACE inhibition appeared to be protective only in women in CACTI where the prevalence of its use was twofold higher compared with the EDC.

Glycaemic control modifies the haptoglobin 2 allele-conferred susceptibility to coronary artery disease in Type 1 diabetes.

AIMS: We aimed to assess whether the association of the haptoglobin 2 allele with coronary artery disease is modified by glycaemic control in a prospective cohort study of individuals with childhood-onset Type 1 diabetes. METHODS: Coronary artery disease events (death from coronary artery disease, confirmed myocardial infarction, stenosis ≥50%, revascularization) were assessed between 1986 and 2013 among 480 individuals with Type 1 diabetes (baseline age 28 years; diabetes duration 19 years). Better glycaemic control was defined as an updated mean HbA1c during follow-up of <8% (64 mmol/mol). RESULTS: In crude models, the incidence of coronary artery disease increased with the number of haptoglobin 2 alleles (hazard ratio 1.34, 95% CI 1.05-1.71). This association was more pronounced in those with better than in those with worse glycaemic control (P interaction = 0.05) and remained essentially unaltered after multivariable adjustments (hazard ratio 2.65, 95% CI 1.30-5.41 in those with better glycaemic control and hazard ratio 1.20, 95% CI 0.93-1.56 in those with worse glycaemic control). CONCLUSIONS: These results suggest that, although better control may reduce the incidence of coronary artery disease in Type 1 diabetes, a residual risk related to the haptoglobin 2 allele remains.

Magnetic resonance imaging-quantified small bowel motility is a sensitive marker of response to medical therapy in Crohn's disease.

BACKGROUND: Magnetic resonance enterography (MRE) can measure small bowel motility, reduction in which reflects inflammatory burden in Crohn's Disease (CD). However, it is unknown if motility improves with successful treatment. AIM: To determine if changes in segmental small bowel motility reflect response to anti-TNFα therapy after induction and longer term. METHODS: A total of 46 patients (median 29 years, 19 females) underwent MRE before anti-TNFα treatment; 35 identified retrospectively underwent repeat MRE after median 55 weeks of treatment and 11 recruited prospectively after median 12 weeks. Therapeutic response was defined by physician global assessment (retrospective group) or a ≥3 point drop in the Harvey-Bradshaw Index (prospective group), C-reactive protein (CRP) and the MaRIA score. Two independent radiologists measured motility using an MRE image-registration algorithm. We compared motility changes in responders and nonresponders using the Mann-Whitney test. RESULTS: Anti-TNFα responders had significantly greater improvements in motility (median = 73.4% increase from baseline) than nonresponders (median = 25% reduction, P < 0.001). Improved MRI-measured motility was 93.1% sensitive (95%CI: 78.0-98.1%) and 76.5% specific (95% CI: 52.7-90.4%) for anti-TNFα response. Patients with CRP normalisation (<5 mg/L) had significantly greater improvements in motility (median = 73.4% increase) than those with persistently elevated CRP (median = 5.1%, P = 0.035). Individuals with post-treatment MaRIA scores of <11 had greater motility improvements (median = 94.7% increase) than those with post-treatment MaRIA score >11 (median 15.2% increase, P = 0.017). CONCLUSIONS: Improved MRI-measured small bowel motility accurately detects response to anti-TNFα therapy for Crohn's disease, even as early as 12 weeks. Motility MRI may permit early identification of nonresponse to anti-TNFα agents, allowing personalised treatment.

Prevalence and incidence of clinically recognized cases of Type 1 diabetes in children and adolescents in Rwanda, Africa.

AIMS: To determine prevalence and incidence estimates for clinically recognized cases of Type 1 diabetes from the Life For a Child Program (LFAC) with onset < 26 years in six representative districts, and the capital, of Rwanda. METHODS: Cases were identified from the LFAC registry and visits to district hospitals. Denominators were calculated from district-level population surveys. Period prevalence data were collected from 1 August 2011 to 31 July 2012 and annual incidence rates were calculated, retrospectively, for 2004-2011. Ninety-five per cent confidence intervals (95% CI) were calculated using a Poisson distribution. RESULTS: The prevalence of known Type 1 diabetes in seven districts in Rwanda for ages < 26 years was 16.4 [95% CI 14.6-18.4]/100 000 and for < 15 years was 4.8 [3.5-6.4]/100 000. Prevalence was higher in females (18.5 [15.8-21.4]/100 000) than males (14.1 [11.8-16.7]/100 000; P = 0.01) and rates increased with age. The annual incidence rate for those < 26 years was stable between 2007 and 2011 with a mean incidence over that time of 2.7 [2.0-3.7]/100 000 ( < 15 years = 1.2 [0.5-2.0]/100 000). Incidence rates were higher in females than males and peaked in males at ages 17 and 22 years and in females at age 18 years. CONCLUSIONS: Our report of known Type 1 diabetes cases shows lower incidence and prevalence rates in Rwanda than previously reported in the USA and most African countries. Incidence of recognized cases has increased over time, but has recently stabilized. However, the likelihood of missed cases due to death before diagnosis and misdiagnosis is high and therefore more definitive studies are needed.

Diabetes autoantibodies do not predict progression to diabetes in adults: the Diabetes Prevention Program.

AIMS: To determine if the presence of diabetes autoantibodies predicts the development of diabetes among participants in the Diabetes Prevention Program. METHODS: A total of 3050 participants were randomized into three treatment groups: intensive lifestyle intervention, metformin and placebo. Glutamic acid decarboxylase (GAD) 65 autoantibodies and insulinoma-associated-2 autoantibodies were measured at baseline and participants were followed for 3.2 years for the development of diabetes. RESULTS: The overall prevalence of GAD autoantibodies was 4.0%, and it varied across racial/ethnic groups from 2.4% among Asian-Pacific Islanders to 7.0% among non-Hispanic black people. There were no significant differences in BMI or metabolic variables (glucose, insulin, HbA(1c), estimated insulin resistance, corrected insulin response) stratified by baseline GAD antibody status. GAD autoantibody positivity did not predict diabetes overall (adjusted hazard ratio 0.98; 95% CI 0.56-1.73) or in any of the three treatment groups. Insulinoma-associated-2 autoantibodies were positive in only one participant (0.033%). CONCLUSIONS: These data suggest that 'diabetes autoimmunity', as reflected by GAD antibodies and insulinoma-associated-2 autoantibodies, in middle-aged individuals at risk for diabetes is not a clinically relevant risk factor for progression to diabetes.

Metabolic syndrome components and their response to lifestyle and metformin interventions are associated with differences in diabetes risk in persons with impaired glucose tolerance.

AIMS: To determine the association of metabolic syndrome (MetS) and its components with diabetes risk in participants with impaired glucose tolerance (IGT), and whether intervention-related changes in MetS lead to differences in diabetes incidence. METHODS: We used the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) revised MetS definition at baseline and intervention-related changes of its components to predict incident diabetes using Cox models in 3234 Diabetes Prevention Program (DPP) participants with IGT over an average follow-up of 3.2 years. RESULTS: In an intention-to-treat analysis, the demographic-adjusted hazard ratios (95% confidence interval) for diabetes in those with MetS (vs. no MetS) at baseline were 1.7 (1.3-2.3), 1.7 (1.2-2.3) and 2.0 (1.3-3.0) for placebo, metformin and lifestyle groups, respectively. Higher levels of fasting plasma glucose and triglycerides at baseline were independently associated with increased risk of diabetes. Greater waist circumference (WC) was associated with higher risk in placebo and lifestyle groups, but not in the metformin group. In a multivariate model, favourable changes in WC (placebo and lifestyle) and high-density lipoprotein cholesterol (placebo and metformin) contributed to reduced diabetes risk. CONCLUSIONS: MetS and some of its components are associated with increased diabetes incidence in persons with IGT in a manner that differed according to DPP intervention. After hyperglycaemia, the most predictive factors for diabetes were baseline hypertriglyceridaemia and both baseline and lifestyle-associated changes in WC. Targeting these cardiometabolic risk factors may help to assess the benefits of interventions that reduce diabetes incidence.

A UK retrospective observational study of clinical outcomes and healthcare resource utilisation of infliximab treatment in Crohn's disease.

BACKGROUND: Crohn's disease (CD) places a substantial burden on healthcare systems, with the majority of costs arising from hospitalisation and surgery. AIM: To evaluate the 'real-world' clinical effectiveness, impact on healthcare utilisation and cost of infliximab for the treatment of CD in UK practice. METHODS: A non-interventional, retrospective analysis of medical records from patients with CD treated with infliximab at 18 hospital centres across the UK. The primary objective was to compare cumulative clinical outcomes and healthcare resource utilisation for the 0- to 24-month post-infliximab period with the 12 months preceding infliximab treatment. Predefined outcomes included the number of elective surgical procedures, hospitalisations and healthcare provider consultations. Costs associated with healthcare utilisation were collected from the perspective of the UK National Health Service (NHS). RESULTS: The study involved 380 patients. Infliximab significantly reduced the mean number of elective (from 0.18 to 0.11; P = 0.0035) and non-elective (from 0.46 to 0.29; P < 0.0001) hospitalisations, and the number of consultations with gastroenterologists, gastrointestinal surgeons and radiologists (from 4.0 to 3.5, from 0.7 to 0.5 and from 0.5 to 0.2, respectively; all P < 0.001); all decreases were associated with significant cost reductions. The mean number of elective surgical procedures (including correction of severe anal fistulae and abscess drainage) was significantly reduced. CONCLUSIONS: The observed reductions in numbers of hospitalisations, surgical procedures and consultations with healthcare professionals are key indicators of the clinical effectiveness of infliximab for the treatment of CD. These benefits result in overall decreases in healthcare resource utilisation, which translate into cost savings for the NHS.

Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study.

AIMS: Whether long-term cardiovascular risk is reduced by the Diabetes Prevention Program interventions is unknown. The aim of this study was to determine the long-term differences in cardiovascular disease risk factors and the use of lipid and blood pressure medications by the original Diabetes Prevention Program intervention group. METHODS: This long-term follow-up (median 10 years, interquartile range 9.0-10.5) of the three-arm Diabetes Prevention Program randomized controlled clinical trial (metformin, intensive lifestyle and placebo), performed on 2766 (88%) of the Diabetes Prevention Program participants (who originally had impaired glucose tolerance), comprised a mean of 3.2 years of randomized treatment, approximately 1-year transition (during which all participants were offered intensive lifestyle intervention) and 5 years follow-up (Diabetes Prevention Program Outcomes Study). During the study, participants were followed in their original groups with their clinical care being provided by practitioners outside the research setting. The study determined lipoprotein profiles and blood pressure and medication use annually. RESULTS: After 10 years' follow-up from Diabetes Prevention Program baseline, major reductions were seen for systolic (-2 to -3) and diastolic (-6 to -6.5 mmHg) blood pressure, and for LDL cholesterol (-0.51 to -0.6 mmol/l) and triglycerides (-0.23 to -0.25 mmol/l) in all groups, with no between-group differences. HDL cholesterol also rose significantly (0.14 to 0.15 mmol/l) in all groups. Lipid (P = 0.01) and blood pressure (P = 0.09) medication use, however, were lower for the lifestyle group during the Diabetes Prevention Program Outcomes Study. CONCLUSION: Overall, intensive lifestyle intervention achieved, with less medication, a comparable long-term effect on cardiovascular disease risk factors, to that seen in the metformin and placebo groups.

Femoral-gluteal adiposity is not associated with insulin sensitivity in type 1 diabetes.

AIMS: To quantify and compare associations between femoral-gluteal adiposity and insulin sensitivity in adults with Type 1 diabetes mellitus with adults with normal glucose tolerance. METHODS: Individuals with Type 1 diabetes (n = 28) were recruited from the Pittsburgh Epidemiology of Diabetes Complication study, a 24-year prospective study of childhood-onset diabetes, and compared cross-sectionally with individuals with normal glucose tolerance (n = 56) of similar age, sex and BMI. Insulin sensitivity was defined as whole-body glucose disposal measured by hyperinsulinaemic-euglycaemic clamps. Adiposity was quantified by dual energy X-ray absorptiometry. RESULTS: Individuals with Type 1 diabetes exhibited lower insulin sensitivity (5.8 vs. 8.2 mg min(-1) kg fat-free mass(-1), P < 0.01), lower total fat mass (20.1 vs. 29.0 kg, P < 0.001) and lower proportional leg fat mass (36.0 vs.37.7%, P = 0.03), but similar proportional trunk fat (% trunk fat mass) compared with individuals with normal glucose tolerance. Overall, results from linear regression demonstrated that higher % leg fat mass (P < 0.01) and lower % trunk fat mass (P < 0.01) were independently associated with lower insulin sensitivity after adjustments for age, sex, height, total fat mass (kg) and diabetes status. Higher % leg fat mass was independently associated with higher insulin sensitivity in individuals with normal glucose tolerance (P < 0.01) after similar adjustment; significant associations were not observed in Type 1 diabetes. CONCLUSIONS: Reduced insulin sensitivity is a prominent feature of Type 1 diabetes and is associated with total and abdominal adiposity. Compared with adults with normal glucose tolerance, leg fat mass does not show any positive association with insulin sensitivity in Type 1 diabetes.

Review article: defining remission in ulcerative colitis.

BACKGROUND: There is no international agreement on scoring systems used to measure disease activity in ulcerative colitis, nor is there a validated definition for disease remission. AIM: To review the principles and components for defining remission in ulcerative colitis and propose a definition that will help improve patient outcomes. METHODS: A review of current standards of remission from the perspective of clinical trials, guidelines, clinical practice and patients was conducted by the authors. Selected literature focused on the components of a definition of remission, the utility of a definition and treatment strategies, based on current definitions. RESULTS: Different definitions of remission affect the assessment of outcome and make it difficult to compare trials. In the clinic, endoscopy is rarely used to confirm remission, because mucosal healing has only recently begun to be related to the duration of subsequent remission in a way that will affect clinical practice. Histopathology may be the ultimate arbiter of mucosal healing. There is no agreement on the definition of remission in current guidelines. Patient-defined remission may predict endoscopic remission, but has yet to be shown to predict duration of remission. CONCLUSIONS: A standard based on clinical symptoms and endoscopy is proposed. Histopathology is a third dimension of remission that may have prognostic value. The definition of remission should help predict long-term outcome. The expectations of patients and their physicians need to be raised, as the goal of treatment of active ulcerative colitis should be to induce remission.

The assessment of clinical distal symmetric polyneuropathy in type 1 diabetes: a comparison of methodologies from the Pittsburgh Epidemiology of Diabetes Complications Cohort.

Distal symmetrical polyneuropathy (DSP) is the most common type of diabetic neuropathy, but often difficult to diagnose reliably. We evaluated the cross-sectional association between three point-of-care devices, Vibratron II, NC-stat(®), and Neurometer(®), and two clinical protocols, MNSI and monofilament, in identifying those with DSP, and/or amputation/ulcer/neuropathic pain (AUP), the two outcomes of major concern. This report presents data from 195 type 1 diabetic participants of the Epidemiology of Diabetes Complications (EDC) Study attending the 18-year examination (2004-2006). Participants with physician-diagnosed DSP, AUP or who were abnormal on the NC-stat, and the Vibratron II, MNSI, and monofilament were older (p<0.05) and had a longer duration of diabetes (p < 0.05). There was no difference by sex for DSP, AUP, or any testing modality, with the exception of NCstat (motor). The Vibratron II and MNSI showed the highest sensitivity for DSP (>87%) and AUP (>80%), whereas the monofilament had the highest specificity (98% DSP, 94% AUP) and positive predictive value (89% DSP, 47% AUP), but lowest sensitivity (20% DSP, 30% AUP). The MNSI also had the highest negative predictive value (83%) and Youden's Index (37%) and currently presents the single best combination of sensitivity and specificity of DSP in type 1 diabetes.

Randomised clinical trial: early assessment after 2 weeks of high-dose mesalazine for moderately active ulcerative colitis - new light on a familiar question.

BACKGROUND: Rapid resolution of rectal bleeding and stool frequency are important goals for ulcerative colitis therapy and may help guide therapeutic decisions. AIM: To explore patient diary data from ASCEND I and II for their relevance to clinical decision making. METHODS: Data from two randomised, double-blind, Phase III studies were combined. Patients received mesalazine (mesalamine) 4.8 g/day (Asacol 800 mg MR) or 2.4 g/day (Asacol 400 mg MR). Time to improvement or resolution of rectal bleeding and stool frequency was assessed and the proportion of patients experiencing symptom improvement or resolution at day 14 evaluated using survival analysis. Symptoms after 14 days were compared to week 6. A combination of prespecified and post hoc analyses were used. RESULTS: Median times to resolution and improvement of both rectal bleeding and stool frequency were shorter with 4.8 g/day than 2.4 g/day (resolution, 19 vs. 29 days, P = 0.020; improvement, 7 vs. 9 days, P = 0.024). In total, 73% of patients experienced improvement in both rectal bleeding and stool frequency by day 14 with 4.8 g/day, compared to 61% with 2.4 g/day. More patients achieved symptom resolution by day 14 with 4.8 g/day than 2.4 g/day (43% vs. 30%; P = 0.035). Symptom relief after 14 days was associated with a high rate of symptom relief after 6 weeks. CONCLUSIONS: High-dose mesalazine 4.8 g/day provides rapid relief of the cardinal symptoms of moderately active ulcerative colitis. Symptom relief within 14 days was associated with symptom relief at 6 weeks in the majority of patients. Day 14 is a practical timepoint at which response to treatment may be assessed and decisions regarding therapy escalation made (Clinicaltrials.gov: NCT00577473, NCT00073021).

Characterizing sudden death and dead-in-bed syndrome in Type 1 diabetes: analysis from two childhood-onset Type 1 diabetes registries.

AIMS: Type 1 diabetes mellitus increases the risk for sudden unexplained death, generating concern that diabetes processes and/or treatments underlie these deaths. Young (< 50 years) and otherwise healthy patients who are found dead in bed have been classified as experiencing 'dead-in-bed' syndrome. METHODS: We thus identified all unwitnessed deaths in two related registries (the Children's Hospital of Pittsburgh and Allegheny County) yielding 1319 persons with childhood-onset (age < 18 years) Type 1 diabetes diagnosed between 1965 and 1979. Cause of death was determined by a Mortality Classification Committee (MCC) of at least two physician epidemiologists, based on the death certificate and additional records surrounding the death. RESULTS: Of the 329 participants who had died, the Mortality Classification Committee has so far reviewed and assigned a final cause of death to 255 (78%). Nineteen (8%) of these were sudden unexplained deaths (13 male) and seven met dead-in-bed criteria. The Mortality Classification Committee adjudicated cause of death in the seven dead-in-bed persons as: diabetic coma (n =4), unknown (n=2) and cardiomyopathy (n=1, found on autopsy). The three dead-in-bed individuals who participated in a clinical study had higher HbA(1c) , lower BMI and higher daily insulin dose compared with both those dying from other causes and those surviving. CONCLUSIONS: Sudden unexplained death in Type 1 diabetes seems to be increased 10-fold and associated with male sex, while dead-in-bed individuals have a high HbA(1c) and insulin dose and low BMI. Although sample size is too small for definitive conclusions, these results suggest specific sex and metabolic factors predispose to sudden unexplained death and dead-in-bed death.

Retinal microaneurysm count predicts progression and regression of diabetic retinopathy. Post-hoc results from the DIRECT Programme.

OBJECTIVE: To study the association between baseline retinal microaneurysm score and progression and regression of diabetic retinopathy, and response to treatment with candesartan in people with diabetes. METHODS: This was a multicenter randomized clinical trial. The progression analysis included 893 patients with Type 1 diabetes and 526 patients with Type 2 diabetes with retinal microaneurysms only at baseline. For regression, 438 with Type 1 and 216 with Type 2 diabetes qualified. Microaneurysms were scored from yearly retinal photographs according to the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Retinopathy progression and regression was defined as two or more step change on the ETDRS scale from baseline. Patients were normoalbuminuric, and normotensive with Type 1 and Type 2 diabetes or treated hypertensive with Type 2 diabetes. They were randomized to treatment with candesartan 32 mg daily or placebo and followed for 4.6 years. RESULTS: A higher microaneurysm score at baseline predicted an increased risk of retinopathy progression (HR per microaneurysm score 1.08, P < 0.0001 in Type 1 diabetes; HR 1.07, P = 0.0174 in Type 2 diabetes) and reduced the likelihood of regression (HR 0.79, P < 0.0001 in Type 1 diabetes; HR 0.85, P = 0.0009 in Type 2 diabetes), all adjusted for baseline variables and treatment. Candesartan reduced the risk of microaneurysm score progression. CONCLUSIONS: Microaneurysm counts are important prognostic indicators for worsening of retinopathy, thus microaneurysms are not benign. Treatment with renin-angiotensin system inhibitors is effective in the early stages and may improve mild diabetic retinopathy. Microaneurysm scores may be useful surrogate endpoints in clinical trials.