Pieter C. Dagnelie

Influence of phenotype at diagnosis and of other potential prognostic factors on the course of inflammatory bowel disease.

OBJECTIVES:Disease course in inflammatory bowel disease (IBD) is variable and difficult to predict. To optimize prognosis, it is of interest to identify phenotypic characteristics at disease onset and other prognostic factors that predict disease course. The aim of this study was to evaluate such factors in a population-based IBD group.METHODS:IBD patients diagnosed between 1 January 1991 and 1 January 2003 were included. A follow-up questionnaire was developed and medical records were reviewed. Patients were classified according to phenotype at diagnosis and risk factors were registered. Disease severity, cumulative medication use, and “surgical” and “nonsurgical” recurrence rates were calculated as outcome parameters.RESULTS:In total, 476 Crohns disease (CD), 630 ulcerative colitis (UC), and 81 indeterminate colitis (IC) patients were diagnosed. In CD (mean follow-up 7.6 years), 50% had undergone resective surgery. In UC (mean follow-up 7 years), colectomy rate was 8.3%. First year cumulative recurrence rates per 100 patient-years for CD, UC, and IC were 53, 44, and 42%, respectively. In CD, small bowel localization and stricturing disease were negative prognostic factors for surgery, as was young age. Overall recurrence rate was increased by young age and current smoking. In UC, extensive colitis increased surgical risk. In UC, older age at diagnosis initially increased recurrence risk but was subsequently protective.CONCLUSIONS:This population-based IBD study showed high recurrence rates in the first year. In CD, small bowel localization, stricturing disease, and young age were predictive for disease recurrence. In UC, extensive colitis and older age at diagnosis were negative prognostic predictors.

Adenosine triphosphate. Established and potential clinical applications

Adenosine 5′-triphosphate (ATP) is a purine nucleotide found in every cell of the human body. In addition to its well established role in cellular metabolism, extracellular ATP and its breakdown product adenosine, exert pronounced effects in a variety of biological processes including neurotransmission, muscle contraction, cardiac function, platelet function, vasodilatation and liver glycogen metabolism. These effects are mediated by both P1 and P2 receptors. A cascade of ectonucleotidases plays a role in the effective regulation of these processes and may also have a protective function by keeping extracellular ATP and adenosine levels within physiological limits. In recent years several clinical applications of ATP and adenosine have been reported. In anaesthesia, low dose adenosine reduced neuropathic pain, hyperalgesia and ischaemic pain to a similar degree as morphine or ketamine. Postoperative opioid use was reduced. During surgery, ATP and adenosine have been used to induce hypotension. In patients with haemorrhagic shock, increased survival was observed after ATP treatment. In cardiology, ATP has been shown to be a well tolerated and effective pulmonary vasodilator in patients with pulmonary hypertension. Bolus injections of ATP and adenosine are useful in the diagnosis and treatment of paroxysmal supraventricular tachycardias. Adenosine also allowed highly accurate diagnosis of coronary artery disease. In pulmonology, nucleotides in combination with a sodium channel blocker improved mucociliary clearance from the airways to near normal in patients with cystic fibrosis. In oncology, there are indications that ATP may inhibit weight loss and tumour growth in patients with advanced lung cancer. There are also indications of potentiating effects of cytostatics and protective effects against radiation tissue damage. Further controlled clinical trials are warranted to determine the full beneficial potential of ATP, adenosine and uridine 5′-triphosphate.

Influence of Infrarenal Neck Length on Outcome of Endovascular Abdominal Aortic Aneurysm Repair

Purpose: To evaluate the influence of the infrarenal neck length on clinical outcome after endovascular abdominal aortic aneurysm repair (EVAR). Methods: Data were analyzed from 3499 patients enrolled in the EUROSTAR registry between January 1999 and April 2005 who underwent EVAR with a Talent or Zenith endograft and had detailed morphological data recorded. The study cohort was divided into 3 groups according to infrarenal neck length: >15 mm (reference group A, n=2822), 11 to 15 mm (group B, n=485), and ≤10 mm (group C, n=192). Uni- and multivariate analyses were performed to evaluate differences in clinical outcomes among the study groups. Results: After correction for confounders, proximal type I endoleak within 30 days occurred in 10.9% of group C compared to 2.6% of group A (OR 4.46, 95% CI 2.61 to 7.61). Within 48 months of follow-up (median 12 months), the incidence of proximal endoleaks was higher in groups B (9.6%; HR 1.98, 95% CI 1.16 to 3.38) and C (11.3%; HR 2.132, 95% CI 1.17 to 4.60) compared to group A (3.4%). Conclusion: Our study indicates that endovascular treatment of abdominal aortic aneurysms with infrarenal neck length <15 mm is associated with significantly increased risk of short- and midterm proximal endoleaks after EVAR. The greater risk of proximal endoleaks should be weighed against the risks of alternative treatment modalities.

Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies.

Aims/hypothesisSeveral case-control studies have examined the association between the Gly972Arg variant in the IRS-1 gene and Type 2 diabetes, but most had limited power and results could therefore be conflicting.MethodsWe systematically reviewed the literature by means of a meta-analysis and investigated sources of heterogeneity in results of different studies.ResultsThe summary risk ratio, based on 3408 cases and 5419 control cases from 27 studies, was 1.25 (95% CI 1.05–1.48). The results, however, differed according to the type of study, method of verifying non-diabetic status of the control subjects, and age of the case subjects. Population-based studies reported lower odds ratios than hospital-based studies (OR 0.98, 95% CI 0.74–1.30 vs OR 1.43, 95% CI 1.17–1.74). Also, the diagnostic test to exclude diabetes amongst control subjects interacted with the association between the IRS-1 Gly972Arg variant and Type 2 diabetes (p=0.03). Finally, the odds ratio reduced with increasing age (p=0.03).Conclusion/interpretationOverall, carriers of the 972Arg variant of the IRS-1 gene are at a 25% increased risk of having Type 2 diabetes compared with non-carriers. The odds ratios are generally higher in hospital-based studies, including relatively young, symptomatic, cases.

Diet, anthropometric measures and prostate cancer risk: A review of prospective cohort and intervention studies

We reviewed 37 prospective cohort and four intervention studies on potential dietary risk factors for prostate cancer, published between 1966 and September 2003. Some studies were limited by small size, crude measurement of dietary exposure and limited control for confounders. Intervention and prospective cohort studies support a protective role against prostate cancer for selenium, and possibly for vitamin E, pulses and tomatoes/lycopene. Overall consumption of meat, eggs, vegetables, fruit, coffee, tea, carotenoids and vitamins A, C and D was not consistently related to prostate cancer risk. Intervention studies also indicate that supplementation with β‐carotene does not lower prostate cancer risk, except possibly in men with low β‐carotene status at baseline. For specific types of meat, alcoholic drinks, dairy products, fat and anthropometric measures, most cohort studies suggest either an increased risk or no relation with prostate cancer. For calcium, two cohort studies suggest an increased risk at very high calcium intakes (>2000 mg/day). In conclusion, prospective studies are consistent with a protective role for selenium, and possibly vitamin E, pulses and tomatoes/lycopene, in the aetiology of prostate cancer. Studies are inconclusive on the role of meat, dairy products, fat, vegetables, fruits, alcohol and anthropometric measures, whereas a very high calcium intake appears to be positively associated with prostate cancer risk.

Energy restriction and the risk of spontaneous mammary tumors in mice: A meta-analysis

Our meta‐analysis was aimed at providing a systematic review of the literature regarding the effect of energy restriction on spontaneous mammary tumors in mice and at providing a more precise pooled (summary) estimate of the risk of mammary tumors. A sensitivity analysis was conducted to obtain insight in potential heterogeneity between the animal studies. A literature search was conducted with the following terms to identify relevant articles: animal studies, mammary tumors, fat restricted, dietary carbohydrates, energy restriction and calorie restriction. A criteria list for the assessment of quality items (i.e., study characteristics) in animal experiments was developed that was intended to quantitatively assess potential factors that underlie heterogeneous results of different animal experiments. Incidence figures were used to calculate the risk difference. The pooled risk difference was calculated by random effects meta regression analysis. Fourteen animal experiments were included in this meta‐analysis. Publication bias could not be identified. The pooled risk difference for the 14 studies was −0.55 with a narrow 95% confidence interval (−0.69; −0.41), implying that the energy‐restricted animal groups developed 55% less mammary tumors than the control groups. No heterogeneity could be detected between the studies based on study characteristics that included the age of mice at the start of intervention, duration of intervention, allocation of the mice, use of ad libitum control group, fertility of the mice and the type of energy‐providing nutrient (fat, carbohydrate or protein). This meta‐analysis confirms that energy restriction in itself consistently protects against the development of mammary tumor in mice, irrespective of the type of restricted nutrient or other study characteristics.

Diet as a risk factor for the development of ulcerative colitis

OBJECTIVE:Dietary factors have been considered as a possible risk factor for ulcerative colitis (UC). However, available data are inconsistent. The aim of the present study was to evaluate the etiological role of dietary factors in the development of UC.METHODS:Recently diagnosed (<6 Months) UC patients (n = 43) and age- and gender-matched population controls (n = 43) were studied in a case-control design. The cross-check dietary history method was used to assess dietary intake of 5 yr before the study. Adipose tissue fatty acid composition was used as a biomarker of long-term fat intake. Conditional logistic regression-derived odds ratios (OR), and 95% confidence intervals (CI) were used for statistical analysis. Dietary intake ORs were adjusted for energy intake.RESULTS:High intakes of monounsaturated fat (OR: 33.9 [95% CI 2.6–443.1]), polyunsaturated fat (OR: 5.1 [95% CI 1.0–26.7]), and vitamin B6 (OR: 6.9 [95% CI 1.6–30.7]) were associated with an increased risk to develop UC. No other significant associations were found with UC risk.CONCLUSIONS:High intakes of mono- and polyunsaturated fat and vitamin B6 may enhance the risk of developing UC. Whether this observation is a true risk factor in the development of UC or rather a reflection of a certain dietary lifestyle needs to be investigated.

Etiology of atopy in infancy: the KOALA Birth Cohort Study.

The aim of the KOALA Birth Cohort Study in the Netherlands is to identify factors that influence the clinical expression of atopic disease with a main focus on lifestyle (e.g., anthroposophy, vaccinations, antibiotics, dietary habits, breastfeeding and breast milk composition, intestinal microflora composition, infections during the first year of life, and gene–environment interaction). The recruitment of pregnant women started in October 2000. First, participants with ‘conventional lifestyles’ (n = 2343) were retrieved from an ongoing prospective cohort study (n = 7020) on pregnancy‐related pelvic girdle pain. In addition, pregnant women (n = 491) with ‘alternative lifestyles’ with regard to child rearing practices, dietary habits (organic, vegetarian), vaccination schemes and/or use of antibiotics, were recruited through organic food shops, anthroposophic doctors and midwives, Steiner schools, and dedicated magazines. All participants were enrolled between 14 and 18 wk of gestation and completed an intake questionnaire on family history of atopy and infant care intentions. Documentation of other relevant variables started in the pregnant mother and covered the first and third trimester as well as early childhood by repeated questionnaires at 14–18, 30, and 34 wk of gestation and 3, 7, 12, and 24 months post‐partum. A subgroup of participants, including both conventional and alternative lifestyles, was asked to consent to maternal blood sampling, breast milk and a faecal sample of the infant at 1 month post‐partum, capillary blood at age 1 yr, venous blood and observation of manifestation of atopic dermatitis during home visits at the age of 2 yr (using the UK working party criteria and the severity scoring of atopic dermatitis index), and buccal swabs for DNA isolation from child–parent trios. From the start, ethical approval and informed consent procedures included gene–environment interaction studies. Follow‐up at 3 and 7 months post‐partum was completed with high response rates (respectively 90% and 88% in the conventional group, and 97% and 97% in the alternative group). The home visits at 2 yr of age will be completed in 2005. Preliminary results show that we have succeeded in recruiting a large population with various lifestyle choices with a fairly large contrast with regard to dietary habits (including organic foods, vegetarian diet), vaccination schemes and/or use of antibiotics. We have also been able to collect a large number of faecal samples (n = 1176) and capillary blood samples at age 1 yr (n = 956). Furthermore, a large proportion of the participants have consented with genetic studies. Mid 2006 we expect to report our first results on the relationship between the various exposures in early life and childhood atopy. An outline of the focus and design of the KOALA Birth Cohort Study is presented.

Early life exposure to antibiotics and the subsequent development of eczema, wheeze, and allergic sensitization in the first 2 years of life: the KOALA Birth Cohort Study

OBJECTIVES. Antibiotic exposure in early life may be associated with atopic disease development either by interfering with bacterial commensal flora or by modifying the course of bacterial infections. We evaluated early life exposure to antibiotics and the subsequent development of eczema, wheeze, and allergic sensitization in infancy. METHODS. Information on antibiotic use in the first 6 months and eczema and wheeze until age 2 was collected by repeated questionnaires in 2764 families participating in the KOALA (Child, Parent and Health: Lifestyle and Genetic Constitution [in Dutch]) Birth Cohort Study in the Netherlands. Antibiotic intake was evaluated both as maternal antibiotic use during breastfeeding and infant oral medication. Venous blood samples taken from 815 infants at 2 years of age were analyzed for total and specific immunoglobulin E against common food and inhalant allergens using a radioallergosorbent test. Multivariate logistic regression analysis was used to adjust for confounding factors. RESULTS. During the first 2 years, eczema was present in 32% of all infants, recurrent wheeze in 11%, and prolonged wheezing in 5%. At 2 years old, 27% of children were sensitized against ≥1 allergen. At 6 months old, 11% had been exposed to antibiotics through breast milk and 20% directly through medication. The risk for recurrent wheeze, and prolonged wheeze was higher in infants directly exposed to antibiotics through medication, also after excluding from the analyses children who wheezed in the same period as an antibiotic had been used (avoiding reverse causation). Antibiotic use through breastfeeding was associated with recurrent wheeze, but prolonged wheeze was not. Eczema and sensitization were not associated with antibiotic exposure. CONCLUSIONS.We demonstrated that early antibiotic use preceded the manifestation of wheeze but not eczema or allergic sensitization during the first 2 years of life. Different biological mechanisms may underlie the etiology of wheeze compared with eczema or sensitization. Antibiotic exposure through breastfeeding enhanced the risk for recurrent wheeze, but this needs further confirmation.

Fatigue and health-related quality of life in inflammatory bowel disease: results from a population-based study in the Netherlands: the IBD-South Limburg cohort.

Background: The importance of fatigue in chronic disease has been increasingly recognized; however, little is known about fatigue in inflammatory bowel disease (IBD). The aim of the present study was to investigate the prevalence and severity of fatigue and the impact on health‐related quality of life (HRQoL) in patients included in a population‐based IBD cohort in the Netherlands. Methods: IBD patients, diagnosed between January 1st, 1991, and January 1st, 2003, were followed up for a median of 7.1 years. They completed a questionnaire, which included a disease activity score, the Multidimensional Fatigue Inventory (MFI‐20), the Inflammatory Bowel Disease Questionnaire (IBDQ), and the Short Form health survey (SF‐36). Hemoglobin levels were recorded. Results: Data were available in 304 Crohns disease (CD), 368 ulcerative colitis (UC), and 35 indeterminate colitis (IC) patients. During quiescent disease, the prevalence of fatigue was nearly 40%. MFI‐20 and HRQoL scores were significantly worse in IBD patients having active disease. In a multivariate analysis, disease activity was positively related with the level of fatigue in both CD and UC. In UC, anemia influenced the general fatigue score independently of disease activity. Disease activity as well as fatigue were independently associated with an impaired IBDQ. Conclusions: In IBD, even in remission, fatigue is an important feature. Both in CD and in UC, fatigue determined HRQoL independently of disease activity or anemia. This implies that in IBD patients physicians need to be aware of fatigue in order to better understand its impact and to improve the HRQoL. (Inflamm Bowel Dis 2010)