Ramipril sensitizes platelets to nitric oxide : implications for therapy in high-risk patients

Objectives
Using 2 sequential studies in HOPE (Heart Outcomes Prevention Evaluation) study–type patients, the aims of this study were: 1) to test the hypothesis that ramipril improves platelet nitric oxide (NO) responsiveness: and 2) to explore biochemical and physiological effects of ramipril in a cohort selected on the basis of platelet NO resistance.

Background
Ramipril prevents cardiovascular events, but the bases for these effects remain uncertain. NO resistance at both the platelet and vascular levels is present in a substantial proportion of patients with diabetes or ischemic heart disease and is an independent risk factor for cardiovascular events.

Methods
Study 1 was a double-blind, randomized comparison of ramipril (10 mg) with placebo in a cohort of patients (n = 119) with ischemic heart disease or diabetes plus additional coronary risk factor(s), in which effects on platelet responsiveness to NO were compared. Study 2 was a subsequent short-term evaluation of the effects of ramipril in a cohort of subjects (n = 19) with impaired platelet NO responsiveness in whom additional mechanistic data were sought.

Results
In study 1, ramipril therapy increased platelet responsiveness to NO relative to the extent of aggregation (p < 0.001), but this effect occurred primarily in patients with severely impaired baseline NO responsiveness (n = 41). In study 2, ramipril also improved platelet NO responsiveness (p < 0.01), and this improvement was correlated directly with increased NO-stimulated platelet generation of cyclic guanosine monophosphate (p < 0.02) but not with changes in plasma thrombospondin-1 levels.

Conclusions
Ramipril ameliorates platelet NO resistance in HOPE study–type patients, with associated increases in soluble guanylate cyclase responsiveness to NO. This effect is likely to contribute to treatment benefit and define patients in whom ramipril therapy is particularly effective.

Interleukin-6 and tumor necrosis factor-α are not increased in patients with type 2 diabetes: Evidence that plasma interleukin-6 is related to fat mass and not insulin responsiveness

Aims/hypothesis. Our aim was to examine the possible direct relationship of interleukin-6 and TNFα with insulin sensitivity in humans. Methods. We carried out two series of euglycaemic-hyperinsulinaemic clamp experiments. In the first (CLAMP1), skeletal muscle mRNA expression and plasma concentrations of IL-6 and TNFα were examined in patients with Type 2 diabetes (n=6), subjects matched for age (n=6), and young healthy (n=11) control subjects during a 120-min supra-physiological hyperinsulinaemic (40 mU·m -2·min-1) euglycaemic clamp. In the second series of experiments (CLAMP2), patients with Type 2 diabetes (n=6) and subjects matched for age (n=7) were studied during a 240-min high-physiological hyperinsulinaemic (7 mU·m-2·min-1) euglycaemic clamp, during which arterial and venous (femoral and subclavian) blood samples were measured for IL-6 and TNFα flux. Results. In both experiments the glucose infusion rate in the patients was markedly lower than that in the other groups. In CLAMP1, basal skeletal muscle IL-6 and TNFα mRNA were the same in all groups. They were not affected by insulin and they were not related to the glucose infusion rate. In CLAMP2, neither cytokine was released from the arm or leg during insulin stimulation in either group. In both experiments plasma concentrations of these cytokines were similar in the patients and in the control subjects, although in CLAMP1 the young healthy control group had lower (p<0.05) plasma IL-6 concentrations. Using data from all subjects, a strong positive correlation (r=0.85; p<0.00001) was observed between basal plasma IL-6 and BMI. Conversely, a negative relationship (r=-0.345; p<0.05) was found between basal plasma TNFα and BMI, although this was not significant when corrected for BMI. When corrected for BMI, no relationship was observed between either basal plasma IL-6 or TNFα and GIR. Conclusions/interpretation. These data show that the increased circulating IL-6 concentrations seen in patients with Type 2 diabetes are strongly related to fat mass and not insulin responsiveness, and suggest that neither IL-6 nor TNFα are indicative of insulin resistance.

Disassociation of muscle triglyceride content and insulin sensitivity after exercise training in patients with Type 2 diabetes

Aim/hypothesis. We determined the effect of exercise training on insulin sensitivity and muscle lipids (triglyceride [TGm] and long-chain fatty acyl CoA [LCACoA] concentration) in patients with Type 2 diabetes. Methods. Seven patients with Type 2 diabetes and six healthy control subjects who were matched for age, BMI, % body fat and VO2peak participated in a 3 days per week training program for 8 weeks. Insulin sensitivity was determined pre- and post-training during a 120 min euglycaemic- hyperinsulinaemic clamp and muscle biopsies were obtained before and after each clamp. Oxidative enzyme activities [citrate synthase (CS), β-hydroxy-acyl- CoA (β-HAD)] and TGm were determined from basal muscle samples pre- and post training, while total LCACoA content was measured in samples obtained before and after insulin-stimulation, pre- and post training. Results. The training-induced increase in VO2peak (∼20%, p<0.01) was similar in both groups. Compared with control subjects, insulin sensitivity was lower in the diabetic patients before and after training (∼60%; p<0.05), but was increased to the same extent in both groups with training (∼30%; p<0.01). TGm was increased in patients with Type 2 diabetes (170%; p<0.05) before, but was normalized to levels observed in control subjects after training. Basal LCACoA content was similar between groups and was unaltered by training. Insulin-stimulation had no detectable effect on LCACoA content. CS and β-HAD activity were increased to the same extent in both groups in response to training (p<0.001). Conclusion/interpretation. We conclude that the enhanced insulin sensitivity observed after short-term exercise training was associated with a marked decrease in TGm content in patients with Type 2 diabetes. However, despite the normalization of TGm to levels observed in healthy individuals, insulin resistance was not completely reversed in the diabetic patients.

Severe hypoglycaemia in type 1 diabetes mellitus: underlying drivers and potential strategies for successful prevention

Hypoglycaemia remains an over-riding factor limiting optimal glycaemic control in type 1 diabetes. Severe hypoglycaemia is prevalent in almost half of those with long-duration diabetes and is one of the most feared diabetes-related complications. In this review, we present an overview of the increasing body of literature seeking to elucidate the underlying pathophysiology of severe hypoglycaemia and the limited evidence behind the strategies employed to prevent episodes. Drivers of severe hypoglycaemia including impaired counter-regulation, hypoglycaemia-associated autonomic failure, psychosocial and behavioural factors and neuroimaging correlates are discussed. Treatment strategies encompassing structured education, insulin analogue regimens, continuous subcutaneous insulin infusion pumps, continuous glucose sensing and beta-cell replacement therapies have been employed, yet there is little randomized controlled trial evidence demonstrating effectiveness of new technologies in reducing severe hypoglycaemia. Optimally designed interventional trials evaluating these existing technologies and using modern methods of teaching patients flexible insulin use within structured education programmes with the specific goal of preventing severe hypoglycaemia are required. Individuals at high risk need to be monitored with meticulous collection of data on awareness, as well as frequency and severity of all hypoglycaemic episodes.

Structural classification of proteins through amino acid sequence using interval type-2 fuzzy logic system

This paper introduces a new multi-output interval type-2 fuzzy logic system (MOIT2FLS) that is automatically constructed from unsupervised data clustering method and trained using heuristic genetic algorithm for a protein secondary structure classification. Three structure classes are distinguished including helix, strand (sheet) and coil which correspond to three outputs of the MOIT2FLS. Quantitative properties of amino acids are used to characterize the twenty amino acids rather than the widely used computationally expensive binary encoding scheme. Amino acid sequences are parsed into learnable patterns using a local moving window strategy. Three clustering tasks are performed using the adaptive vector quantization method to derive an equal number of initial rules for each type of secondary structure. Genetic algorithm is applied to optimally adjust parameters of the MOIT2FLS with the purpose of maximizing the Q3 measure. Comprehensive experimental results demonstrate the strong superiority of the proposed approach over the traditional methods including Chou-Fasman method, Garnier-Osguthorpe-Robson method, and artificial neural network models.

An interval type-2 fuzzy logic system-based method for prediction interval construction

This paper introduces a new non-parametric method for uncertainty quantification through construction of prediction intervals (PIs). The method takes the left and right end points of the type-reduced set of an interval type-2 fuzzy logic system (IT2FLS) model as the lower and upper bounds of a PI. No assumption is made in regard to the data distribution, behaviour, and patterns when developing intervals. A training method is proposed to link the confidence level (CL) concept of PIs to the intervals generated by IT2FLS models. The new PI-based training algorithm not only ensures that PIs constructed using IT2FLS models satisfy the CL requirements, but also reduces widths of PIs and generates practically informative PIs. Proper adjustment of parameters of IT2FLSs is performed through the minimization of a PI-based objective function. A metaheuristic method is applied for minimization of the non-linear non-differentiable cost function. Performance of the proposed method is examined for seven synthetic and real world benchmark case studies with homogenous and heterogeneous noise. The demonstrated results indicate that the proposed method is capable of generating high quality PIs. Comparative studies also show that the performance of the proposed method is equal to or better than traditional neural network-based methods for construction of PIs in more than 90% of cases. The superiority is more evident for the case of data with a heterogeneous noise. © 2014 Elsevier B.V.

Restoration of self-awareness of hypoglycemia in adults with long-standing type 1 diabetes: hyperinsulinemic-hypoglycemic clamp substudy results from the HypoCOMPaSS trial.

OBJECTIVE: Impaired awareness of hypoglycemia (IAH) and defective counterregulation significantly increase severe hypoglycemia risk in type 1 diabetes (T1D). We evaluated restoration of IAH/defective counterregulation by a treatment strategy targeted at hypoglycemia avoidance in adults with T1D with IAH (Gold score ≥4) participating in the U.K.-based multicenter HypoCOMPaSS randomized controlled trial. RESEARCH DESIGN AND METHODS: Eighteen subjects with T1D and IAH (mean ± SD age 50 ± 9 years, T1D duration 35 ± 10 years, HbA1c 8.1 ± 1.0% [65 ± 10.9 mmol/mol]) underwent stepped hyperinsulinemic-hypoglycemic clamp studies before and after a 6-month intervention. The intervention comprised the HypoCOMPaSS education tool in all and randomized allocation, in a 2 × 2 factorial study design, to multiple daily insulin analog injections or continuous subcutaneous insulin infusion therapy and conventional glucose monitoring or real-time continuous glucose monitoring. Symptoms, cognitive function, and counterregulatory hormones were measured at each glucose plateau (5.0, 3.8, 3.4, 2.8, and 2.4 mmol/L), with each step lasting 40 min with subjects kept blinded to their actual glucose value throughout clamp studies. RESULTS: After intervention, glucose concentrations at which subjects first felt hypoglycemic increased (mean ± SE from 2.6 ± 0.1 to 3.1 ± 0.2 mmol/L, P = 0.02), and symptom and plasma metanephrine responses to hypoglycemia were higher (median area under curve for symptoms, 580 [interquartile range {IQR} 420-780] vs. 710 [460-1,260], P = 0.02; metanephrine, 2,412 [-3,026 to 7,279] vs. 5,180 [-771 to 11,513], P = 0.01). Glycemic threshold for deterioration of cognitive function measured by four-choice reaction time was unchanged, while the color-word Stroop test showed a degree of adaptation. CONCLUSIONS: Even in long-standing T1D, IAH and defective counterregulation may be improved by a clinical strategy aimed at hypoglycemia avoidance.

Self-monitoring of blood glucose versus self-monitoring of urine glucose in adults with newly diagnosed Type 2 diabetes receiving structured education: a cluster randomized controlled trial.

AIMS: To compare the effectiveness and acceptability of self-monitoring of blood glucose with self-monitoring of urine glucose in adults with newly diagnosed Type 2 diabetes. METHODS: We conducted a multi-site cluster randomized controlled trial with practice-level randomization. Participants attended a structured group education programme, which included a module on self-monitoring using blood glucose or urine glucose monitoring. HbA1c and other biomedical measures as well as psychosocial data were collected at 6, 12 and 18 months. A total of 292 participants with Type 2 diabetes were recruited from 75 practices. RESULTS: HbA1c levels were significantly lower at 18 months than at baseline in both the blood monitoring group [mean (se) -12 (2) mmol/mol; -1.1 (0.2) %] and the urine monitoring group [mean (se) -13 (2) mmol/mol; -1.2 (0.2)%], with no difference between groups [mean difference adjusted for cluster effect and baseline value = -1 mmol/mol (95% CI -3, 2); -0.1% (95% CI -0.3, 0.2)]. Similar improvements were observed for the other biomedical outcomes, with no differences between groups. Both groups showed improvements in total treatment satisfaction, generic well-being, and diabetes-specific well-being, and had a less threatening view of diabetes, with no differences between groups at 18 months. Approximately one in five participants in the urine monitoring arm switched to blood monitoring, while those in the blood monitoring arm rarely switched (18 vs 1% at 18 months; P < 0.001). CONCLUSIONS: Participants with newly diagnosed Type 2 diabetes who attended structured education showed similar improvements in HbA1c levels at 18 months, regardless of whether they were assigned to blood or urine self-monitoring.

Medical data classification using interval type-2 fuzzy logic system and wavelets

This paper introduces an automated medical data classification method using wavelet transformation (WT) and interval type-2 fuzzy logic system (IT2FLS). Wavelet coefficients, which serve as inputs to the IT2FLS, are a compact form of original data but they exhibits highly discriminative features. The integration between WT and IT2FLS aims to cope with both high-dimensional data challenge and uncertainty. IT2FLS utilizes a hybrid learning process comprising unsupervised structure learning by the fuzzy c-means (FCM) clustering and supervised parameter tuning by genetic algorithm. This learning process is computationally expensive, especially when employed with high-dimensional data. The application of WT therefore reduces computational burden and enhances performance of IT2FLS. Experiments are implemented with two frequently used medical datasets from the UCI Repository for machine learning: the Wisconsin breast cancer and Cleveland heart disease. A number of important metrics are computed to measure the performance of the classification. They consist of accuracy, sensitivity, specificity and area under the receiver operating characteristic curve. Results demonstrate a significant dominance of the wavelet-IT2FLS approach compared to other machine learning methods including probabilistic neural network, support vector machine, fuzzy ARTMAP, and adaptive neuro-fuzzy inference system. The proposed approach is thus useful as a decision support system for clinicians and practitioners in the medical practice. copy; 2015 Elsevier B.V. All rights reserved.

Adoption and maintenance of gym-based strength training in the community setting in adults with excess weight or type 2 diabetes: a randomized controlled trial

BACKGROUND: Participant adoption and maintenance is a major challenge in strength training (ST) programs in the community-setting. In adults who were overweight or with type 2 diabetes (T2DM), the aim of this study was to compare the effectiveness of a standard ST program (SST) to an enhanced program (EST) on the adoption and maintenance of ST and cardio-metabolic risk factors and muscle strength. METHODS: A 12-month cluster-randomized controlled trial consisting of a 6-month adoption phase followed by a 6-month maintenance phase. In 2008-2009, men and women aged 40-75 years (n = 318) with T2DM (n = 117) or a BMI >25 (n = 201) who had not participated in ST previously were randomized into either a SST or an EST program (which included additional motivationally-tailored behavioral counselling). Adoption and maintenance were defined as undertaking ≥ 3 weekly gym-based exercise sessions during the first 6-months and from 6-12 months respectively and were assessed using a modified version of the CHAMPS (Community Healthy Activity Models Program for Seniors) instrument. RESULTS: Relative to the SST group, the adjusted odds ratio (OR) of adopting ST for all participants in the EST group was 3.3 (95 % CI 1.2 to 9.4). In stratified analyses including only those with T2DM, relative to the SST group, the adjusted OR of adopting ST in the EST group was 8.2 (95 % CI 1.5-45.5). No significant between-group differences were observed for maintenance of ST in either pooled or stratified analyses. In those with T2DM, there was a significant reduction in HbA1c in the EST compared to SST group during the adoption phase (net difference, -0.13 % [-0.26 to -0.01]), which persisted after 12-months (-0.17 % [-0.3 to -0.05]). CONCLUSIONS: A behaviorally-focused community-based EST intervention was more effective than a SST program for the adoption of ST in adults with excess weight or T2DM and led to greater improvements in glycemic control in those with T2DM. TRIAL REGISTRATION: Registered at ACTRN12611000695909 (Date registered 7/7/2011).

The need to revise the current methods to measure and assess static recrystallization behavior

Heterogeneous deformation developed during "static recrystallization (SRX) tests" poses serious questions about the validity of the conventional methods to measure softening fraction. The challenges to measure SRX and verify a proposed kinetic model of SRX are discussed and a least square technique is utilized to quantify the error in a proposed SRX kinetic model. This technique relies on an existing computational-experimental multi-layer formulation to account for the heterogeneity during the post interruption hot torsion deformation. The kinetics of static recrystallization for a type 304 austenitic stainless steel deformed at 900 °C and strain rate of 0.01s^-1 is characterized implementing the formulation. Minimizing the error between the measured and calculated torque-twist data, the parameters of the kinetic model and the flow behavior during the second hit are evaluated and compared with those obtained based on a conventional technique. Typical static recrystallization distributions in the test sample will be presented. It has been found that the major differences between the conventional and the presented technique results are due to the heterogeneous recrystallization in the cylindrical core of the specimen where the material is still partially recrystallized at the onset of the second hit deformation. For the investigated experimental conditions, the core is confined in the first two-thirds of the gauge radius, when the holding time is shorter than 50 s and the maximum pre-strain is about 0.5.

Evaluation of electrochemical methods for determination of the seebeck coefficient of redox electrolytes

Recent advances in thermoelectrochemical cells, which are being developed for harvesting low grade waste heat, have shown the promise of cobalt bipyridyl salts as the active redox couple. The Seebeck coefficient, Se, of a redox couple determines the open circuit voltage achievable, for a given temperature gradient, across the thermoelectrochemical cell. Thus, the accurate determination of this thermodynamic parameter is key to the development and study of new redox electrolytes. Further, techniques for accurate determination of Se using only one half of the redox couple reduces the synthetic requirements. Here, we compare three different experimental techniques for measuring Se of a cobalt tris(bipyridyl) redox couple in ionic liquid electrolytes. The use of temperature dependent cyclic voltammetry (CV) in isothermal and non-isothermal cells was investigated in depth, and the Se values compared to those from thermo-electromotive force measurements. Within experimental error, the Se values derived from CV methods were found to be in accordance with those obtained from electromotive force (emf) measurements. The applicability of cyclic voltammetry techniques for determining Se when employing only one part of the redox couple was demonstrated.

Multi-output interval type-2 fuzzy logic system for protein secondary structure prediction

A new multi-output interval type-2 fuzzy logic system (MOIT2FLS) is introduced for protein secondary structure prediction in this paper. Three outputs of the MOIT2FLS correspond to three structure classes including helix, strand (sheet) and coil. Quantitative properties of amino acids are employed to characterize twenty amino acids rather than the widely used computationally expensive binary encoding scheme. Three clustering tasks are performed using the adaptive vector quantization method to construct an equal number of initial rules for each type of secondary structure. Genetic algorithm is applied to optimally adjust parameters of the MOIT2FLS. The genetic fitness function is designed based on the Q3 measure. Experimental results demonstrate the dominance of the proposed approach against the traditional methods that are Chou-Fasman method, Garnier-Osguthorpe-Robson method, and artificial neural network models.

Suicidal ideation reported by adults with type 1 or type 2 diabetes: results from Diabetes MILES-Australia

AIMS: To examine the prevalence and correlates of suicidal ideation in a community-based sample of adults with Type 1 or Type 2 diabetes.

METHODS: Participants were 3338 adults aged 18-70 years with Type 1 diabetes (n=1376) or Type 2 diabetes (non-insulin: n=1238; insulin: n=724) from a national survey administered to a random sample registered with the National Diabetes Services Scheme. Depression and suicidal ideation were assessed using the Patient Health Questionnaire, and diabetes-specific distress with the Problem Areas In Diabetes scale. Separate logistic regression analyses by diabetes type/treatment were used to determine relative contribution to suicidal ideation.

RESULTS: Overall, we observed a suicidal ideation rate of 14% in our sample. Participants with Type 2 diabetes using insulin reported more frequent depressive symptoms, and were more likely to report recent suicidal ideation (19%) compared with those with either Type 1 diabetes or Type 2 diabetes not using insulin (14 and 12%, respectively). After controlling for depression, there was little difference in the prevalence of suicidal ideation between diabetes types/treatments, but higher diabetes-specific distress significantly increased the odds of suicidal ideation.

CONCLUSIONS: As suicidal ideation is a significant risk factor for a suicide attempt, the findings have implications for healthcare professionals, pointing to the importance of adequate screening and action plans for appropriate follow-up of those reporting depression. Our findings are also indicative of the psychological toll of diabetes more generally, and the need to integrate physical and mental healthcare for people with diabetes. This article is protected by copyright. All rights reserved.

Intensifying insulin regimen after basal insulin optimization in adults with type 2 diabetes: a 24-week, randomized, open-label trial comparing insulin glargine plus insulin glulisine with biphasic insulin aspart (LanScape)

AIM: To test the hypothesis that a 'basal plus' regimenadding once-daily main-meal fast-acting insulin to basal insulin once dailywould be non-inferior to biphasic insulin twice daily as assessed by glycated haemoglobin (HbA1c) concentration (predefined as ≤0.4%), but would provide superior treatment satisfaction. METHODS: This open-label trial enrolled adults to an 8- or 12-week run-in period, during which oral therapies except metformin were stopped and insulin glargine dose was titrated. Those with fasting glucose <7 mmol/l but HbA1c >7% (53 mmol/mol) were randomized to insulin glargine/glulisine once daily (n = 170) or insulin aspart/aspart protamine 30/70 twice daily (n = 165) for 24 weeks, with dose titration to glucose targets using standardized algorithms. RESULTS: For HbA1c, the basal plus regimen was non-inferior to biphasic insulin (least squares mean difference, 0.21%, upper 97.5% confidence limit 0.38%) meeting the predefined non-inferiority margin of 0.4%. Treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire change version and Insulin Treatment Satisfaction Questionnaire total scores) significantly favoured basal plus. No difference was observed between the basal plus and the biphasic insulin groups in responders (HbA1c <7%, 20.6 vs 27.9%; p = 0.12), weight gain (2.06 vs 2.50 kg; p = 0.2), diabetes-specific quality of life (Audit of Diabetes-Dependent Quality of Life average weighted impact (AWI) score) and generic health status (five-dimension European Quality of Life questionnaire). Overall hypoglycaemia rates were similar between groups (15.3 vs 18.2 events/patient-year; p = 0.22); nocturnal hypoglycaemia was higher with the basal plus regimen (5.7 vs 3.6 events/patient-year; p = 0.02). CONCLUSION: In long-standing type 2 diabetes with suboptimal glycaemia despite oral therapies and basal insulin, the basal plus regimen was non-inferior to biphasic insulin for biomedical outcomes, with a similar overall hypoglycaemia rate but more nocturnal events.