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Effects of a cognitive behavioural treatment (CBT) in type 2 diabetes patients were studied in a randomised controlled trial. Patients were recruited from a diabetes care system (DCS). The intervention group (n = 76) received managed care from the DCS and CBT. The control group (n = 78) received managed care only. Effects on risk of developing coronary heart disease (CHD), clinical characteristics, lifestyle, determinants of behaviour change, quality of life, and depression were assessed after 6 and 12 months. The intervention did not result in a significant reduction of CHD risk (difference between intervention and control group was -0.32 % (95 % CI: -2.27; 1.63). The amount of heavy physical activity increased significantly in the intervention group at 6 months [intervention versus control group was 20.14 min/day (95 % CI: 4.6; 35.70)]. Quality of life and level of depression improved as well. All effects disappeared after 6 months. No effects were found on clinical characteristics. © 2012 Springer Science+Business Media, LLC.

Background The burden of health care expenditure on national budgets has increased dramatically over the past decade. A pilot study in our hospital demonstrated that many unnecessary diagnostic tests were performed routinely. The aim of this study was to reduce the costs of unnecessary diagnostic tests. Methods All diagnostic costs between 2006 and 2008 of the internal medicine department of the VU University Centre were evaluated. A target was set to reduce diagnostic expenditure by 7.5% in 2009 compared to 2008. A few interventions were introduced including introducing posters and pocket cards detailing the costs of diagnostic tests, six weekly feedback on diagnostics costs, mentorship of junior doctors, unbundling panel tests and increasing protocol adherence. Main outcome measures were the reduction in the total diagnostic costs and the total number of laboratory tests performed in the internal medicine department in 2009. Results In 2009, we achieved a 13% reduction in the total diagnostic costs compared to 2008. The department of internal medicine spent 2.80 million euro and 2.45 million euro on the diagnostic tests in 2008 and 2009 respectively and thereby saved 350.000 euro in 2009. The largest reduction was achieved by reducing the number of laboratory tests performed. Conclusion Introduction of a few simple measures to improve awareness among the physicians led to a significant reduction in the diagnostic costs in the department of internal medicine. Extending these measures to the entire hospital and even entire country will in our opinion lead to significant reduction in the health care costs.

OBJECTIVE Patients with type 2 diabetes mellitus (T2DM) underestimate their risk of developing severe complications, and they do not always understand the risk communication by their caregivers. The aim of this study was to investigate the effects of an intervention focused on the communication of the absolute 10-year risk of developing cardiovascular disease (CVD) in patients with T2DM. RESEARCH DESIGN AND METHODS A randomized controlled trial was performed in T2DM patients newly referred to the Diabetes Care System (DCS) West-Friesland, a managed-care system in the Netherlands. The intervention group (n = 131) received a six-step CVD risk communication. Control subjects (n = 130) received standard managed care. The primary outcome measure was appropriateness of risk perception (difference between actual CVD risk calculated by the UK Prospective Diabetes Study risk engine and risk perception). Secondary outcome measures were illness perceptions, attitude and intention to change behavior, satisfaction with the communication, and anxiety and worry about CVD risk. Patients completed questionnaires at baseline, at 2 weeks (immediately after the intervention), and at 12 weeks. RESULTS Appropriateness of risk perception improved between the intervention and control groups at 2 weeks. This effect disappeared at 12 weeks. No effects were found on illness perceptions, attitude and intention to change behavior, or anxiety and worry about CVD risk. Patients in the intervention group were significantly more satisfied with the communication. CONCLUSIONS This risk communication method improved patients’ risk perception at 2 weeks but not at 12 weeks. Negative effects were not found, as patients did not become anxious or worried after the CVD risk communication.

The treatment of choice of H. pylori infections is a 7-day triple-therapy with a proton pump inhibitor (PPI) plus amoxicillin and either clarithromycin or metronidazole, depending on local antibiotic resistance rates. The data on efficacy of eradication therapy in a group of rheumatology patients on long-term NSAID therapy are reported here. This study was part of a nationwide, multicenter RCT that took place in 2000-2002 in the Netherlands. Patients who tested positive for H. pylori IgG antibodies were included and randomly assigned to either eradication PPI-triple therapy or placebo. After completion, follow-up at 3 months was done by endoscopy and biopsies were sent for culture and histology. In the eradication group 13% (20/152, 95% CI 9-20%) and in the placebo group 79% (123/155, 95% CI 72-85%) of the patients were H. pylori positive by histology or culture. H. pylori was successfully eradicated in 91% of the patients who were fully compliant to therapy, compared to 50% of those who were not (difference of 41%; 95% CI 18-63%). Resistance percentages found in isolates of the placebo group were: 4% to clarithromycin, 19% to metronidazole, 1% to amoxicillin and 2% to tetracycline.

OBJECTIVE To investigate the relationship among A1C, fasting plasma glucose (FPG), and 2-h postload plasma glucose in the Dutch general population and to evaluate the results of using A1C for screening and diagnosis of diabetes. RESEARCH DESIGN AND METHODS In 2006–2007, 2,753 participants of the New Hoorn Study, aged 40–65 years, who were randomly selected from the population of Hoorn, the Netherlands, underwent an oral glucose tolerance test (OGTT). Glucose status (normal glucose metabolism [NGM], intermediate hyperglycemia, newly diagnosed diabetes, and known diabetes) was defined by the 2006 World Health Organization criteria. Spearman correlations were used to investigate the agreement between markers of hyperglycemia, and a receiver operating characteristic (ROC) curve was calculated to evaluate the use of A1C to identify newly diagnosed diabetes. RESULTS In the total population, the correlations between fasting plasma glucose and A1C and between 2-h postload plasma glucose and A1C were 0.46 and 0.33, respectively. In patients with known diabetes, these correlations were 0.71 and 0.79. An A1C level of ≥5.8%, representing 12% of the population, had the highest combination of sensitivity (72%) and specificity (91%) for identifying newly diagnosed diabetes. This cutoff point would identify 72% of the patients with newly diagnosed diabetes and include 30% of the individuals with intermediate hyperglycemia. CONCLUSIONS In patients with known diabetes, correlations between glucose and A1C are strong; however, moderate correlations were found in the general population. In addition, based on the diagnostic properties of A1C defined by ROC curve analysis, the advantage of A1C compared with OGTT for the diagnosis of diabetes is limited.

BACKGROUND: Maintenance use of nonsteroidal anti-inflammatory drugs (NSAIDs) is often complicated by gastropathy. In non-NSAID users, eradication of Helicobacter pylori is associated with decreased mucosal inflammation, and may halt the progression to atrophy and intestinal metaplasia, but the continuous use of NSAIDs may interfere with these processes. GOAL: To investigate the effect of H. pylori eradication on gastric mucosal histology during long-term NSAID use, with and without gastroprotective therapy. STUDY: Patients were eligible for inclusion if they were on long-term NSAIDs and were H. pylori-positive on serologic testing. Patients were randomly assigned to either eradication or placebo. Gastritis was assessed according to the updated Sydney classification for activity, chronic inflammation, gastric glandular atrophy, intestinal metaplasia, and H. pylori density. RESULTS: Biopsy specimens were available for histology of 305 patients. Of these, 48% were on chronic gastroprotective medication. Significant less active gastritis, inflammation, and H. pylori density was found in the eradication group compared with the placebo group in both corpus and antrum (P

Objective: To assess whether insulin sensitivity can explain the associations of leg-fat mass (LFM) and trunk-fat mass (TFM) with the cardiovascular disease (CVD) risk profile in healthy European men and women. Methods and Procedures: We studied 142 healthy men and women of a multicenter European study on insulin sensitivity, aged 30–60 years, from the centres in Hoorn, the Netherlands and Rome, Italy. Whole-body dual-energy X-ray absorptiometry (DXA) was used to determine fat and lean soft tissue mass in the trunk and legs. Fasting glucose, insulin, and lipid levels were measured. Insulin sensitivity (M/I-ratio) was measured during a euglycemic-hyperinsulinemic clamp. Associations between fat distribution and CVD risk factors were studied with linear regression analyses with adjustment for other body compartments, and subsequent adjustment for insulin sensitivity. Results: In men, larger LFM was significantly and independently associated with lower triglyceride levels (TGs) and higher high-density lipoprotein (HDL) cholesterol (P < 0.10) and tended to be associated also with lower low-density lipoprotein (LDL) cholesterol, and lower fasting insulin levels. In women, larger LFM was associated with favorable values of all CVD risk factors, although the associations were not statistically significant. In both sexes, larger TFM was independently and significantly associated with unfavorable values of most CVD risk factors, and most associations did not markedly change after adjustment for insulin sensitivity. Discussion: In a relatively young and healthy European population, larger LFM is associated with a lower and TFM with a higher cardiovascular and metabolic risk, which can not be explained by insulin sensitivity.

Patients with type 2 diabetes mellitus (DM2) have an increased risk of cardiovascular disease (CVD). Myeloperoxidase (MPO), expressed in leukocytes and released upon activation, is associated with CVD and endothelial dysfunction. Postprandial leukocyte recruitment and activation with subsequent MPO release may contribute to atherosclerosis and CVD. We hypothesized that MPO may increase in the postprandial state because of postprandial leukocyte recruitment and/or activation, especially in subjects with DM2. One hundred postmenopausal women, aged 50 to 65 years (66 with normal glucose metabolism [NGM] and 34 with DM2), received 2 consecutive fat-rich meals and 2 consecutive carbohydrate-rich meals on separate occasions. Blood samples were taken before (t = 0) and at 2, 4, and 8 hours after breakfast; lunch was given at t = 4. Plasma MPO concentration was measured by sandwich enzyme-linked immunosorbent assay. The number of leukocytes in fasting blood samples was higher in DM2 compared with NGM (6.1 +/- 1.4 and 5.4 +/- 1.2 x 10(9)/L, respectively; P.05). Baseline MPO concentration did not significantly differ between NGM and DM2 (51.4 +/- 12.9 and 54.5 +/- 18.4 mug/L, respectively; P = .39). Baseline MPO was positively associated with leukocytes (r = 0.20, P.05) and inversely associated with high-density lipoprotein cholesterol (r = -0.22, P.05). Leukocytes increased from 5.0 +/- 1.5 to 6.1 +/- 1.5 x 10(9)/L and from 5.8 +/- 1.4 to 6.6 +/- 1.4 x 10(9)/L in NGM and DM2, respectively (both P.01), after the fat-rich meals. In contrast to our hypothesized increase in MPO, we found a significant decrease in MPO in NGM (both meal types) and DM2 (fat-rich meals only). Our findings provide no support to our initial hypothesis that meal-induced release of MPO might be a mechanism that contributes to CVD risk.

Both postprandial hyperglycemia and hypertriglyceridemia have been identified as risk markers for cardiovascular disease, but parameters associated with these postprandial responses are largely unknown. The objective was to assess whether usually measured clinical and biochemical parameters can predict postprandial glucose and triglyceride responses and whether these responses are associated with each other. Postmenopausal women, 76 with normal glucose metabolism (NGM) and 41 with type 2 diabetes mellitus (T2DM), received 2 consecutive fat-rich meals and carbohydrate-rich meals on separate occasions. Blood samples were taken before and at t = 1, 2, 4, 6, and 8 hours after breakfast; lunch was given at t = 4 hours. Regression analysis was performed with incremental area under the postprandial triglyceride curve (triglyceride-iAUC) and glucose curve (glucose-iAUC) after fat-rich and carbohydrate-rich meals, respectively. In women with NGM, fasting triglycerides, hemoglobin A(1c), total cholesterol, and, inversely, high-density lipoprotein cholesterol were independently associated with triglyceride-iAUC; and age and fasting triglycerides were independently associated with glucose-iAUC. In women with T2DM, fasting triglycerides were independently associated with triglyceride-iAUC, whereas hemoglobin A(1c) and fasting glucose were stronger than fasting triglycerides associated with glucose-iAUC. Glucose-iAUC and triglyceride-iAUC were associated with each other in women with T2DM, but not in those with NGM. The association between glucose-iAUC and triglyceride-iAUC in women with T2DM and the association of fasting triglycerides with both glucose-iAUC and triglyceride-iAUC in NGM and T2DM suggest a common underlying mechanism for postprandial increments in glucose and triglycerides, especially in T2DM. Commonly measured clinical and biochemical parameters can only partly explain postprandial glucose and triglyceride excursions.

Introduction In early sepsis stages, optimal treatment could contribute to prevention of progression to severe sepsis. Therefore, we investigated if there was an association between time to antibiotics and relevant clinical outcomes in hospitalized emergency department (ED) patients with mild to severe sepsis stages. Methods This is a prospective multicenter study in three Dutch EDs. Patients were stratified into three categories of illness severity, as assessed by the predisposition, infection, response, and organ failure (PIRO) score: PIRO score 1 to 7, 8 to 14 and >14 points, reflected low, intermediate, and high illness severity, respectively. Consecutive hospitalized ED patients with a suspected infection who were treated with intravenous antibiotics were eligible to participate in the study. The primary outcome measure was the number of surviving days outside the hospital at day 28 which was used as an inverse measure of hospital length of stay (LOS). The secondary outcome measure was 28-day mortality, taking into account the time to mortality. Multivariable Cox regression analysis was used to estimate the association between time to antibiotics and the primary and secondary outcome measures corrected for confounders, including appropriateness of antibiotics and initial ED resuscitation, in three categories of illness severity. Results Of the 1,168 included patients, 112 died (10%), while 85% and 95% received antibiotics within three and six hours, respectively. No association between time to antibiotics and surviving days outside the hospital or mortality was found. Only in PIRO group 1 to 7 was delayed administration of antibiotics (>3 hours) associated with an increase in surviving days outside the hospital at day 28 (hazard ratio: 1.46, 95% confidence interval: 1.05 to 2.02 after correction for potential confounders). Conclusions In ED patients with mild to severe sepsis who received antibiotics within six hours after ED presentation, a reduction in time to antibiotics was not found to be associated with an improvement in relevant clinical outcomes.

Objective— The mechanisms responsible for the increased cardiovascular disease risk that accompanies type 2 diabetes (T2D) remain poorly understood. It is commonly held that endothelial dysfunction and low-grade inflammation can explain, at least in part, why deteriorating glucose tolerance is associated with cardiovascular disease. However, there is no direct evidence for this contention. Methods and Results— In this population-based study (n=631), T2D was cross-sectionally associated with both endothelial dysfunction and low-grade inflammation, whereas impaired glucose metabolism (IGM) was associated only with low-grade inflammation. These findings were independent of other risk factors that accompany T2D or IGM. During a follow-up of 11.7 years (median; range 0.5 to 13.2 years), low-grade inflammation was associated with a greater risk of cardiovascular mortality (hazard ratio, 1.43 [95% CI, 1.17 to 1.77] per 1 SD difference). For endothelial dysfunction, the association with cardiovascular mortality was stronger in diabetic (hazard ratio, 1.87 [95% CI, 1.43 to 2.45]) than in nondiabetic individuals (hazard ratio, 1.23 [95% CI, 0.86 to 1.75]; P interaction=0.06). Finally, T2D-associated endothelial dysfunction and low-grade inflammation explained ≈43% of the increase in cardiovascular mortality risk conferred by T2D. Conclusions— These data emphasize the necessity of randomized controlled trials of strategies that aim to decrease cardiovascular disease risk by improving endothelial function and decreasing low-grade inflammation, especially for T2D patients.

Individuals with type 1 diabetes have mild performance deficits on a range of neuropsychological tests compared with nondiabetic control subjects. The mechanisms underlying this cognitive deterioration are still poorly understood, but chronic hyperglycemia is now emerging as a potential determinant, possibly through microvascular changes in the brain. In 24 type 1 diabetic patients, we tested at euglycemia and at acute hypoglycemia whether the presence of proliferative diabetic retinopathy, as a marker of microvascular disease, adversely affects the ability of the brain to respond to standardized hypoglycemia, using functional magnetic resonance imaging with a cognitive task. Patients with retinopathy, compared with patients without, showed less deactivation (hence, an increased response) in the anterior cingulate and the orbital frontal gyrus during hypoglycemia compared with euglycemia (P < 0.05). Task performance and reaction time were not significantly different for either group. We conclude that microvascular damage in the brain of patients with retinopathy caused this increased brain response to compensate for functional loss.

Background The added value of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning as a function of pretest risk assessment in indeterminate pulmonary nodules is still unclear. Objective To obtain an external validation of the prediction model according to Swensen and colleagues, and to quantify the potential added value of FDG-PET scanning as a function of its operating characteristics in relation to this prediction model, in a population of patients with radiologically indeterminate pulmonary nodules. Design, setting, and patients Between August 1997 and March 2001, all patients with an indeterminate solitary pulmonary nodule who had been referred for FDG-PET scanning were retrospectively identified from the database of the PET center at the VU University Medical Center. Results One hundred six patients were eligible for the study, and 61 patients (57%) proved to have malignant nodules. The goodness-of-fit statistic for the model (according to Swensen) indicated that the observed proportion of malignancies did not differ from the predicted proportion (p = 0.46). PET scan results, which were classified using the 4-point intensity scale reading, yielded an area under the evaluated receiver operating characteristic curve of 0.88 (95% confidence interval [CI], 0.77 to 0.91). The estimated difference of 0.095 (95% CI, −0.003 to 0.193) between the PET scan results classified using the 4-point intensity scale reading and the area under the curve (AUC) from the Swensen prediction was not significant (p = 0.058). The PET scan results, when added to the predicted probability calculated by the Swensen model, improves the AUC by 13.6% (95% CI, 6 to 21; p=0.0003). Conclusion The clinical prediction model of Swensen et al was proven to have external validity. However, especially in the lower range of its estimates, the model may underestimate the actual probability of malignancy. The combination of visually read FDG-PET scans and pretest factors appears to yield the best accuracy.

Background: Type 2 diabetes (DM2) and impaired glucose metabolism (IGM) are associated with an increased cardiovascular disease risk. Impaired endothelial synthesis of nitric oxide (NO) is an important feature of atherothrombosis and can be estimated from endothelium-dependent flow-mediated dilation (FMD). It is controversial whether or not FMD is impaired in DM2 and IGM. We investigated this issue in a population-based setting. Methods and results: In the study population ( n =650; 246 with normal glucose metabolism (NGM), 135 with IGM and 269 with DM2; mean age: 67.6 years), FMD and endothelium-independent nitroglycerine-mediated dilation (NMD) were ultrasonically estimated from the brachial artery and expressed as the absolute change in diameter in mm. The increase in diameter (mean ± standard deviation) in NGM, IGM and DM2 was 0.19±0.15, 0.19±0.18 and 0.13±0.17 for FMD and 0.45±0.21, 0.43±0.24 and 0.45±0.25 for NMD. After adjustment for age, sex, baseline diameter and percentage increase in peak systolic velocity, DM2, as compared to NGM, remained associated with impaired FMD (regression coefficient β (95%CI)) as compared to NGM, −0.06mm (−0.09 to −0.03). IGM was not associated with impaired FMD ( β , 0.01mm (−0.02 to 0.04)). Additional adjustment for conventional cardiovascular risk factors did not alter these associations. Hyperglycemia or hyperinsulinemia explained 2% of the association between DM2 and FMD. NMD was not associated with glucose tolerance. Conclusions: This study shows that DM2 is independently associated with impaired FMD. Hyperglycemia and hyperinsulinemia contribute minimally to this association. Impaired FMD may therefore, in part, explain the increased cardiovascular disease risk in DM2, whereas the normal FMD in IGM suggests that other forms of endothelial dysfunction are important in explaining the increased cardiovascular disease risk in IGM.

Objective: To examine variables associated with bone mineral density (BMD) in patients with rheumatoid arthritis (RA). Methods: We investigated 373 patients with low to moderately active RA. Patients with low disease activity were recruited from a cohort of patients in clinical remission. Patients with moderately active disease were included in a trial comparing the effects of long term high intensity exercise programme and conventional physical therapy. Demographic and clinical data were collected. Bone mineral density (BMD) was measured by means of dual x ray absorptiometry (DXA). Associations between demographic and clinical measurements on the one hand and BMD on the other were investigated in regression analyses. Results: The patient group consisted of middle aged, mainly female, patients. The median (interquartile range) disease duration was 7 (4 to 13) years, the mean disease activity score (standard deviation) was 3.2 (1.4). Of the group, 66% was rheumatoid factor positive, and 83% (n = 304) had never used corticosteroids. The median Larsen score of hands and feet was 27 (5 to 61). Greater age and low body mass index were related to low BMD at the hip and spine. High Larsen score for hands and feet was significantly associated with low BMD at the hip. The use of corticosteroids was not independently associated with BMD. The results of the multiple regression analyses also applied to the subgroup of corticosteroid naive patients. Conclusion: BMD data of patients with low to moderately active RA demonstrated an association between high radiological RA damage and low BMD at the hip, which suggests an association between the severity of RA and the risk of generalised bone loss, which also occurred in corticosteroid naive patients.

OBJECTIVE—To investigate whether screening-detected diabetic patients differ from diabetic patients newly diagnosed in general practice with regard to the presence of microvascular complications. RESEARCH AND DESIGN METHODS—Diabetic patients, identified by a population-based targeted screening procedure consisting of a screening questionnaire and a fasting capillary whole-blood glucose measurement followed by diagnostic testing, were compared with patients newly diagnosed with diabetes in general practice. Retinopathy was assessed with fundus photography, impaired foot sensitivity was assessed with Semmes-Weinstein monofilaments, and the presence of microalbuminuria was measured by means of the albumin-to-creatinine ratio (ACR). RESULTS—A total of 195 screening-detected type 2 diabetic patients and 60 patients newly diagnosed in general practice participated in the medical examination. The prevalence of retinopathy was higher in screening-detected type 2 diabetic patients than in patients newly diagnosed in general practice, but not significantly higher. The prevalence of retinopathy was 7.6% (95% CI 4.6–12.4) in screening-detected type 2 diabetic patients and 1.9% (0.3–9.8) in patients newly diagnosed in general practice. The prevalence of impaired foot sensitivity was similar in both groups, 48.1% (40.9–55.3) and 48.3% (36.2–60.7), respectively. The ACR was 0.61 (interquartile range 0.41–1.50) in screening-detected type 2 diabetic patients and 0.99 (0.53–2.49) in patients newly diagnosed in general practice. The difference in prevalence of microalbuminuria was not statistically significant. The prevalence of microalbuminuria was 17.2% (95% CI 12.5–23.2) and 26.7% (17.1–39.0) in screening-detected type 2 diabetic patients and patients newly diagnosed in general practice, respectively. CONCLUSIONS—Targeted screening for type 2 diabetes (with a screening questionnaire as a first step) resulted in the identification of previously undiagnosed diabetic patients with a considerable prevalence of microvascular complications.

The phenomenon of improved diabetes self-management following participation in a clinical trial, with subsequent improvement of glycaemic control, has been acknowledged in literature but has received little attention. Also, the potential implications of such a 'study effect' for clinical research are poorly explored. We review the literature and describe the effects on glycaemic and psychological outcomes in long-term poorly controlled type 1 diabetes patients participating in a qualification phase of a Good Clinical Practice (GCP) trial. Improved glycaemic control following participation in a clinical trial is best understood as the result of improved patients' instrumental coping behaviours, including increased self-monitoring of blood glucose (SMBG). Such improvement in self-care with ensuing improved glycaemic control has important consequences for trial design. Firstly, benefits seen in uncontrolled trials should be interpreted with extreme caution. Secondly, unspecific study effects and the effect of a given intervention may not simply be additive. Therefore, it is wise to include a run-in or qualification phase of adequate length before randomization in a clinical trial. A stable baseline HbA(1c) can thus be reached, upon which the specific effect of an intervention can be properly judged. Also, in a multi-centre trial, a qualification phase of sufficient length will help diminish differences in terms of intensity of care provided in participating centres. Copyright (C) 2003 John Wiley Sons, Ltd

Offspring of consanguineous couples are at increased risk of congenital disorders. The risk increases as parents are more closely related. Individuals that have the same degree of relatedness according to their pedigree, show variable genomic kinship coefficients. To investigate whether we can differentiate between couples with high- and low risk for offspring with congenital disorders, we have compared the genomic kinship coefficient of consanguineous parents with a child affected with an autosomal recessive disorder with that of consanguineous parents with only healthy children, corrected for the degree of pedigree relatedness. 151 consanguineous couples (73 cases and 78 controls) from 10 different ethnic backgrounds were genotyped on the Affymetrix platform and passed quality control checks. After pruning SNPs in linkage disequilibrium, 57,358 SNPs remained. Kinship coefficients were calculated using three different toolsets: PLINK, King and IBDelphi, yielding five different estimates (IBDelphi, PLINK (all), PLINK (by population), King robust (all) and King homo (by population)). We performed a one-sided Mann Whitney test to investigate whether the median relative difference regarding observed and expected kinship coefficients is bigger for cases than for controls. Furthermore, we fitted a mixed effects linear model to correct for a possible population effect. Although the estimated degrees of genomic relatedness with the different toolsets show substantial variability, correlation measures between the different estimators demonstrated moderate to strong correlations. Controls have higher point estimates for genomic kinship coefficients. The one-sided Mann Whitney test did not show any evidence for a higher median relative difference for cases compared to controls. Neither did the regression analysis exhibit a positive association between case–control status and genomic kinship coefficient. In this case–control setting, in which we compared consanguineous couples corrected for degree of pedigree relatedness, a higher degree of genomic relatedness was not significantly associated with a higher likelihood of having an affected child. Further translational research should focus on which parts of the genome and which pathogenic mutations couples are sharing. Looking at relatedness coefficients by determining genome-wide SNPs does not seem to be an effective measure for prospective risk assessment in consanguineous parents., NA

OBJECTIVE—To assess in a randomized crossover trial the efficacy of continuous subcutaneous insulin infusion in improving glycemic control and health-related quality of life in type 1 diabetic patients with long-standing poor glycemic control. RESEARCH DESIGN AND METHODS—A total of 79 patients in 11 Dutch centers were randomized to 16 weeks of continuous subcutaneous insulin infusion followed by 16 weeks intensive injection therapy or the reverse order. Glycemic control was assessed by HbA1c, self-reported hypoglycemic events, and blood glucose memory meter read outs. Changes in quality of life were assessed by self-report questionnaires administered at baseline and 16 weeks. RESULTS—As the drop-out rate after crossover was high (17 of 79 patients [22%]), we analyzed the trial as a parallel clinical trial, using data of the first half of the crossover phase only. At 16 weeks, mean HbA1c was 0.84% (95% CI −1.31 to −0.36) lower in the continuous subcutaneous insulin infusion group compared with the insulin injection group (P = 0.002). Stability of blood glucose self-measurement values, expressed as SD of the nine-point blood glucose profiles, improved in the insulin pump group by 29.3 ± 41.1 vs. 8.2 ± 36.5% in the injection group (P = 0.039). The number of mild hypoglycemic episodes per patient-week was 0.99 (95% CI 0.11–1.87) higher in the insulin pump group (P = 0.028). Weight gain was similar in both groups. Scores on the Short-Form 36-Item subscales ‘general health’ and ‘mental health’ improved in the continuous subcutaneous insulin infusion group, compared with stable values in the injection group (P = 0.048 and 0.050, respectively). CONCLUSIONS—Continuous subcutaneous insulin infusion improves glycemic control and some aspects of health-related quality of life in patients with a history of long-term poor glycemic control.

Objective Several factors predict joint damage in early rheumatoid arthritis (RA). In the context of a trial in early RA, we studied the relationship between clinical signs in individual joints and their propensity to develop progressive damage. Methods The COBRA (Combinatietherapie Bij Reumatoide Artritis) multicenter trial compared the efficacy of prednisolone, methotrexate, and sulfasalazine against sulfasalazine alone in 155 patients with early RA. Two blinded observers interpreted radiographs in sequence (using the Sharp/Van der Heijde scoring system); in each center, one blinded observer performed clinical assessments every 3 months. The current analysis is based on clinical and radiologic data of the individual metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of 135 patients. Conditional stepwise logistic regression analyzed the relationship between damage (progression) and clinical signs at baseline and followup for each of these joints individually in each patient. Results Combination therapy strongly retarded the progression of damage. Progression was stronger in patients with rheumatoid factor, HLA–DR4, and high levels of disease activity at baseline. At baseline, 6% of the MCP and PIP joints showed damage; after 1 year, disease had progressed in 10% of these joints. Baseline damage, swelling, or pain in a joint independently and strongly predicted the progression of damage in that joint (P < 0.001). Each additional point in the swelling score (range 0–2) tripled the risk for subsequent progression. Each additional point on the Sharp scale (range 0–8 per joint) and each additional point on the pain scale (range 0–3) doubled the risk. The mean pain and swelling scores over the year were even stronger predictors of damage. Conclusion Local expression of early RA disease activity, both at baseline and at 1-year followup, is strongly related to progression of damage in the individual joint.

OBJECTIVE—Measures of baroreflex sensitivity, heart rate variability (HRV), and the classical Ewing test parameters are currently used for the diagnosis of diabetic autonomic neuropathy and for mortality risk stratification after myocardial infarction. However, the strengths of the associations of these measures of autonomic function with risk of mortality have never been compared in one study population. Furthermore, no evidence is available on the possible effect of glucose tolerance on these associations. RESEARCH DESIGN AND METHODS—The study population (n = 605) consisted of a glucose tolerance–stratified sample from a general population (50–75 years of age). Cardiac cycle duration and continuous finger arterial pressure were measured under two conditions: at rest and on metronome breathing. From these readings, seven parameters of autonomic function were assessed (one Ewing, five HRV, and one baroreflex sensitivity). RESULTS—During 9 years of follow-up, 101 individuals died, 43 from cardiovascular causes. Subjects with diabetes and low levels of the autonomic function parameters, indicating impaired autonomic function, had an approximately doubled risk of mortality. This association was consistent, though not statistically significant, for all parameters. The elevated risk was not observed in subjects without diabetes, hypertension, or prevalent cardiovascular disease. CONCLUSIONS—Impaired autonomic function is associated with all-cause and cardiovascular mortality. Moreover, the results of the present study suggest that cardiac autonomic dysfunction in patients already at risk (diabetes, hypertension, or history of cardiovascular disease) may be especially hazardous.

Consultation with another physician is considered to be an important safeguard of the practice of euthanasia and physician-assisted suicide. The objective is to describe the frequency and characteristics of consultation in cases of euthanasia or physician-assisted suicide (EAS) in the Netherlands. Data from two cross-sectional descriptive nationwide surveys, carried out in 1995, were used. Questionnaires were mailed to physicians attending 6060 deaths, identified from death certificates, and a stratified sample of 405 physicians were interviewed. In 1990, a cross-sectional descriptive postal survey of a random sample of 1042 general practitioners took place. Consultation took place in 63% of cases of EAS in the Netherlands, in 99% of the cases reported to the public prosecutor and in approximately 37% of unreported cases. In almost half of the unreported cases the decision had been discussed less formally with at least one colleague. In 1990, 7% of general practitioners met all 8 criteria for good consultation; this increased to 64% in 1995. Of the respondents, 26% had at some time advised against performing euthanasia or assisted suicide when acting as a consultant. This study shows that approximately two thirds of all cases of EAS are safeguarded by consultation. Although in the majority of these cases the consultation is of good quality, there is certainly still room for improvement. The quality of consultation could be improved, for instance, by appointing independent and specifically trained consultants.

Objective. To determine the influence of reading series of films in chronological order, in pairs with unknown time sequence, or as single films, on precision and sensitivity to change. Methods. Two studies were performed with 10 and 12 patients fulfilling the American College of Rheumatology criteria. In Study 1, two sets of films with a I yr interval were scored in chronological order, in pairs, and as single films. In Study 2, four sets of films, with a I yr interval each, were scored in chronological order, as single films and as single-pair (right and left together). All films were scored with the Sharp/van der Heijde method by two independent observers. Data were analysed with a repeated measures ANOVA using a full mixed effects model. Two gencralizability (G) coefficients were constructed for reliability and for changc. Results. Study I: the interobserver reliability was similar for the three methods (G reliability chronological 0.94, paired 0.88, single 0.93 ); progression was a mean increase (averaged over patients, observers and methods) from 26 to 37 (P = 0.046). The sensitivity for change was greater for the chronological than for the paired and single scoring (G change 0.39, 0.22 and 0.24, respectively). Study 2: the interobserver reliability was 0.86 for chronological, 0.76 for single-pair and 0.91 for single readings. Significantly more progression was measured with the chronological compared with thc single-paired and single methods (15.9 vs 8.5 and 8.3; P = 0.0001). A constant progression was suggested by chronological reading, in contrast to a stabilization in the other two methods after I yr. Conclusion. Reading films in chronological order is most sensitive to change in a time period up to 3 yr follow-up; this was already present after I yr, but even more pronounced with longer follow-up.

Abstract —Microalbuminuria (MA) is associated with increased cardiovascular and all-cause mortality. It has been proposed that MA reflects generalized atherosclerosis and may thus predict mortality. To investigate this hypothesis, we studied the associations between, on the one hand, MA and peripheral arterial disease (PAD), a generally accepted marker of generalized atherosclerosis, and, on the other hand, cardiovascular and all-cause mortality in an age-, sex-, and glucose tolerance-stratified sample (n=631) of a population-based cohort aged 50 to 75 years followed prospectively for 5 years. At baseline, the albumin-to-creatinine ratio (ACR) was measured in an overnight spot urine sample; MA was defined as ACR >2.0 mg/mmol. PAD was defined as an ankle-brachial pressure index below 0.90 and/or a history of a peripheral arterial bypass or amputation. After 5 years of follow-up, 58 subjects had died (24 of cardiovascular causes). Both MA and PAD were associated with a 4-fold increase in cardiovascular mortality. After adjusting for age, sex, diabetes mellitus, hypertension, levels of total and HDL-cholesterol and triglyceride, body mass index, smoking habits, and preexistent ischemic heart disease, the relative risks (RR) (95% confidence intervals) were 3.2 (1.3 to 8.1) for MA and 2.4 (0.9 to 6.1) for PAD. When both MA and PAD were included in the multivariate analysis, the RRs were 2.9 (1.1 to 7.3) for MA and 2.0 (0.7 to 5.7) for PAD. MA and PAD were both associated with an about 2-fold increase in all-cause mortality. The RRs of all-cause mortality associated with MA and PAD were about 4 times higher among hypertensive than among normotensive subjects. We conclude that both MA and PAD are associated with an increased risk of cardiovascular mortality. MA and PAD are mutually independent risk indicators. The associations of MA and PAD with all-cause mortality are somewhat weaker. They are more pronounced in the presence of hypertension than in its absence. These data suggest that MA affects mortality risk through a mechanism different from generalized atherosclerosis.

With the aging of the population, the medical and social costs of skeletal fragility leading to fractures will cause an immense burden on society unless effective prophylactic and therapeutic regimens can be developed. Exercise is suggested as a possible regimen against involutional bone loss. The purpose of the present meta-analysis is to address a quantitative review of the randomized controlled trials (RCTs) and nonrandomized controlled trials (CTs) on the effects of exercise training programs on bone mass, measured as bone mineral density (BMD) or bone mineral content (BMC), of the lumbar spine (LS) and the femoral neck (FN) in pre- and postmenopausal women. The literature from 1966 through December 1996 was searched for published RCTs and CTs. Study treatment effect is defined as the difference between percentage change in bone mass per year in the training group and the control group. Overall treatment effects (OTs) with the 95% confidence intervals of these study treatment effects were calculated using inverse-variance weighting. Of the 62 articles identified, 25 met the inclusion criteria and were maintained for further analyses. The weighted OTs for the RCTs showed very consistently that the exercise training programs prevented or reversed almost 1% of bone loss per year in both LS and FN for both pre- and postmenopausal women. The two OTs that could be calculated for strength training programs did not reach significance. The OTs for the CTs were almost twice as high as those for the RCTs, which gives an indication of the confounding introduced by the nonrandom allocation of the subjects to groups.

Objectives: To investigate the occurrence of 27 chronic medical conditions in a cohort of adults with and without hearing impairment, and to examine the association between these conditions and hearing ability. Design: The National Longitudinal Study on Hearing (NL-SH study) is a large prospective study among adults aged 18 to 70 years, conducted via the internet in the Netherlands. Hearing ability was measured with a digits-in-noise test and comorbidity was assessed through self-report. Study sample: Cross-sectional data of 890 hearing-impaired and 975 normally-hearing adults were analyzed. Both descriptive statistics and multinomial logistic regression analyses were conducted. Results: Of the NL-SH participants with insufficient or poor hearing ability, 78.5% reported to suffer from at least one additional chronic condition. This proportion was larger than in the normally-hearing group (68.6% with one or more chronic conditions and 37.7% with two or more). After adjustment for age and gender, 'dizziness causing falling', 'diabetes' and 'arthritis types other than osteoarthritis and rheumatic arthritis' were significantly associated with poor hearing ability. Conclusions: Our results show that some previously reported associations do not only occur in older age groups, but also in younger cohorts. Comorbidity is relevant in the rehabilitation (multi-disciplinary care) and the clinical encounter. © 2014 British Society of Audiology, International Society of Audiology, and Nordic Audiological Society.

Objective: To investigate the association between hearing status, socioeconomic status and work status. Participants: Cross-sectional data of 18-64 year old participants (N=1888) from the National Longitudinal Study on Hearing (NL-SH) were used. Both normal hearing and hearing impaired subjects participated. Methods: Hearing ability in noise was measured with the National Hearing test, an online speech-in-noise test. Educational level, monthly income, being primary income earner and working status (i.e. paid employment, unemployed and looking for work, unfit for work, voluntary work, household work, being a student, or taking early retirement, and the type of work contract) were assessed with a questionnaire. Logistic regression analyses were applied. Results: Participants with poorer hearing ability were less likely to be found in the upper categories of educational level and income, having paid work > 12 hours per week, being a student, or taking early retirement. On the other hand they were more likely to look for work or to be unfit for work. No associations were found with voluntary work and household work. Discussion: Hearing ability seems to be related to both socioeconomic status and being employed. Our findings underline the importance of rehabilitation programs in audiology, aimed at supporting people with hearing impairment to help them to successfully enter or re-enter the workforce. © 2013 - IOS Press and the authors. All rights reserved.

Objective To compare rates of sustained low and minimal disease activity and remission according to the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria during 3-year followup in rheumatoid arthritis (RA) patients treated with etanercept and adalimumab in routine care. Methods Four hundred seven RA patients previously unexposed to tumor necrosis factor antagonists were treated with etanercept (n = 203) or adalimumab (n = 204) and assessed at 3- and later 6-month intervals. Treatment allocation was at the discretion of the treating rheumatologist. Clinical parameters were measured at each time point, as were anti-adalimumab antibodies in adalimumab-treated patients. Achievement of clinical outcome was defined as the occurrence of sustained (at least 12 consecutive months) low disease activity (28-joint Disease Activity Score [DAS28]

In shock, organ perfusion is of vital importance because organ oxygenation is at risk. NO, the main endothelial-derived vasodilator, is crucial for organ perfusion and coronary patency. The availability of NO might depend on the balance between a substrate (arginine) and an inhibitor (asymmetric dimethylarginine; ADMA) of NO synthase. Therefore, we investigated the relationship of arginine, ADMA and their ratio with circulatory markers, disease severity, organ failure and mortality in shock patients. In forty-four patients with shock (cardiogenic n 17, septic n 27), we prospectively measured plasma arginine and ADMA at intensive care unit admission, Acute Physiology and Chronic Health Evaluation (APACHE) II-(predicted mortality) and Sequential Organ Failure Assessment (SOFA) score, and circulatory markers to investigate their relationship. Arginine concentration was decreased (34·6 (sd 17·9) μmol/l) while ADMA concentration was within the normal range (0·46 (sd 0·18) μmol/l), resulting in a decrease in the arginine:ADMA ratio. The ratio correlated with several circulatory markers (cardiac index, disseminated intravascular coagulation, bicarbonate, lactate and pH), APACHE II and SOFA score, creatine kinase and glucose. The arginine:ADMA ratio showed an association (OR 0·976, 95 % CI 0·963, 0·997, P = 0·025) and a diagnostic accuracy (area under the curve 0·721, 95 % CI 0·560, 0·882, P = 0·016) for hospital mortality, whereas the arginine or ADMA concentration alone or APACHE II-predicted mortality failed to do so. In conclusion, in shock patients, the imbalance of arginine and ADMA is related to circulatory failure, organ failure and disease severity, and predicts mortality. We propose a pathophysiological mechanism in shock: the imbalance of arginine and ADMA contributes to endothelial and cardiac dysfunction resulting in poor organ perfusion and organ failure, thereby increasing the risk of death.

Aim To examine whether reduced cognitive functioning can be observed in early stages of left ventricular (LV) dysfunction and heart failure. Methods and results In 313 individuals aged 59–87 years from the longitudinal non-demented population-based Hoorn Study, echocardiography was performed to measure markers of LV systolic and diastolic function at baseline (2000–01) and follow-up (2005–09), together with standardized physical examinations and brain natriuretic peptide (BNP) measurements. Heart failure was assessed echocardiographically at the follow-up examination only. Cognitive tests for information processing speed, memory, and attention and executive functioning were administered at follow-up. Linear regression analyses showed that baseline markers of LV diastolic function, but not LV systolic function, were associated with lower scores on attention and executive functioning at follow-up. Individuals with higher baseline BNP had lower scores on all three cognitive domains: standardized regression coefficients were −0.16 (–0.26 to −0.05), −0.17 (–0.28 to −0.05), and −0.28 (–0.37 to −0.19). Worse LV systolic and diastolic function at follow-up were associated with a worse performance on attention and executive functioning. Furthermore, individuals with heart failure at follow-up had lower scores on attention and executive functioning: −0.21 (–0.41 to −0.00). Higher BNP at follow-up was also associated with worse attention and executive functioning, even after adjustment for baseline BNP. Conclusions Worse cognitive functioning can already be observed in early stages of LV dysfunction and heart failure. BNP is a target for further investigation as a risk factor for cognitive decline in the general population.

OBJECTIVE To investigate the relationship among A1C, fasting plasma glucose (FPG), and 2-h postload plasma glucose in the Dutch general population and to evaluate the results of using A1C for screening and diagnosis of diabetes. RESEARCH DESIGN AND METHODS In 2006–2007, 2,753 participants of the New Hoorn Study, aged 40–65 years, who were randomly selected from the population of Hoorn, the Netherlands, underwent an oral glucose tolerance test (OGTT). Glucose status (normal glucose metabolism [NGM], intermediate hyperglycemia, newly diagnosed diabetes, and known diabetes) was defined by the 2006 World Health Organization criteria. Spearman correlations were used to investigate the agreement between markers of hyperglycemia, and a receiver operating characteristic (ROC) curve was calculated to evaluate the use of A1C to identify newly diagnosed diabetes. RESULTS In the total population, the correlations between fasting plasma glucose and A1C and between 2-h postload plasma glucose and A1C were 0.46 and 0.33, respectively. In patients with known diabetes, these correlations were 0.71 and 0.79. An A1C level of ≥5.8%, representing 12% of the population, had the highest combination of sensitivity (72%) and specificity (91%) for identifying newly diagnosed diabetes. This cutoff point would identify 72% of the patients with newly diagnosed diabetes and include 30% of the individuals with intermediate hyperglycemia. CONCLUSIONS In patients with known diabetes, correlations between glucose and A1C are strong; however, moderate correlations were found in the general population. In addition, based on the diagnostic properties of A1C defined by ROC curve analysis, the advantage of A1C compared with OGTT for the diagnosis of diabetes is limited.

The aim of the study was to test whether fasting or postprandial cholesteryl ester transfer protein (CETP) concentrations are associated with postprandial changes in high-density lipoprotein cholesterol (HDL-c) concentrations after fat-rich or carbohydrate-rich meals. Postmenopausal women (76 with normal glucose metabolism [NGM], 41 with type 2 diabetes mellitus [T2DM], and 38 T2DM women with statin therapy [T2DM-ST]) received 2 consecutive fat-rich or carbohydrate-rich meals on separate occasions. Linear regression analysis was performed to assess the associations of fasting CETP and postprandial changes of CETP with postprandial changes in HDL-c. Mean plasma HDL-c concentrations decreased significantly after the fat-rich meals: 0.18 +/- 0.09 mmol/L in NGM, 0.16 +/- 0.09 mmol/L in T2DM, and 0.14 +/- 0.08 mmol/L in T2DM-ST women. This effect was smaller after using carbohydrate-rich meals: 0.12 +/- 0.09 mmol/L in the NGM, 0.12 +/- 0.08 mmol/L in the T2DM, and 0.10 +/- 0.05 mmol/L in the T2DM-ST study group. Higher fasting but not postprandial CETP concentrations were associated with a larger postprandial decrease in HDL-c (beta -0.034; 95% confidence interval, -0.067 to -0.001) after the fat-rich meals. This association was independent of the postprandial increase in triglycerides and similar among the 3 study groups. A high fasting CETP concentration may contribute to the postprandial atherogenic lipoprotein profile in postmenopausal women by decreasing HDL-c after fat-rich meals. This effect is independent from the postprandial increase in triglycerides.

Background: In the setting of multiple remission and relapse periods of a chronic disease, simple endpoint analysis does not fully capture all relevant information, and we need methods to additionally describe both the duration of remission as well as the interruptions in this desired state. Probably the two-state continuous Markov process model comprises the best mathematical approach to data analysis. However, this approach is complex and not intuitive to clinicians. In this paper we propose a simple scoring system and a graph that can enhance the information about the remission experience in a trial or cohort study. Methods: The continuity rewarded ('ConRew') score sums up periods in remission, and rewards extended periods by placing more value on uninterrupted periods than on interrupted periods. The 'patient vector graph' attempts to plot each patient's remission experience over time as a horizontal line (the 'vector') that is visible when the patient is in remission, but interrupted whenever relapse occurs. In this way a pattern is formed that conveys the number of patients experiencing remission, their individual total duration and interruptions, and time when these occur. Results: In a dataset of a randomized trial in early rheumatoid arthritis, the graph clearly showed both early and late benefit of one group over the other. The scoring system demonstrated the main benefit was in the number of remission periods, not in their 'uninterruptedness'. Conclusion: Both approaches proved feasible and added extra information. © 2010 Elsevier Inc. All rights reserved.

Background Many patients with type 2 diabetes (T2DM) are not able to reach the glycaemic target level of HbA1c < 7.0%, and therefore are at increased risk of developing severe complications. Transition to insulin therapy is one of the obstacles in diabetes management, because of barriers of both patient and health care providers. Patient empowerment, a patient-centred approach, is vital for improving diabetes management. We developed a web-based self-management programme for insulin titration in T2DM patients. The aim of our study is to investigate if this internet programme helps to improve glycaemic control more effectively than usual care. Methods/Design T2DM patients (n = 248), aged 35–75 years, with an HbA1c ≥ 7.0%, eligible for treatment with insulin and able to use the internet will be selected from general practices in two different regions in the Netherlands. Cluster randomisation will be performed at the level of general practices. Patients in the intervention group will use a self-developed internet programme to assist them in self-titrating insulin. The control group will receive usual care. Primary outcome is the difference in change in HbA1c between intervention and control group. Secondary outcome measures are quality of life, treatment satisfaction, diabetes self-efficacy and frequency of hypoglycaemic episodes. Results will be analysed according to the intention-to-treat principle. Discussion An internet intervention supporting self-titration of insulin therapy in T2DM patients is an innovative patient-centred intervention. The programme provides guided self-monitoring and evaluation of health and self-care behaviours through tailored feedback on input of glucose values. This is expected to result in a better performance of self-titration of insulin and consequently in the improvement of glycaemic control. The patient will be enabled to 'discover and use his or her own ability to gain mastery over his/her diabetes' and therefore patient empowerment will increase. Based on the self-regulation theory of Leventhal, we hypothesize that additional benefits will be achieved in terms of increases in treatment satisfaction, quality of life and self-efficacy. Trial registration Dutch Trial Register TC1316.

Background Diabetes specific emotional problems interfere with the demanding daily management of living with type 2 diabetes mellitus (T2DM). Possibly, offering direct feedback on diabetes management may diminish the presence of diabetes specific emotional problems and might enhance the patients' belief they are able to manage their illness. It is hypothesized that self-monitoring of glucose in combination with an algorithm how and when to act will motivate T2DM patients to become more active participants in their own care leading to a decrease in diabetes related distress and an increased self-efficacy. Methods and design Six hundred patients with T2DM (45 ≤ 75 years) who receive care in a structured diabetes care system, HbA1c ≥ 7.0%, and not using insulin will be recruited and randomized into 3 groups; Self-monitoring of Blood Glucose (SMBG), Self-monitoring of Urine Glucose (SMUG) and usual care (n = 200 per group). Participants are eligible if they have a known disease duration of over 1 year and have used SMBG or SMUG less than 3 times in the previous year. All 3 groups will receive standardized diabetes care. The intervention groups will receive additional instructions on how to perform self-monitoring of glucose and how to interpret the results. Main outcome measures are changes in diabetes specific emotional distress and self-efficacy. Secondary outcome measures include difference in HbA1c, patient satisfaction, occurrence of hypoglycaemia, physical activity, costs of direct and indirect healthcare and changes in illness beliefs. Discussion The IN CONTROL-trial is designed to explore whether feedback from self-monitoring of glucose in T2DM patients who do not require insulin can affect diabetes specific emotional distress and increase self-efficacy. Based on the self-regulation model it is hypothesized that glucose self-monitoring feedback changes illness perceptions, guiding the patient to reduce emotional responses to experienced threats, and influences the patients ability to perform and maintain self-management skills. Trial registration Current Controlled Trials ISRCTN84568563

Background: Hypertriglyceridemia is a cardiovascular risk factor. Apolipoprotein C-III (apoC-III) is an important determinant of the catabolic rate of triglyceride-rich lipoproteins. The aim of this study was to investigate the prognostic value of plasma apoC-III concentrations for cardiovascular mortality.Methods: We performed this prospective study in 2244 subjects (ages 49–77 years) who participated in the Hoorn Study. During a mean follow-up of 15 years, 504 individuals died: 231 of cardiovascular disease, 180 of cancer, and 93 of other causes. Cardiovascular disease risk factors and plasma apoC-III concentrations were measured at baseline.Results: The age- and sex-adjusted plasma apoC-III concentration was prospectively associated with cardiovascular mortality (P < 0.001). After adjustment for traditional risk factors, including fasting triglycerides, the hazard ratio (95% CI) for cardiovascular death between the highest and the lowest quartile of apoC-III was 1.85 (1.02–3.38). High concentrations of apoC-III did not appear to be associated with noncardiovascular mortality.Conclusions: In this general population cohort, a high apoC-III concentration in plasma, independently of fasting triglycerides and other traditional risk factors, predicts cardiovascular mortality.

This study compared classical and model-based beta-cell responses during an oral glucose tolerance test (OGTT) and a meal tolerance test (MTT) in a population-based cohort. Individuals with normal glucose metabolism (NGM, n = 161), impaired glucose metabolism (IGM, n = 19) and type 2 diabetes mellitus (DM, n = 20) underwent a 75g-OGTT and an MTT (75 g carbohydrates, 50 g fat, 24 g proteins). Classical estimates of beta-cell function (insulinogenic index and the ratio of areas under insulin and glucose curves) were calculated. Mathematical modelling was used to determine beta-cell glucose sensitivity, rate sensitivity and potentiation. Insulin sensitivity was characterized by three surrogate estimates. Both classical and model-based estimates of beta-cell function were higher during MTT than during OGTT (P < 0.05). Regarding the model-based parameters, especially beta-cell sensitivity was increased following MTT as compared with OGTT (P < 0.05). Both during OGTT and MTT, across most parameters describing beta-cell function, the largest reduction in beta-cell response occurred between IGM and DM, while the largest reduction in insulin sensitivity occurred between NGM and IGM. We conclude that beta-cell response is stronger after a mixed meal than after an OGTT with equal carbohydrate quantity, both for classical and model-based parameters. The higher response was mostly explained by higher beta-cell sensitivity during the meal.

To study the influence of diabetes mellitus (DM) types 1 and 2 on the thickness, radius of curvature, equivalent refractive index, and power of the lens.Observational cross-sectional study.One hundred fourteen patients with DM type 1, 112 patients with DM type 2, and 75 control subjects.Lens thickness and the anterior and posterior radius of the lens were measured by means of corrected Scheimpflug imaging. Ocular refraction was determined with Hartmann-Shack aberrometry. The equivalent refractive index and the power of the lens were calculated from these parameters. Several systemic parameters (e.g., duration of DM, glycated hemoglobin, and type of medication) and ocular comorbidity (e.g., level of diabetic retinopathy) were recorded.The thickness, anterior and posterior radii, equivalent refractive index, and power of the lens.The lenses of the patients with DM type 1 were significantly thicker and more convex, compared with those of the control group (P0.001). Furthermore, there was a significant decrease in the equivalent refractive index of their lenses compared with the control group. No difference in lens parameters was found between the patients with DM type 2 and the control group. In the DM type 1 group, the duration of DM was an important determinant of lens biometry; the independent effects of the duration of DM per year on lens thickness, anterior radius, posterior radius, and equivalent refractive index were respectively 95%, 88%, 207%, and 45% of the effect of age per year. Lens power and ocular refraction were not affected by DM types 1 or 2.The results of the present study show that DM type 1 has a major impact on lens biometry. Furthermore, the difference in effect of DM types 1 and 2 on lens biometry may indicate a fundamental difference in pathogenesis. The decrease in equivalent refractive index of the lens seemed to compensate for the profound increase in lens convexity in patients with DM type 1, resulting in no significant change in lens power or ocular refraction with the duration of DM.

PURPOSE To determine the influence of diabetes mellitus (DM) type 1 and type 2 on the thickness, radius of curvature, power, and asphericity of the cornea. METHODS In this observational cross-sectional study, 102 patients with DM type 1, 101 patients with DM type 2, and 69 healthy subjects were measured by means of Scheimpflug imaging to determine central corneal thickness and the radius and asphericity of the anterior and posterior corneal surfaces. Corneal power was calculated from these parameters. Several systemic parameters (eg, duration of diabetes, glycated hemoglobin, blood glucose levels, and type of medication) and ocular comorbidity (eg, stage of retinopathy) were recorded. RESULTS Patients with DM type 1 and 2 had significantly smaller posterior corneal radii (P < 0.05) than those of healthy subjects (men: 6.49/6.48/6.64 mm; women: 6.36/6.30/6.49 mm). As a result, the optical power of the posterior corneal surface of the patients with diabetes differed from that of the healthy subjects (P < 0.01; men: DM, -6.2 D; healthy, -6.0 D; women: DM, -6.3 D; healthy, -6.2 D). However, corneal thickness, anterior radius and asphericity, and overall corneal power did not differ significantly between the groups. Furthermore, none of the systemic factors or ocular comorbidity had any influence on the corneal thickness or shape. CONCLUSIONS DM affects the posterior corneal radius, resulting in a small change in posterior corneal power. However, chronic DM does not seem to significantly influence the overall corneal power.

Background: Helicobacter pylori and nonsteroidal antiinflammatory drugs (NSAIDs) are the major causes of gastroduodenal ulcers. Studies on the benefit of eradication of H. pylori in NSAID users yielded conflicting results. Objective: To investigate whether H. pylori eradication in patients on long-term NSAIDs reduces the incidence of gastroduodenal ulcers. Methods: Patients on long-term NSAID treatment and who are H. pylori positive on serologic testing, were randomly assigned to either H. pylori eradication (omeprazole, amoxicillin, and clarithromycin) or placebo. Primary endpoint was the presence of endoscopic gastric or duodenal ulcers 3 months after randomization. Results: One hundred sixty-five (48%) of a total of 347 patients were on gastroprotective medication. At endoscopy, gastroduodenal ulcers were diagnosed in 6 (4%) and 8 (5%) patients in the eradication and placebo group, respectively (p =.65). During follow-up of 12 months, no symptomatic ulcers or ulcer complications developed. No significant differences were found in the development of gastroduodenal erosions, dyspepsia, or in quality of life. Conclusion: H. pylori eradication therapy in patients on long-term NSAID treatment had no beneficial effect on the occurrence of ulcers, erosions, or dyspepsia. Ulcer rates in both study arms are remarkably low, in both patients with and without gastroprotective therapy. © 2007 The Authors.

OBJECTIVE— We studied acute changes in markers of glycoxidative and lipoxidative stress, including oxidized LDL, Nε-(carboxyethyl)-lysine (CEL), Nε-(carboxymethyl)-lysine (CML), and 3-deoxyglucosone (3DG), following two consecutive meals. RESEARCH DESIGN AND METHODS— Postmenopausal women (27 with normal glucose metabolism [NGM], 26 with type 2 diabetes) received two consecutive fat-rich meals and two consecutive carbohydrate-rich meals on two occasions. Glucose and triglyceride concentrations were measured at baseline and 1, 2, 4, 6, and 8 h following breakfast; lunch was given at 4 h. Oxidized LDL–to–LDL cholesterol ratio, CEL, CML, and 3DG were measured at baseline and at 8 h. RESULTS— Fasting oxidized LDL–to–LDL cholesterol ratio, 3DG, and CML were higher in women with type 2 diabetes compared with women with NGM and were comparable to the postprandial values at 8 h in NGM. Postprandial rises in the oxidized LDL–to–LDL cholesterol ratio and 3DG were similar in both groups. However, the oxidized LDL–to–LDL cholesterol ratio increased more after the fat-rich meals, whereas CML and 3DG increased more after the carbohydrate-rich meals. After the fat-rich meals, the increase in the oxidized LDL–to–LDL cholesterol ratio correlated with postprandial triglycerides, whereas the increase in 3DG was correlated with postprandial glucose. CONCLUSIONS— The acute changes in markers of glycoxidative and lipoxidative stress in both type 2 diabetes and NGM suggest that postabsorptive oxidative stress may partly underlie the association of postprandial derangements and cardiovascular risk.

Mild renal insufficiency is a risk factor for cardiovascular disease (CVD). Both a decline in GFR and (micro)albuminuria are associated with greater cardiovascular mortality. In ESRD, arterial stiffness, an important cause of CVD, is known to be greater, but few data exist in individuals with mild renal insufficiency or microalbuminuria. This study investigated the association of impaired renal function expressed as lower GFR or greater urinary albumin excretion with arterial stiffness. In a population-based study in 806 individuals (402 men), mean age 68 yr (range 50 to 87), peripheral arterial stiffness (by compliance and distensibility of the carotid, brachial, and femoral arteries and by the carotid elastic modulus [E(inc)]) and central arterial stiffness (by total systemic arterial compliance, carotid-femoral transit time, and aortic augmentation index) were measured ultrasonically. GFR was estimated (eGFR) by the Modification of Diet in Renal Disease (MDRD) formula. Urinary albumin excretion was expressed as urinary albumin/creatinine ratio (UACR). eGFR was 60.6 +/- 11.1 ml/min per 1.73 m(2). Median UACR was 0.57 mg/mmol (range 0.1 to 26.6). After adjustment for age, mean arterial pressure (MAP), gender, and glucose tolerance status (GTS), each 5-ml/min per 1.73 m(2) lower eGFR was associated with a lower distensibility coefficient of the carotid (regression coefficient beta -0.20 10(-3)/kPa; 95% confidence interval [CI] -0.34 to -0.07 10(-3)/kPa) and brachial artery (-0.15 10(-3)/kPa; 95% CI -0.28 to -0.03 10(-3)/kPa) and a greater carotid E(inc) (0.02 kPa; 95% CI 0.0004 to 0.04 kPa). No statistically significant association was found of eGFR with other arterial stiffness indices. After adjustment for age, MAP, gender, and GTS, a greater UACR (per quartile) was associated with a greater E(inc) (0.03 kPa; 95% CI 0.001 to 0.07 kPa) and a trend to a lower distensibility coefficient (-0.24 10(-3)/kPa; 95% CI -0.49 to 0.02 10(-3)/kPa) of the carotid artery. After adjustment for age, MAP, gender, and GTS, a greater UACR (per quartile) was in addition associated with a shorter carotid-femoral transit time (-1.67 ms; 95% CI -3.24 to -0.10 ms). These associations were not substantially changed by mutual adjustment for eGFR and UACR. In individuals with mild renal insufficiency, both a lower eGFR and a greater albumin excretion, even below levels that are considered to reflect microalbuminuria, are independently associated with greater arterial stiffness. Moreover, these associations were mutually independent. These findings may explain, in part, why eGFR and microalbuminuria are associated with greater risk for CVD and suggest that amelioration of arterial stiffness could be a target of intervention.

Individuals with type 1 diabetes have mild performance deficits on a range of neuropsychological tests compared with nondiabetic control subjects. The mechanisms underlying this cognitive deterioration are still poorly understood, but chronic hyperglycemia is now emerging as a potential determinant, possibly through microvascular changes in the brain. In 24 type 1 diabetic patients, we tested at euglycemia and at acute hypoglycemia whether the presence of proliferative diabetic retinopathy, as a marker of microvascular disease, adversely affects the ability of the brain to respond to standardized hypoglycemia, using functional magnetic resonance imaging with a cognitive task. Patients with retinopathy, compared with patients without, showed less deactivation (hence, an increased response) in the anterior cingulate and the orbital frontal gyrus during hypoglycemia compared with euglycemia (P0.05). Task performance and reaction time were not significantly different for either group. We conclude that microvascular damage in the brain of patients with retinopathy caused this increased brain response to compensate for functional loss.

Mechanical loading and estrogen play important roles in bone homeostasis. The aim of this study was to evaluate the effects of mechanical loading on trabecular bone in the proximal femur of ovariectomized rats. We hypothesized that mechanical loading suppresses bone resorption and increases bone formation, which differs from the suppressive effects of estrogen on both resorption and formation. Furthermore, we expected to find changes in trabecular architecture elicited by the effects of mechanical loading and estrogen deficiency. Sixty female Wistar rats, 12 weeks old, were assigned to either the sedentary groups sham surgery (SED), ovariectomy (SED+OVX), and ovariectomy with estrogen replacement (SED+OVX+E2) or to the exercise groups EX, EX+OVX, EX+OVX+E2. Following ovariectomy, 5 μg 17ß-estradiol was given once weekly to the estrogen replacement groups. Exercise consisted of running with a backpack (load ±20% of body weight) for 15 minutes/day, 5 days/week, for 19 weeks. Dual-energy X-ray absorptiometry (DXA) scans were performed before (T 0), during (T6), and after (T19) the exercise period to obtain bone mineral content (BMC) and bone mineral density (BMD) data. After the exercise program, all rats were killed and right and left femora were dissected and prepared for micro-CT scanning and histomorphometric analysis of the proximal femoral metaphysis. After 19 weeks, increases in BMC (P = 0.010) and BMD (P = 0.031) were significant. At T19, mechanical loading had a significant effect on BMC (P = 0.025) and BMD (P = 0.010), and an interaction between mechanical loading and estrogen (P = 0.023) was observed. Bone volume and trabecular number decreased significantly after ovariectomy, while trabecular separation, mineralizing surface, bone formation rate, osteoclast surface, degree of anisotropy, and structure model index increased significantly after ovariectomy (P < 0.05). Trabecular bone turnover and structural parameters in the proximal femur were not affected by exercise. Estrogen deficiency resulted in a less dense and more oriented trabecular bone structure with increased marrow cavity and a decreased number of trabeculae. In conclusion, mechanical loading has beneficial effects on BMC and BMD of the ovariectomized rat. This indicates that the load in the backpack was high enough to elicit an osteogenic response sufficient to compensate for the ovariectomy-induced bone loss. The results confirm that estrogen suppresses both bone resorption and bone formation in the proximal metaphysis in the femoral head of our rat-with-backpack model. The effects of mechanical loading on the trabecular bone of the femoral head were not significant. This study suggests that the effect of mechanical loading in the rat-with-backpack model mainly occurs at cortical bone sites.

The added value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning as a function of pretest risk assessment in indeterminate pulmonary nodules is still unclear.To obtain an external validation of the prediction model according to Swensen and colleagues, and to quantify the potential added value of FDG-PET scanning as a function of its operating characteristics in relation to this prediction model, in a population of patients with radiologically indeterminate pulmonary nodules.Between August 1997 and March 2001, all patients with an indeterminate solitary pulmonary nodule who had been referred for FDG-PET scanning were retrospectively identified from the database of the PET center at the VU University Medical Center.One hundred six patients were eligible for the study, and 61 patients (57%) proved to have malignant nodules. The goodness-of-fit statistic for the model (according to Swensen) indicated that the observed proportion of malignancies did not differ from the predicted proportion (p = 0.46). PET scan results, which were classified using the 4-point intensity scale reading, yielded an area under the evaluated receiver operating characteristic curve of 0.88 (95% confidence interval [CI], 0.77 to 0.91). The estimated difference of 0.095 (95% CI, -0.003 to 0.193) between the PET scan results classified using the 4-point intensity scale reading and the area under the curve (AUC) from the Swensen prediction was not significant (p = 0.058). The PET scan results, when added to the predicted probability calculated by the Swensen model, improves the AUC by 13.6% (95% CI, 6 to 21; p = 0.0003).The clinical prediction model of Swensen et al was proven to have external validity. However, especially in the lower range of its estimates, the model may underestimate the actual probability of malignancy. The combination of visually read FDG-PET scans and pretest factors appears to yield the best accuracy.

Mild renal insufficiency is associated with increased left ventricular mass in men, but not in women: An arterial stiffness-related phenomenon—The Hoorn Study. Background Mild renal insufficiency has recently been recognized as an important risk factor for cardiovascular disease (CVD). The mechanisms underlying this association are incompletely understood. Increased left ventricular mass (LVM) is an independent risk factor for CVD, which is particularly common in end-stage renal disease (ESRD) and which has been shown to be associated with mild renal insufficiency. Increased arterial stiffness has also been shown to be an independent risk factor for CVD in ESRD and has also been associated with mild renal insufficiency. We hypothesized that the association between mild renal insufficiency and increased LVM could be mediated through increased arterial stiffness, and that this may be one of the pathways linking mild renal insufficiency to CVD. We therefore investigated, in a cross-sectional population-based study, the influence of increased arterial stiffness on the association between renal function and LVM. Methods The study population consisted of 742 elderly individuals (373 men and 369 women). Renal function was estimated by the serum creatinine level in μmol/L; by the Cockcroft-Gault formula inmL /min and by the Modification of Diet in Renal Disease (MDRD) formula. LVM was obtained by echocardiography. Results The mean estimates of renal function in men and women were, respectively, 103.7 (SD 17.0) and 86.8 (SD 11.2) μmol/L for the serum creatinine level; 63.4 (SD 12.9) and 61.4 (SD 11.0)mL /min/1.73m 2 for the Cockcroft-Gault formula; and 59.7 (SD 10.8) and 60.9 (SD 10.5)mL /min per 1.73m 2 for the MDRD formula. LVM was 93.1 (SD 26.4) g/m 2 in men and 86.7 (SD 22.3) g/m 2 in women. In men, impaired renal function, as estimated by the Cockcroft-Gault and the MDRD formula, was significantly associated with greater LVM after adjustment for age, glucose tolerance, hypertension, and prior CVD [regression coefficient β (95% CI), 1.28 (0.22 to 2.33) g/m 2 and 1.63 (0.41 to 2.86) g/m 2 per 5mL /min/1.73m 2 decrease, respectively]. However, the association between impaired renal function and increased LVM was not statistically significant after adjustment for arterial stiffness estimates [regression coefficient β (95% CI), 0.02 (-1.60 to 1.64) g/m 2 and 0.54 (-1.25 to 2.33) g/m 2 per 5mL /min/1.73m 2 decrease, respectively]. In women, impaired renal function was not significantly associated with greater LVM. Conclusion Our study shows that in a general elderly population, even mild impairment of renal function is associated with adverse changes in left ventricular structure. In men, but not in women, this leads to greater LVM, a process that may be related to increases in arterial stiffness. Importantly, these novel findings suggest that such changes occur early in the process of renal functional deterioration, which may explain, in part, the increase in cardiovascular risk in men with mildly impaired renal function.

Objective To examine the prevalence of and risk factors for low bone mineral density (BMD) and vertebral fractures in patients with systemic lupus erythematosus (SLE). Methods We studied 107 SLE patients. Demographic and clinical data were collected, and radiographs of the thoracic and lumbar spine and BMD measurements by dual x-ray absorptiometry were performed. Vertebral deformities were scored according to the method of Genant et al: fractures were defined as a reduction of ≥20% of the vertebral body height. Osteoporosis was defined as a T score less than −2.5 SD and osteopenia as a T score less than −1.0 SD in at least 1 region of measurement. Results Osteopenia was present in 39% of the patients and osteoporosis in 4% (93% female; mean age 41.1 years). In multiple regression analysis, low BMD in the spine was associated with a low body mass index (BMI), postmenopausal status, and 25-hydroxyvitamin D deficiency. Low BMD in the hip was associated with low BMI and postmenopausal status. At least 1 vertebral fracture was detected in 20% of the patients. Vertebral fractures were associated with ever use of intravenous methylprednisolone and male sex. Conclusion Risk factors for low BMD in SLE patients are low BMI, postmenopausal status, and vitamin D deficiency. While osteoporosis defined as a low T score was found in only 4% of the patients, osteoporotic vertebral fractures were detected in 20%. The high prevalence of low BMD and vertebral fractures implies that more attention must be paid to the prevention and treatment of osteoporosis and fractures in SLE.