Brenda W.C. Bongaerts

Alcohol consumption, type of alcoholic beverage and risk of colorectal cancer at specific subsites

Within the Netherlands Cohort Study on diet and cancer, we investigated associations between total alcohol consumption, specific alcoholic beverage consumption and risk of colorectal cancer (CRC) according to anatomical subsite. Hazard Ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Analyses were performed on 2,323 CRC cases, available after 13.3 years of follow‐up. Compared to abstaining, alcohol consumption of ≥30.0 g/day (∼3 alcoholic drinks) was positively associated with the risk of CRC (HR: 1.32, 95% CI: 1.06–1.65). Analyses restricted to subjects who reported to have consumed equal amounts of alcohol 5 years before baseline compared to baseline, showed elevated risk estimates for consumers of ≥30.0 g of total alcohol per day as well (HR: 1.53, 95% CI: 1.16–2.01). Suggestive of a subsite‐specific effect, cancer risk seemed to increase from proximal colon through rectum; HR: 1.29, 95% CI: 0.85–1.96 for proximal colon cancer, HR: 1.41, 95% CI: 0.94–2.11 for distal colon cancer, HR: 2.07, 95% CI: 1.03–4.18 for rectosigmoid cancer and HR: 1.69, 95% CI: 1.08–2.64 for rectal cancer. No associations were observed between consumption of alcoholic beverages and CRC risk when compared with the nondrinkers of the specific beverage and after adjustment for total alcohol intake. No evidence was found for sex‐specific effects of alcohol and alcoholic beverages. In conclusion, our data showed a positive association between alcohol consumption and risk of CRC, which seemed to be mainly explained by the alcoholic content of alcoholic beverages, rather than other constituents. Also, cancer risk may vary according to anatomical subsite.

Micro-RNA profiling in human serum reveals compartment-specific roles of miR-571 and miR-652 in liver cirrhosis.

Background and Aims Micro-RNAs (miRNAs) have recently emerged as crucial modulators of molecular processes involved in chronic liver diseases. The few miRNAs with previously proposed roles in liver cirrhosis were identified in screening approaches on liver parenchyma, mostly in rodent models. Therefore, in the present study we performed a systematic screening approach in order to identify miRNAs with altered levels in the serum of patients with chronic liver disease and liver cirrhosis. Methods We performed a systematic, array-based miRNA expression analysis on serum samples from patients with liver cirrhosis. In functional experiments we evaluated the relationship between alterations of miRNA serum levels and their role in distinct cellular compartments involved in hepatic cirrhosis. Results The array analysis and the subsequent confirmation by qPCR in a larger patient cohort identified significant alterations in serum levels of miR-513-3p, miR-571 and miR-652, three previously uncharacterized miRNAs, in patients with alcoholic or hepatitis C induced liver cirrhosis. Of these, miR-571 serum levels closely correlated with disease stages, thus revealing potential as a novel biomarker for hepatic cirrhosis. Further analysis revealed that up-regulation of miR-571 in serum reflected a concordant regulation in cirrhotic liver tissue. In isolated primary human liver cells, miR-571 was up-regulated in human hepatocytes and hepatic stellate cells in response to the pro-fibrogenic cytokine TGF-β. In contrast, alterations in serum levels of miR-652 were stage-independent, reflecting a concordant down-regulation of this miRNA in circulating monocytes of patients with liver cirrhosis, which was inducible by proinflammatory stimuli like bacterial lipopolysaccharide. Conclusion Alterations of miR571 and miR-652 serum levels in patients with chronic liver disease reflect their putative roles in the mediation of fibrogenic and inflammatory processes in distinct cellular compartments involved in the pathogenesis of liver cirrhosis.

Older Subjects With Diabetes and Prediabetes Are Frequently Unaware of Having Distal Sensorimotor Polyneuropathy The KORA F4 Study

OBJECTIVE Distal sensorimotor polyneuropathy (DSPN) is a severe complication of type 2 diabetes. This study aimed to assess the prevalence of unawareness of DSPN in prediabetes and diabetes in a sample of the older population of Augsburg, Germany. RESEARCH DESIGN AND METHODS Glucose tolerance status was determined in 61- to 82-year-old participants of the population-based KORA F4 Study (2006–2008) (n = 1,100). Clinical DSPN was defined as the presence of bilaterally impaired foot-vibration perception and/or bilaterally impaired foot-pressure sensation. DSPN case subjects were considered unaware of their condition when answering “no” to the question, “Has a physician ever told you that you are suffering from nerve damage, neuropathy, polyneuropathy, or diabetic foot?” RESULTS Clinical DSPN was prevalent in 154 (14%) participants, 140 of whom were unaware of their disorder. At a prevalence of 23.9% (95% CI 12.6–38.8), participants with combined impaired fasting glucose and impaired glucose tolerance had the highest prevalence of DSPN. Of these, 10 of 11 (91%) were unaware of having clinical DSPN. Participants with known diabetes had an equally high prevalence of DSPN [22.0% (16.2–28.9)], with 30 of the 39 (77%) DSPN case subjects unaware of having the disorder. Among subjects with known diabetes who reported to have had their feet examined by a physician, 18 of 25 (72%) clinical DSPN case subjects emerged unaware of having DSPN. CONCLUSIONS Our findings showed a high prevalence of unawareness of having clinical DSPN among the prediabetic and diabetic groups and an insufficient frequency of professional foot examinations, suggesting inadequate attention to diabetic foot prevention practice.

Postchallenge Hyperglycemia Is Positively Associated With Diabetic Polyneuropathy The KORA F4 study

OBJECTIVE To assess the prevalence of distal sensorimotor polyneuropathy (DSPN) in an older population and to examine its relationship with prediabetes. RESEARCH DESIGN AND METHODS Glucose tolerance status was determined in 61- to 82-year-old participants (n = 1,100) of the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 Survey (2006–2008). Clinical DSPN was defined as bilaterally impaired foot-vibration perception and/or foot-pressure sensation. RESULTS Prevalence of clinical DSPN was similar in subjects with known diabetes (22.0%) and subjects with combined impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) (23.9%). Among prediabetic subgroups, IFG-IGT, but not isolated-IFG and -IGT, was associated with a higher risk of clinical DSPN, compared with normal glucose tolerance. A J-shaped association was observed between clinical DSPN and quartiles of 2-h postchallenge glucose, but not with fasting glucose and HbA1c levels. CONCLUSIONS Subjects with IFG-IGT and known diabetes had a similar prevalence of clinical DSPN. Elevated 2-h postload glucose levels appeared important for disease risk.

Association of Subclinical Inflammation With Polyneuropathy in the Older Population KORA F4 study

OBJECTIVE Inflammatory processes have been implicated in the pathogenesis of diabetic distal sensorimotor polyneuropathy (DSPN), but their possible relationship has not been assessed at the population level. RESEARCH DESIGN AND METHODS We determined serum concentrations of mediators of subclinical inflammation among 1,047 participants 61–82 years of age from the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study (Germany). Logistic and linear regression models were fitted to assess associations between immune mediators (log-transformed) and the presence of clinical DSPN (dichotomous variable) or Michigan Neuropathy Screening Instrument (MNSI) examination score (continuous variable), respectively. RESULTS Serum concentrations of the anti-inflammatory interleukin (IL)-1 receptor antagonist (IL-1RA) were positively associated with the presence of DSPN and higher MNSI scores in age-adjusted and sex-adjusted analyses, whereas IL-6, IL-18, and soluble intercellular adhesion molecule-1 were positively associated with only MNSI scores. No associations were observed for adiponectin, C-reactive protein, or tumor necrosis factor-α. Associations for IL-1RA and IL-6 with the MNSI score remained statistically significant after additional adjustment for waist circumference, height, hypertension, cholesterol, smoking, alcohol intake, physical activity, history of myocardial infarction or stroke, presence of neurological conditions, and use of nonsteroidal anti-inflammatory drugs. CONCLUSIONS We conclude that DSPN is linked to proinflammatory and anti-inflammatory, possibly compensatory, processes in the older general population. Future studies should clarify the temporal sequence and causality of these associations.

Circulating Levels of Interleukin 1-Receptor Antagonist and Risk of Cardiovascular Disease: Meta-Analysis of Six Population-Based Cohorts

Objective— Interleukin (IL)-1&bgr; represents a key cytokine in the development of cardiovascular disease (CVD). IL-1&bgr; is counter-regulated by IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor. This study aimed to identify population-based studies on circulating IL-1RA and incident CVD in a systematic review, estimate the association between IL-1RA and incident CVD in a meta-analysis, and to test whether the association between IL-1RA and incident CVD is explained by other inflammation-related biomarkers in the MONICA/KORA Augsburg case–cohort study (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg). Approach and Results— We performed a systematic literature search and identified 5 cohort studies on IL-1RA and incident CVD in addition to the MONICA/KORA Augsburg case–cohort study for a meta-analysis based on a total of 1855 CVD cases and 18 745 noncases with follow-up times between 5 and 16 years. The pooled standardized hazard ratio (95% confidence interval) for incident CVD was 1.11 (1.06–1.17) after adjustment for age, sex, anthropometric, metabolic, and lifestyle factors (P<0.0001). There was no heterogeneity in effect sizes (I2=0%; P=0.88). More detailed analyses in the MONICA/KORA study showed that the excess risk for CVD was attenuated by ≥10% after additional separate adjustment for serum levels of high-sensitivity C-reactive protein, IL-6, myeloperoxidase, soluble E-selectin, or soluble intercellular adhesion molecule-1. Conclusions— Serum IL-1RA levels were positively associated with risk of CVD after adjustment for multiple confounders in a meta-analysis of 6 population-based cohorts. This association may at least partially reflect a response to triggers inducing subclinical inflammation, oxidative stress, and endothelial activation.

Alcohol consumption and distinct molecular pathways to colorectal cancer

High alcohol consumption is related to colorectal cancer (CRC). Our objective was to study associations between alcohol consumption and risk of CRC according to characteristics of aetiological pathways: the chromosomal instability (CIN) and the microsatellite instability (MIN) pathway. We classified CIN+ tumours (tumours with either a truncating APC mutation, an activating K-ras mutation or overexpression of p53), MIN+ tumours (tumours lacking hMLH1 expression) and CIN- /MIN- tumours (tumours without these defects). In the Netherlands Cohort Study on diet and cancer, 120852 men and women, aged 55-69 years, completed a questionnaire on risk factors for cancer at baseline (1986). Case-cohort analyses were conducted using 573 CRC cases with complete data after 7 x 3 years of follow-up, excluding the first 2 x 3 years. Adjusted incidence rate ratios (RR) and 95 % confidence intervals (CI) were estimated. Compared with abstaining, alcohol consumption of >or=30 g/d was positively associated with the risk of CRC irrespective of genetic or molecular aberrations present, although statistical significance was not reached (RR 1 x 35 (95 % CI 0 x 9-2 x 0) for the CIN+ tumours, RR 1 x 59 (95 % CI 0 x 4-5 x 8) for the MIN+ tumours and RR 1.15 (95 % CI 0 x 5-2 x 7) for the CIN- /MIN- tumours). Beer, wine and liquor consumption were, independent of their alcoholic content, not consistently associated with the risk of CRC within the defined subgroups. In conclusion, our results indicate that a daily alcohol consumption of >or=30 g is associated with an increase in risk of CRC, independent of the presence or absence of the studied characteristics of different aetiological pathways.

Differential Association Between Biomarkers of Subclinical Inflammation and Painful Polyneuropathy: Results From the KORA F4 Study

OBJECTIVE Inflammatory processes have been implicated in the pathogenesis of painful neuropathy in rodents, but the relationship between inflammatory biomarkers and painful distal sensorimotor polyneuropathy (DSPN) has not been assessed in population-based studies. Therefore, we investigated whether circulating levels of seven pro- and anti-inflammatory immune mediators were associated with painful DSPN in older individuals in a large population-based study. RESEARCH DESIGN AND METHODS The study population consisted of individuals with painless (n = 337) and painful DSPN (n = 54) from a source population (n = 1,047) of men and women aged 61–82 years who participated in the German KORA F4 survey (2006–2008). We measured circulating levels of seven immune mediators and assessed their associations with the presence of painful DSPN using multiple logistic regression models. RESULTS After adjustment for age and sex, we found positive associations between serum concentrations of the cytokine interleukin (IL)-6 and the soluble intercellular adhesion molecule (sICAM)-1 and painful DSPN (P = 0.004 and P = 0.005, respectively), whereas no associations were observed for C-reactive protein, IL-18, tumor necrosis factor-α, adiponectin, and IL-1 receptor antagonist (IL-1RA, P = 0.07–0.38). Associations between IL-6 and sICAM-1 and painful DSPN remained significant after additional adjustment for waist circumference, height, hypertension, cholesterol, smoking, alcohol intake, physical activity, history of myocardial infarction and/or stroke, presence of other neurological conditions, and use of nonsteroidal anti-inflammatory drugs (P = 0.005 and P = 0.016, respectively). CONCLUSIONS Painful DSPN is linked to systemic subclinical and vascular inflammation in the older population independent of anthropometric, lifestyle, and metabolic confounders.

Effectiveness of chronic care models for the management of type 2 diabetes mellitus in Europe: a systematic review and meta-analysis

Objectives We evaluated the effectiveness of European chronic care programmes for type 2 diabetes mellitus (characterised by integrative care and a multicomponent framework for enhancing healthcare delivery), compared with usual diabetes care. Design Systematic review and meta-analysis. Data sources MEDLINE, Embase, CENTRAL and CINAHL from January 2000 to July 2015. Eligibility criteria Randomised controlled trials focussing on (1) adults with type 2 diabetes, (2) multifaceted diabetes care interventions specifically designed for type 2 diabetes and delivered in primary or secondary care, targeting patient, physician and healthcare organisation and (3) usual diabetes care as the control intervention. Data extraction Study characteristics, characteristics of the intervention, data on baseline demographics and changes in patient outcomes. Data analysis Weighted mean differences in change in HbA1c and total cholesterol levels between intervention and control patients (95% CI) were estimated using a random-effects model. Results Eight cluster randomised controlled trials were identified for inclusion (9529 patients). One year of multifaceted care improved HbA1c levels in patients with screen-detected and newly diagnosed diabetes, but not in patients with prevalent diabetes, compared to usual diabetes care. Across all seven included trials, the weighted mean difference in HbA1c change was −0.07% (95% CI −0.10 to −0.04) (−0.8 mmol/mol (95% CI −1.1 to −0.4)); I2=21%. The findings for total cholesterol, LDL-cholesterol and blood pressure were similar to HbA1c, albeit statistical heterogeneity between studies was considerably larger. Compared to usual care, multifaceted care did not significantly change quality of life of the diabetes patient. Finally, measured for screen-detected diabetes only, the risk of macrovascular and mircovascular complications at follow-up was not significantly different between intervention and control patients. Conclusions Effects of European multifaceted diabetes care patient outcomes are only small. Improvements are somewhat larger for screen-detected and newly diagnosed diabetes patients than for patients with prevalent diabetes.

Perceived risk of diabetes seriously underestimates actual diabetes risk: The KORA FF4 study

Objective Early detection of diabetes and prediabetic states is beneficial for patients, but may be delayed by patients´ being overly optimistic about their own health. Therefore, we assessed how persons without known diabetes perceive their risk of having or developing diabetes, and we identified factors associated with perception of diabetes risk. Research design and methods 1,953 participants without previously known diabetes from the population-based, German KORA FF4 Study (59.1 years, 47.8% men) had an oral glucose tolerance test. They estimated their probability of having undiagnosed diabetes mellitus (UDM) on a six category scale, and assessed whether they were at risk of developing diabetes in the future. We cross-tabulated glycemic status with risk perception, and fitted robust Poisson regression models to identify determinants of diabetes risk perception. Results 74% (95% CI: 65–82) of persons with UDM believed that their probability of having undetected diabetes was low or very low. 72% (95% CI: 69–75) of persons with prediabetes believed that they were not at risk of developing diabetes. In people with prediabetes, seeing oneself at risk of diabetes was associated with self-rated poor general health (prevalence ratio (PR) = 3.1 (95% CI: 1.4–6.8), parental diabetes (PR = 2.6, 1.9–3.4), high educational level (PR = 1.9 (1.4–2.5)), lower age (PR = 0.7, 0.6–0.8, per 1 standard deviation increase), female sex (PR = 1.2, 0.9–1.5) and obesity (PR = 1.5, 1.2–2.0). Conclusions People with undiagnosed diabetes or prediabetes considerably underestimate their probability of having or developing diabetes. Contrary to associations with actual diabetes risk, perceived diabetes risk was lower in men, lower educated and older persons.